ISBOMC ‘10
5th International Symposium on Bioorganometallic Chemistry
July 05 - 09, 2010, Ruhr-Universität Bochum, Germany
© G Gasser
Book of Abstracts
RESEARCH DEPARTMENT
INTERFACIAL SYSTEMS CHEMISTRY
D FG - Fo r s c h e r g r u p p e 6 3 0
Biological function of
organometallic compounds
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
Contents
Foreword
2
Sponsors
3
Venue and travel directions
4
General Information
6
Conference program
7
Oral presentations
16
Poster presentations
58
List of participants
143
1
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
Foreword
We welcome you to the 5th International Symposium on Bioorganometallic Chemistry
at the Ruhr-Universität Bochum. It is our pleasure to host you at one of the largest
and most dynamic universities in Germany.
Bioorganometallic Chemistry is a rapidly growing field of research at the interface of
various disciplines. It is firmly routed in synthetic chemistry, but its applications range
from biomedicine to medicinal and environmental analysis, modified enzymes and
enzyme mimetics, structural studies of biomolecules and wholly new entities such as
metallo-DNA, RNA and its analogues. The current meeting serves to showcase the
broad variety of Bioorganometallic Chemistry, and the overwhelming interest that we
received further underlines the vibrancy of the field. Indeed, we received many more
applications for oral contributions than we could possibly accommodate in the
scientific program. This has made the task of selecting a diverse and representative
set of speakers of high scientific quality almost a daunting one, and I thank our
colleagues for their support with this task, and all delegates for their understanding.
We are proud to host the biggest-ever ISBOMC conference in Bochum, with > 180
participants from more than 25 countries and all five continents. Bochum University is
an ideal place to host such a meeting, and we will do our best to ensure that you will
carry pleasant memories of the science as well as the venue home. Surely, this is
only possible with the help of many caring hands and minds behind the scene, who
have done a great job in preparing ISBOMC’10, and are ensuring its smooth
operation during the conference. I wish to express my sincere thanks to all those
helpers!
I hope you will enjoy the science and the spirit of the symposium, and continue your
efforts to make Bioorganometallic Chemistry an ongoing success story!
Bochum, July 2010
Nils Metzler-Nolte
2
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
Sponsors
Ruhr-Universität Bochum
The Ruhr-Universität Bochum is one of Germany’s leading research universities. The
University draws its strengths from both the diversity and the proximity of scientific
and engineering disciplines on a single, coherent campus. This highly dynamic
setting enables students and researchers to work across traditional boundaries of
academic subjects and faculties. Host to 32,600 students and 4,700 staff, the RuhrUniversität is a vital institution in the Ruhr area, which has been selected as
European Capital of Culture for the year 2010.
Research Department Interfacial Systems Chemistry
The Research Department IFSC is an interdisciplinary community that brings
together chemical and neighbouring disciplines. Researchers collaborate in the open
spirit of a Research Department to get a fundamental and systemic understanding of
the structural and dynamic complexity of hierarchically structured assemblies and
complex chemical systems.
3
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
Venue and travel directions
The 5th International Symposium on Bioorganometallic Chemistry (ISBOMC `10) will
take place at the convention center ("Veranstaltungszentrum") of the Ruhr-Universität
Bochum. The lecture hall (hall 2a) and poster exhibition hall (hall 1) are located in the
convention centre (Veranstaltungszentrum) on the 4th floor of the Mensa Building.
The reception and registration desk is located direct in front of room 2a. For entering
the 4th floor please use the elevator left or right. Bochum can conveniently be
reached by train from Frankfurt, Düsseldorf and Dortmund airport. For booking,
reservation and timetable information we recommend the webpage from the
Deutsche Bahn (http://www.bahn.de/i/view/GBR/en/index.shtml). From Bochum
central station, take the subway train U35 from the basement level bound for
"Hustadt/Querenburg" and get off after about 5 stops and 10 min travel time at the
station "Ruhr-Universität". During daytime, the subway will go every 5 minutes. When
leaving the platform at "Ruhr-Universität", turn right and walk past the main university
administration building (UV on the map), the central library (UB on the map), and the
Audimax (big bowl-shaped lecture hall) towards the mensa. You can use your
conference badge as a valid ticket for local transport in Bochum during the
conference from 5.7 – 9.7.2010. Please take your conference badge with you
using local transport.
4
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
Conference Venue
U35 subway station
Ruhr-Universität
Bus Stop
Transfer:
- Folkwang
- Zeche Zollverein
- Conference Dinner
Convention Centre
RUB Mensa
Veranstaltungszentrum
4. Floor
Convention Centre 4th floor:
5
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
General information
Bus Transfers
The buses for the excursion to the Folkwang Museum and Zeche Zollverein will wait
10 min walk form the convention centre (marked with the red line and red dot in the
map above). We will offer a guided tour to the buses. Departure for the guided walk
to the bus stop is 2:30 pm on Wednesday (Excursion), July 7th and 6:00 pm on
Thursday (Conference dinner), July 8th from the reception desk in the convention
centre. After the conference dinner several busses will departure at different times
from conference dinner location Henrichshütte. Departure times and all other
important actual news we will announce on the screen at the reception desk.
Poster Session
Please hang up your posters immediately after arrival, latest till Tuesday before the
morning session and remove them on Thursday before the conference dinner. For
adding your poster please contacts the guides in the poster hall and use the material
delivered at the conferewnce venue. The number of the abstract for your poster you
will find on the poster board reserved for you.
Internet connection
You will have access to the internet in the convention centre via WLAN. For getting
connected to the WWW you need a pin number you will get at the reception desk on
demand. This number is personalized and valid for one day. You need a new
number every day.
6
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
Conference program
7
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
Monday, July 5th 2010
16:00 to 18:00 registration
18:00 to 18:15 opening remarks of ISBOMC'10
18:15 to 19:00 opening lecture
Prof. Dr. Chris Orvig (OP-1)
Department of Chemistry
University of British Columbia
Bioorganometallics in Medicinal Inorganic Chemistry
19:00
welcome reception
8
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
Tuesday, July 6th 2010
Session I - Medicinal bioorganometallic chemistry I
09:00 to 09:20 Prof. Dr. Ingo Ott (OP-2)
Institute of Pharmaceutical Chemistry
Technische Universität Braunschweig
Bioorganometallic Solutions for the Design of Novel Gold Anticancer
Metallodrugs
09:20 to 09:40 Dr. Yaw-Kai Yan (OP-3)
Nanyang Technological University, National Institute of Education
Natural Sciences & Science Education Department
Rhenium(I) Tricarbonyl Complexes of Benzaldehyde and Substituted
Salicylaldehyde Dibenzyl Semicarbazones: Synthesis and
Cytotoxicity Studies
09:40 to 10:00 Prof. Dr. Roman Dembinski (OP-4)
Department of Chemistry
Oakland University
Metallo-Nucleosides: Bis(dicobalt hexacarbonyl alkynyl) Derivatives
of 2'-Deoxyuridine. Synthesis and Evaluation of Antiproliferative
Activity Against Human Breast Cancer Cells
10:00 to 10:20 Prof. Dr. Matthias Tacke (OP-5)
School of Chemistry and Chemical Biology
University College Dublin
Novel Metallocene Anticancer Drugs: From Lead to Hit
10:20 to 11:00 coffee break
Session II - Medicinal bioorganometallic chemistry II
11:00 to 11:45 Prof. Dr. Stefan Wölfl (OP-6)
Institute of Pharmacy and Molecular Biotechnology
Universität Heidelberg
Transcriptional Profile of HT-29 Cells upon Treatment with Different
Organometallic Compounds
11:45 to 12:05 Nicolas Barry (OP-7)
Institute of Chemistry
University of Neuchatel
Arene-Ruthenium Metalla-Prisms: New Drug Vectors
12:05 to 12:25 Dr. Christian Gaiddon (OP-8)
UMRS692 Signalisations Moléculaires et Neurodégénérescenc
INSERM - Université de Strasbourg
Design and Characterisation of the Anticancer Properties of
Ruthenium(II) Organometallic Compounds: Chemical Structure
Optimization, Transport and Regulated Signaling Pathways
9
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
12:25 to 12:45 Anusch Arezki (OP-9)
UMR 7223 Organometallic Medicinal Chemistry Group
Ecole Nationale Supérieure de Chimie de Paris
Synthesis and Structure-Activity Relationship of Organometallic
Derivatives of Curcumin as Anticancer Agents
12:45 to 14:00 lunch break
Session III - Medicinal bioorganometallic chemistry III
14:00 to 14:20 Prof. Dr. Domenico Osella (OP-10)
Department of Environmental and Life Sciences
University of Piemonte Orientale
Synthesis, characterization and antiproliferative activity of a series of
Pt(IV) complexes: a QSAR approach to their cytotoxicity
14:20 to 14:40 Prof. Dr. Nataliia I. Shtemenko (OP-11)
Department of Biophysics and Biochemistry
Dnipropetrovs’k National University
Influence of the Rhenium-Platinum antitumor system on tumor
growth and blood antioxidant state
14:40 to 15:00 Daniel Can (OP-12)
Faculty of Inorganic Chemistry
University of Zurich
The [CpM(CO)3]-Moiety (M = Mn, Tc, Re) as Phenyl Ring analog - a
Promising Strategy Towards New Drugs and Radiopharmaceuticals
15:00 to 15:20 Dr. Elizabeth Hillard (OP-13)
UMR 7223 Organometallic Medicinal Chemistry Group
Ecole Nationale Supérieure de Chimie de Paris
Ferrocenyl Flavonoids: Synthesis and Antiproliferative Effects
15:20 to 16:00 coffee break
16:00 to 18:00 poster session
18:00
BBQ dinner: The BBQ will take place on the roof garden of the Bistro
in the Convention centre on floor 1. You can reach the roof garden
with the elevator from the conference hall (1st semi-final game soccer
world cup 2010 ).
10
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
Wednesday, July 7th 2010
Session IV - Medicinal bioorganometallic chemistry IV
09:00 to 09:20 Dr. Alberta Bergamo (OP-14)
Callerio Foundation Onlus
Preclinical Development of Metal-Based Compounds:
Set Up of a Plastic Mouse Model
09:20 to 09:40 Dr. Braja G. Bag (OP-15)
Department of Chemistry and Chemical Technolgy
Vidyasagar University
Arjunolic acid: The First Renewable-Nano Triterpenoid in
Bioorganometallics
09:40 to 10:00 Dr. Gregory S. Smith (OP-16)
Department of Chemistry
University of Cape Town
Anticancer Activity of Multinuclear Ruthenium-Arene Complexes
Coordinated to Dendritic Poly(propyleneimine) Scaffolds
10:00 to 10:20 Dr. Stephan Niland (OP-17)
Center for Molecular Medicine, Department of Vascular Matrix
Biology, Universität Frankfurt am Main
Biofunctionalization of a Generic Collagenous Triple Helix with the
Integrin α2β1 Binding Site
10:20 to 11:00 coffee break
Session V - Medicinal bioorganometallic chemistry V
11:00 to 11:45 award lecture
Prof. Dr. Paul Dyson (OP-18)
Institut des Sciences et Ingénierie Chimiques
Ecole Polytechnique Fédérale de Lausanne (EPFL)
Organometallic Anticancer Drugs: From Simple Structures to
Rational Drug Design Based on a Mechanistic Approach
11:45 to 12:05 Dr. Frederik H. Kriel (OP-19)
AuTEK Biomed, Mintek
Biological Activity of Gold and Silver Bis(Phosphino)Hydrazine
Complexes
12:05 to 12:25 Prof. Dr. Mallayan Palaniandavar (OP-20)
Centre for Bioinorganic Chemistry
School of Chemistry, Bharathidasan University
DNA and Protein Binding, Cleavage and Anticancer Activity of
Organometallic (M = Ru(II), Rh(III) and Ir(III)) Arene Complexes
11
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
12:25 to 12:45 PD Dr. Christian Hartinger (OP-21)
Institute of Inorganic Chemistry
University of Vienna
Organometallic Pyrone and Pyridone Complexes as Anticancer
Agents
12:45 to 14:00 lunch
14:00 to 18:00 excursions to Folkwang-Museum or Zeche Zollverein
(only by separate registration)
18:00
free evening
(2nd half-final game soccer world cup 2010 )
12
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
Thursday, July 8th 2010
Session VI - Enzymes and bioorganometallic supramolecular systems I
09:00 to 09:45 Prof. Dr. Holger Dobbek (OP-22)
Institut für Biologie
Humboldt-Universität Berlin
Metalloenzymes in the bacterial life on carbon monoxide:
A view from structural biology
09:45 to 10:05 Prof. Dr. Wolfgang Weigand (OP-23)
Institut für Anorganische und Analytische Chemie
Friedrich-Schiller-Universität Jena
Models for the Active Site in [FeFe] Hydrogenase with
Silicon-containing Ligands
10:05 to 10:25 Prof. Dr. Andres Jäschke (OP-24)
Institute of Pharmacy and Molecular Biotechnology
Universität Heidelberg
DNA-Organometallic Hybrid Catalysts
10:25 to 11:00 coffee break
Session VII - Enzymes and bioorganometallic supramolecular systems II
11:00 to 11:45 Prof. Dr. Yoshihito Watanabe (OP-25)
Graduate School of Science, Department of Chemistry
Nagoya University
Construction of Organometalloenzymes
11:45 to 12:05 Dr. Fabio Zobi (OP-26)
Institute of Inorganic Chemistry
University of Zürich
CO Releasing Properties of cis-trans-[ReII(CO)2Br2L2]n Complexes:
A Feature Modulated by Ligand Variation for a True Chance at
Medicinal Applications
12:05 to 12:25 Dr. João D. G. Correia (OP-27)
Unidade de Ciências Químicas e Radiofarmacêuticas, ITN
Nitric Oxide Synthase Targeting with 99mTc(I)/Re(I) Complexes
12:25 to 12:45 Dr. Jason M. Lynam (OP-28)
Department of Chemistry
University of York
Mechanistic and Synthetic Studies of Bio-compatible Carbon
Monoxide-Releasing Molecules
12:45 to 14:00 lunch break
13
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
Session VIII - Enzymes and bioorganometallic supramolecular systems III
14:00 to 14:45 Prof. Dr. Morten Meldal (OP-29)
Carlsberg Laboratory
Peptide-carbenes and peptide-phosphines transition metal catalysts
for “Green” solid phase catalysts
14:45 to 15:05 Dr. Pratima Srivastava (OP-30)
UMR 7223 Organometallic Medicinal Chemistry Group
Ecole Nationale Supérieure de Chimie de Paris
Construction of an Immunosensor via Copper-Free ‘Click’ Reaction
Between Azido SAMs and Alkynyl Fischer Carbene Complex.
Application to the detection of Staphyloccal Enterotoxin A
15:05 to 15:25 Prof. Dr. Toshiyuki Moriuchi (OP-31)
Department of Applied Chemistry, Graduate School of Engineering
Osaka University
Polypeptides Induced Self-Association and Emission Properties of
Platinum(II) and Gold(I) Complexes
15:25 to 16:00 coffee break
Session IX - Enzymes and bioorganometallic supramolecular systems IV
16:00 to 16:45 Prof. Dr. Gerard van Koten (OP-32)
Organic Chemistry and Catalysis, Faculty of Science
Utrecht University
Homogeneous and Bio-Catalysis in Concert: Hybrids of ECE-pincer
Organometallics and Lipases
16:45 to 17:05 Jeremy Zimbron (OP-33)
Department of Chemistry
University of Basel
Chemo-Genetic Optimization of DNA Recognition by Metallodrugs
using a Presenter Protein Strategy
17:05 to 17:25 Dr. Johannes A. Eble (OP-34)
Center for Molecular Medicine, Department of Vascular Matrix
Biology, Universität Frankfurt am Main
RAPTA-T interacts with 11 integrin at the molecular level
18:00
departure for conference dinner at Henrichshütte
14
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
Friday, July 9th 2010
Session X - Bioimaging I
09:00 to 09:45 Prof. Dr. John Valliant (OP-35)
Department of Chemistry
McMaster University
TBA
09:45 to 10:05 Anica Dose (OP-36)
Functional Materials Group, School of Physical Science
University of Kent
Syntheses of New Isomeric Analogues of HYNIC for Evaluation
as a Bifunctional Chelator for Technetium-99m
10:05 to 10:25 Prof. Dr. Emanuela Licandro (OP-37)
Dipartimento di Chimica Organica e Industriale
University of Milano
Fluorescent Conjugates Between Dinuclear Rhenium(I) Complexes
and Peptide Nucleic Acids (PNA) for Cell imaging and DNA Targeting
10:25 to 11:00 coffee break
Session XI - Bioimaging II
11:00 to 11:45 Prof. Dr. Kenneth Kam-Wing Lo (OP-38)
Department of Biology and Chemistry
City University of Hong Kong
Design of Cyclometalated Iridium(III) Polypyridine Complexes as
Luminescent Biological Labels and Probes
11:45 to 12:05 Dr. Anne Vessières (OP-39)
UMR 7223 Organometallic Medicinal Chemistry Group
Ecole Nationale Supérieure de Chimie de Paris
Subcellular Imaging of a Re(CO)3 Complex by Photothermal Infrared
Spectromicroscopy (PTIR)
12:05 to 12:25 Prof. Dr. Edward Rosenberg (OP-40)
Department of Chemistry and Biochemistry
University of Montana, Missoula
Dynamical Studies of Bioconjugated Luminescent Ruthenium
Complexes in Lipid Vesicles
12:25 to 12:45 Dr. Gilles Gasser (OP-41)
Institute of Inorganic Chemistry
University of Zürich
Multi-Organometallic-Containing Peptide Nucleic Acids: Preparation
and Biological Applications
12:45 to 13:00 closing remarks and announcement of ISBOMC'12
15
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
Oral presentations
16
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
OP-1
Bioorganometallics in Medicinal Inorganic Chemistry
Chris Orvig*a
a
Medicinal Inorganic Chemistry Group, Department of Chemistry, University of British
Columbia, 2036 Main Mall, Vancouver, BC V6T 1Z1, Canada. E-mail: orvig@chem.ubc.ca
Bioorganometallic chemistry was an oxymoron in the 1970s when Pt compounds emerged for cancer
chemotherapy and Tc compounds took flight as nuclear medicine imaging agents. At that time, the
speaker fastidiously avoided working with technetium carbonyl compounds when he was a graduate
student! Now, thanks to the effort of this community, bioorganometallic chemistry plays a valuable
role to the larger fields of medicinal inorganic chemistry and medicinal chemistry.
Efforts in the speaker's labs to develop organometallic compounds for therapy and diagnosis will be
outlined, focussing on recent results in antimalarial and imaging applications.
17
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
OP-2
Bioorganometallic Solutions for the Design
of Novel Gold Anticancer Metallodrugs
Ingo Ott,*a Riccardo Rubbiani,a Igor Kitanovic,b Hamed Alborzinia,b Suzan Can,b Stefan Wölfl,b
Liliane A. Onambele,c Aram Prokopc
a
Technische Universität Braunschweig, Institute of Pharmaceutical Chemistry, Beethovenstr. 55,
38106, Braunschweig, Germany, b Ruprecht-Karls-Universität Heidelberg, Institut für Pharmazie und
Molekulare Biotechnologie, Im Neuenheimer Feld 364, 69120 Heidelberg, Germany c) Kliniken der
Stadt Köln GmbH; E-mail: ingo.ott@tu-bs.de
Motivated by the success of gold species in the treatment of rheumatoid arthritis and by the promising
outcome of several preclinical studies increasing efforts have been made to develop gold complexes
also for the use in cancer chemotherapy. Concerning the mode of drug action thioredoxin reductase
(TrxR), an enzyme closely related to glutathione reductase (GR), is nowadays considered as the most
relevant molecular target based on the high selectivity of gold species for this enzyme and its
substantial involvement in tumor growth and progression.1-3
Here we wish to present our most recent results obtained with gold(I) bioorganometallics featuring Nheterocyclic carbene (NHC) derived ligands (see the figure below for a relevant example) in
comparison to relevant non organometallic gold(I) phosphine complexes such as auranofin.
Promising antiproliferative effects were noted in MCF-7 breast adenocarcinoma as well as HT-29
colon carcinoma cells and the target compounds were found to be strong and selective inhibitors of
TrxR with an increased stability against glutathione. More detailed studies on a selected gold(I) NHC
complex revealed a strong induction of apoptosis and reactive oxygene species (ROS) formation,
antimitochondrial properties, as well as distinct effects on cellular metabolism.
N
Au Cl
N
Figure: example for a bioactive gold(I) NHC complex
References
1. I. Ott, Coord. Chem. Rev. 2009, 253, 1670-1681.
2. A. Bindoli, M. P. Rigobello, G. Scutari, C. Gabbiani, A. Casini, L. Messori, Coord. Chem. Rev.
2009, 253, 1692-1707.
3. P. J. Barnard, S. J. Berners-Price, Coord. Chem. Rev. 2007, 251, 1889-1902.
18
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
OP-3
Rhenium(I) Tricarbonyl Complexes of Benzaldehyde and Substituted
Salicylaldehyde Dibenzyl Semicarbazones: Synthesis and Cytotoxicity Studies
Yaw-Kai Yan,*aSiti Munira bte Haidad Ali,a and Peng-Foo Peter Leea
a
Nanyang Technological University, National Institute of Education, Natural Sciences & Science
Education Department, 1 Nanyang Walk, Singapore 637616. E-mail: yawkai.yan@nie.edu.sg
Semicarbazones and their metal complexes are attracting interest due to their potential medicinal
applications.1 In particular, metal complexes of salicylaldehyde semicarbazones were shown to have in
vitro anti-cancer activity.2 Since rhenium(I) tricarbonyl complexes of bis(diphenylphosphinomethyl)
amines and 2-(dimethylamino)ethoxide also show cytotoxic activity against several murine and human
cancer cell lines,3 we embarked on a study of the cancer cell cytotoxicity of rhenium(I) tricarbonyl
complexes of N,N-disubstituted salicylaldehyde semicarbazones (SSCs), [ReBr(CO)3(SSC)]. It was
found that these complexes exhibit moderate to high cytotoxicities towards MOLT-4 cells.4 In this
paper, we report our recent work on the synthesis and cytotoxicity screening of benzaldehyde and
substituted salicylaldehyde dibenzyl semicarbazones, and their rhenium(I) tricarbonyl complexes
(Figure). The results show that complexes 2, 3 and 5 are strongly cytotoxic against MOLT-4 cells.
References
1. H. Beraldo, D. Gambino, Minirev. Med. Chem. 2004, 4, 31-39. (b) Z. Afrasiabi, E. Sinn, W. Lin, Y.
Ma, C. Campana, S.B. Padhyé, J. Inorg. Biochem. 2005, 99, 1526-1531. (c) J. Rivadeneira, D.A.
Barrio, G. Arrambide, D. Gambino, L. Bruzzone, S.B. Etcheverry, J. Inorg. Biochem. 2009, 103, 633642.
2. (a) J. Patole, S. Padhye, M.S. Moodbidri, N. Shirsat, Eur. J. Med. Chem. 2005, 40, 1052-1055. (b)
P. Noblia, M. Vieites, B. Parajon-Costa, E. Baran, H. Cerecetto, P. Draper, M. Gonzalez, O. Piro, E.
Castellano, A. Azqueta, A. de Cerain, A. Monge-Vega, D. Gambino, J. Inorg. Biochem. 2005, 99,
443-451.
3. (a) J. Zhang, J.J. Vittal, W. Henderson, J. Wheaton, I.H. Hall, T.S.A. Hor, Y.K. Yan, J. Organomet.
Chem. 2002, 650, 123-132. (b) W. Wang, Y.K. Yan, T.S.A. Hor, J.J. Vittal, J.R. Wheaton, I.H. Hall,
Polyhedron 2002, 21, 1991-1999.
4. J. Ho, W. Y. Lee, P. F. P. Lee, Y. K. Yan, J. Inorg. Biochem., submitted.
19
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
OP-4
Metallo-Nucleosides: Bis(dicobalt hexacarbonyl alkynyl) Derivatives of
2'-Deoxyuridine. Synthesis and Evaluation of Antiproliferative Activity Against
Human Breast Cancer Cells
Roman Dembinski,*a Przemyslaw Wyrebek.a Agnieszka Mikus.a Adam Sniady,.a Laura Hamel,b
and Ingo Ott*b
a
Oakland University, Department of Chemistry, 2200 N. Squirrel Rd., 48309-4477, Rochester, MI,
USA. b Technische Universität Braunschweig, Institute of Pharmaceutical Chemistry, Beethovenstr.
55, 38106 Braunschweig, Germany, E-mail: dembinsk@oakland.edu
In continuation of synthetic pursuit of metallo-nucleosides, in particular dicobalt
hexacarbonyl 5-alkynyl-2'-deoxyuridines,1 novel compounds with two alkynyl groups were
synthesized starting from 5-iodo-2'-deoxyuridine (selected example is illustrated below). The
complexes have been examined for their anti-cancer activity in vitro against MCF-7 and
MDA-MB-231 human breast cancer cell lines or HT-29 (colon carcinoma). The results were
compared to activity of non-coordinated alkynyl precursors.
O
(CO)3
Co Co(CO)3
HN
N
O
HO
O
H
Co(CO)3
Co(CO)3
OH
References
1. (a) C. D. Sergeant, I. Ott, A. Sniady, S. Meneni, R. Gust, A. L. Rheingold, R. Dembinski, Org.
Biomolec. Chem. 2008, 6, 73-80. (b) I. Ott, B. Kircher, R. Dembinski, R. Gust, Expert Opin.
Therapeutic Pat. 2008, 18, 327-336.
20
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
OP-5
Novel Metallocene Anticancer Drugs: From Lead to Hit
Matthias Tackea
a
Centre for Synthesis and Chemical Biology, Conway Institute
UCD School of Chemistry and Chemical Biology, Belfield, Dublin 4, Ireland.
E-mail: matthias.tacke@ucd.ie
Titanocene dichloride derivatives like Titanocene Y were extensively investigated in vitro, in vivo
and ex vivo during the last years.1-5 In addition, details about the mechanism of action became
available, which allowed for choosing renal-cell cancer as one of the appropriate targets. More
recently, the successful substitution patterns of the titanocenes were transmetallated onto vanadium
which has led to isostructural vanadocene dichloride compounds.6, 7 These compounds have started
their preclinical evaluation process with respect to their cytotoxicity and anti-angiogenic activity in
vitro and their tumor volume control and toxicity in vivo. The results allow for the first to look at the
direct comparison of these two promising classes of metallocene compounds; this might allow to
answer the question, which metal is the most promising for further development.
References
1. Bioorganometallic Fulvene-Derived Titanocene Anticancer Drugs, K. Strohfeldt, M. Tacke, Chem.
Soc. Rev., 2008, 37, 1174-1187.
2. In Vitro Anti-Tumor Activity of Bridged and Unbridged Benzyl-Substituted Titanocenes, G. Kelter,
N. Sweeney, K. Strohfeldt, H.-H. Fiebig, M. Tacke, Anti-Cancer Drugs, 2005, 16, 1091-1098.
3. Antitumor Activity of Titanocene Y in Xenografted Caki-1 Tumors in Mice, I. Fichtner, C.
Pampillón, N. J. Sweeney, K. Strohfeldt, M. Tacke, Anti-Cancer Drugs, 2006, 17, 333-336.
4. Antitumor Activity of Titanocene Y in Freshly Explanted Human Breast Tumors and in Xenografted
MCF-7 Tumors in Mice, Anti-Cancer Drugs, 2007, 18, 311-315.
5. Antiproliferative Activity of Titanocene Y against Tumor Colony Forming Units, O. Oberschmidt,
A.-R. Hanauske, C. Pampillón, K. Strohfeldt, N. J. Sweeney, M. Tacke, Anti-Cancer Drugs, 2007, 18,
317-321.
6. Novel Benzyl-Substituted Vanadocene Anticancer Drugs, B. Gleeson, J. Claffey, M. Hogan, H.
Müller-Bunz, D. Wallis, M. Tacke, J. Organometal. Chem., 2009, 694, 1369-1374.
7. Synthesis and Cytotoxicity Studies of Fluorinated Derivatives of Vanadocene Y, B. Gleeson, J.
Claffey, A. Deally, M. Hogan, L. M. Menéndez Méndez, H. Müller-Bunz, S. Patil, D. Wallis, M.
Tacke, Eur. J. Inorg. Chem., 2009, 2804-2810.
Acknowledgement: Support is acknowledged from CESAR, COST, HEA, CSCB and UCD.
21
ISBOMC `10
5.7 – 9.7 Ruhr-Universität Bochum
OP-6
Transcriptional Profile of HT-29 Cells upon Treatment with Different
Organometallic Compounds
Igor Kitanovic,a Ana Kitanovic,a Hamed Alborzinia,a Suzan Can,a Pavlo Holenya,a Elke Lederer,a
Hans-Günther Schmalz,b Annegret Hille,c Ronald Gust,c Ingo Ott,d Aram Prokop,e Melanie Oleszak,f
Yvonne Geldmacher,f William S. Sheldrick,f Gilles Gasser,g Nils Metzler-Nolteh and Stefan Wölfl*a
Institute of Pharmacy and Molecular Biotechnology, University Heidelberg, Germany, b Institute of
Inorganic Chemistry, University of Cologne, Germany, c Institute of Pharmacy, Department of
Pharmaceutical Chemistry, Freie Universität Berlin, Germany, d Institute of Pharmaceutical
Chemistry, Technische Universität Braunschweig, Germany, e Cologne City Hospital, Department of
Oncology, Cologne, Germany, f Faculty of Chemistry and Biochemistry, Department of Analytical
Chemistry, University Bochum, g Institute of Inorganic Chemistry, University of Zurich, h Faculty of
Chemistry and Biochemistry, Department of Bioinorganic Chemistry, University of Bochum. email:
igor.kitanovic@urz.uni-heidelberg.de, wolfl@uni-hd.de
a
In the past several decades metal compounds containing platinum became an essential part of many
clinical protocols for anti-cancer therapy. Considered to be relatively unspecific compounds that block
DNA-replication and cell cycle progression, metal-containing compounds were not in the research
focus of medicinal chemistry. New developments in the chemistry of (bio-)organometallic compounds
however lead to the discovery of several unexpected highly specific activities of new organometallic
compounds and opened new important perspectives in this field.
For cancer therapy cancer cell specific toxicity and apoptosis induction are highly desirable features of
new potential drugs. Within our collaborative network a wide range of new (bio-)orgamometallic
compounds were developed that show very distinct cytotoxic properties suggesting that rather than
acting through a common mechanism different cellular targets are responsible for cytotoxicity and cell
death induction.
We will present a comprehensive analysis of the cellular response of human colorectal
adenocarcinoma cells HT29 with very diverse organometallic compounds: ranging from FeIIsalophenes, through more classical bioorganometallic compounds to bioorganometallic compounds
derived from established (non-metal containing) drugs. To elucidate their specific activity profile,
standard cell based assays were combined with genome wide gene expression profiling using
affymetrix gene expression arrays. Although the substances represent a wide range of different
structures and metal cores, they all are highly cytotoxic and clearly induce apoptosis in HT-29 cells.
For gene expression profiling concentrations just below the IC50 (cytotoxicity) were chosen to obtain
more compound specific alterations in gene expression rather then common cytotoxicity profiles, in
addition mRNAs were collected at different time points critical in the cellular response upon
treatment.
The results obtained show similar response characteristics, but also very compound specific changes.
This clearly indicates very distinct biological properties and suggests common response mechanisms
as well as high selectivity and target specificity.
List of compounds: Hi41, CoASS (AG Gust), MH1 (AG Scheldrick), MeN69 (AG Schmaltz),
FcOHTAM3, ReGG1 (AG Metzler-Nolte)
This work is supported by the DFG as part of the Forschergruppe FOR630.
22
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
OP-7
Arene-Ruthenium Metalla-Prisms: New Drug Vectors
Nicolas Barrya and Bruno Therrien*a
a
University of Neuchatel, Faculty of Science, Institute of Chemistry, 51 Ave de Bellevaux, 2000,
Neuchatel, Switzerland. E-mail: bruno.therrien@unine.ch
Based on “enhanced permeability and retention” (EPR) effect, passive targeting of tumours appears as
a promising solution against the general toxicity, resistance mechanisms and side effects of classical
chemotherapeutics.1 Thus, large drug delivery systems offer in general a better selectivity as compared
to small molecules. Large drug delivery vectors include micelles, nanoparticles and dendrimers;
however, we proposed some years ago a new type of water soluble capsule built from arene-ruthenium
units. These intrinsic cytotoxic metalla-prismatic cages allowed encapsulation of palladium or
platinum complexes inside their cavities,2 as well as the encapsulation of aromatic molecules.3
Moreover, the uptake of encapsulated molecule into cancer cells via fluorescence microscopy was also
studied.4
Host-guest properties have been recently observed with a slightly different arene-ruthenium metallaprism, which does not really change neither the uptake of the guest into cancer cells nor the
cytotoxicity. However, fluorescence microscopy assays seem to show a faster release of the guest
molecule inside cancer cells, thus opening new perspectives for these metalla-cages. These new results
will be the focus of this presentation.
References
1. Y. Matsumura, H. Maeda, Cancer Res. 1986, 46, 6387.
2. B. Therrien, G. Süss-Fink, P. Govindaswamy, A. K. Renfrew, P. J. Dyson, Angew. Chem. Int. Ed.
2008, 47, 3773.
3. J. Mattsson, P. Govindaswamy, J. Furrer, S. Sei, K. Yamaguchi, G. Süss-Fink, B. Therrien,
Organometallics 2008, 27, 4346.
4. O. Zava, J. Mattsson, B. Therrien, P. J. Dyson, Chem. Eur. J. 2010, 16, 1428.
23
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
OP-8
Design and Characterisation of the Anticancer Properties of Ruthenium(II)
Organometallic Compounds: Chemical Structure Optimization, Transport
and Regulated Signaling Pathways
Christian Gaiddon,a* Jenny Marjorie,a Meng Xiangjun,a Leyva L. Mili,b Isabelle Gross,e
Sébastien Harlepp,c Pascal Hébraud,c Anne Boos,d Claude Sirlin,b Michel Pfeffer,b
and Jean-Philippe Loefflera
a
UMRS692 INSERM - Université de Strasbourg, Signalisations Moléculaires et Neurodégénérescence,
11 rue Humann, Strasbourg, France
b
UMR 7177 CNRS- Université de Strasbourg, Institut de Chimie, Strasbourg, France
c
UMR 7504 CNRS, IPCMS, Strasbourg, France
d
UMR 7178 IPHC-DSA, ULP, CNRS, ECPM, Strasbourg France
e
UMRS682 INSERM - Université de Strasbourg, Strasbourg, France
gaiddon@unistra.fr
Cisplatin-derived anticancer therapy has been used for three decades despite its side effects. Other
types of organometallic complexes, namely some ruthenium-derived compounds (RDCs), which
would display cytotoxicity through different modes of action, might represent alternative therapeutic
agents. We have studied both in vitro and in vivo the biological properties of a new class of RDCs that
contain a covalent bond between a ruthenium(II) atom and a carbon. We showed that these RDC
inhibited the growth of various tumors implanted in mice more efficiently than cisplatin. Importantly,
in striking contrast with cisplatin, some of these RDCs did not cause severe side effects on the liver,
kidneys, or the neuronal sensory system. We analyzed the mode of action of these RDC and
demonstrated that they interacted poorly with DNA and induced only limited DNA damages compared
to cisplatin, suggesting alternative transduction pathways. Indeed, we found that target genes of the
endoplasmic reticulum (ER) stress pathway, such as Bip, XBP1, PDI, and CHOP, were activated in
RDC-treated cells. Induction of the transcription factor CHOP, a crucial mediator of ER stress
apoptosis, was also confirmed in tumors treated with RDCs. Activation of factor CHOP led to the
expression of several of its target genes, including pro-apoptotic genes. In addition, the silencing of
CHOP by RNA interference significantly reduced the cytotoxicity of RDCs. Altogether, our results
led us to conclude that RDCs act by an atypical pathway involving CHOP and ER stress, and thus
might provide an interesting alternative for anticancer therapy.
Based on these results, we have now developed new and optimized RDCs with an enhanced
cytotoxicity. We show that they have indeed a greater toxicity in vitro, which is linked to the
activation of different signaling pathways. In order to have a better understanding of the mode of
action of RDCs, we have analyzed their import into cells and compared the transcriptome regulated by
cisplatin and RDCs. We identified various signaling pathways regulated specifically by RDCs that
allowed us to present an interesting and global hypothesis linking the anticancer effect of RDCs, their
redox activity and the alteration of the cellular metabolism.
24
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
OP-9
Synthesis and Structure-Activity Relationship of Organometallic Derivatives
of Curcumin as Anticancer Agents
Anusch Arezki, Emilie Brulé,* and Gérard Jaouen
Chimie ParisTech (ENSCP), Laboratoire Charles Friedel (UMR 7223),
Organometallic Medicinal Chemistry Group
11 rue Pierre et Marie Curie, 75231 Paris Cedex 05, France
E-mail: anusch-arezki@chimie-paristech.fr
Turmeric and especially its main and active constituent curcumin have traditionally been used as a
food preservative, as well as a natural remedy in Ayurvedic and Chinese medicine for centuries. But it
is only within the past few years that modern research has focused on curcumin's biological properties
(antioxidant, anti-inflammatory...) and in particular on the extraordinary actions of curcumin in
preventing and fighting cancer. Curcumin has at least a dozen separate ways of interfering with cancer
progression, but at the same time preserving normal cells.1
In our laboratory, we chose different curcuminoids as starting materials to lead to a novel class of
bioorganometallic anticancer agents by covalently grafting different organometallic ligands to the
curcuminoid skeleton. The synthesis of the new ferrocenyl molecules was primarily done by
substitution of the central carbon of the curcuminoids,2 which has shown to have a crucial influence on
activity against some cancer cells.3 The new complexes were tested in vitro on different cancer cell
lines, such as prostate and skin (melanoma), and showed promising cytotoxic effects on all types. For
some of the ferrocenyl-curcuminoid derivatives, enhanced cytotoxic activity was observed compared
to the organic curcuminoid analogues, with up to a 3- and 4-fold improvement on prostate and
melanoma cells, respectively.
OH
O
MeO
OH
OMe
HO
O
MeO
OMe
R1
OH
R1
R
2
R1: H, OH, OMe
R2: H, OMe
Curcumin
R
2
Fe
= organic linker
Curcumin and ferrocenyl derivatives of several curcuminoids
Due to encouraging results in vitro, the National Institute of Health of the United States is currently
screening, in collaboration with the National Cancer Institute, one selected ferrocenyl curcuminoid on
60 different cancer cell lines (colon, lung, central nervous system,…). Primary single dose testing
revealed a particular selectivity of the compound for certain types of cancer in vitro, which has led to
more detailed investigations, presently ongoing.
Acknowledgement to the Gottlieb-Daimler and Carl-Benz Foundation (Germany) and the Association
pour la Recherche sur le Cancer (ARC) (France) for PhD funding.
References
1. A. Goel, A. B. Kunnumakkara, B. B. Aggarwal, Biochem. Pharmacol. 2008, 75, 787-809.
2. A. Arezki, E. Brulé, G. Jaouen, Organometallics 2009, 28, 1606-1609.
3. L. Lin, Q. Shi, A. K. Nyarko, K. F. Bastow et al. J. Med. Chem. 2006, 49, 3963-3972.
4. P. Anand, A. B. Kunnumakkara, R. A. Newman, B. B. Aggarwal, Mol. Pharm. 2007, 4, 804-818.
25
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
OP-10
Synthesis, characterization and antiproliferative activity of a series of Pt(IV)
complexes: a QSAR approach to their cytotoxicity
Domenico Osella,a Paola Gramatica,b Ester Papa,b Mara Luini,b Elena Monti,b Marzia B. Gariboldi,b
Mauro Ravera,a Elisabetta Gabano,a and Luca Gaviglioa
a
University of Piemonte Orientale “A. Avogadro”, Department of Environmental and Life Sciences,
Viale Michel 11, 15121, Alessandria, Italy. b Department of Structural and Functional Biology,
University of Insubria, Via A. da Giussano 10, 21052 Busto Arsizio (VA), Italy. E-mail:
domenico.osella@mfn.unipmn.it
Octahedral Pt(IV) complexes are usually supposed to behave as antitumor pro-drugs: most of them can
be reduced by the hypoxic environment of the tumour tissue to square planar Pt(II) via a two electron
reduction and loss of axial ligands. Both axial and equatorial ligands play an important role in setting
the redox potential into the biological window and modulating the lipophilicity of Pt(IV) complexes,
whereas the two carrier groups (N-based) determine the antiproliferative potency of the drug.
A large series of Pt(IV) complexes containing different ligands was synthesized, characterized
and tested for in vitro antitumor activity against ovarian carcinoma, A2780, and colon
adenocarcinoma, HCT116, cell lines.
A quantitative structure-activity relationship (QSAR) analysis was performed on this series of Pt(IV)
complexes to find a relationship among cytotoxicity (IC50), reduction peak potential (Ep), partition
coefficient (log Po/w) and theoretical molecular descriptors. The whole set of descriptors was used as
an input set for modeling, in order to identify different structural features of Pt(IV) complexes related
to the in vitro cytotoxicity.
In the resulting models, a lipophilic descriptor (i.e log Po/w or number of secondary sp3 carbon atoms,
nCs) plus an electronic descriptor (Ep, number of oxygen atoms, nO, or total polar surface area,
TPSA(NO)) is necessary for the optimal modeling. This results support the general findings that the
biological behavior of Pt(IV) complexes is related to their uptake, reduction, and structure of the
corresponding Pt(II) metabolites.
26
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
OP-11
Influence of the Rhenium-Platinum antitumor system on tumor growth and blood
antioxidant state
Nataliia I. Shtemenko,a Alexander V. Shtemenkob
a
Department of Biophysics and Biochemistry, Dnipropetrovs’k National University, 72 Gagarin
avenue, Dnipropetrovs’k 49010, Ukraine, bDepartment of Inorganic Chemistry, Ukrainian State
Chemical Technological University, Gagarin avenue 8, Dnipropetrovs’k 49005, Ukraine. E-mail:
ashtemenko@yahoo.com
The novel antitumor system including cluster rhenium compounds and cisplatin (Re-Pt 4:1 system)
has been recently presented1 that was effective in the model of rat’s specific Guerink carcinoma T8
and in the majority of experiments led to disappearance of cancer cells. The approach to circumvent
such drawbacks of the drugs on the base of heavy metal compounds as dose-limiting toxicities
(nephro-, hepato-, neurotoxicity, etc.) by encapsulation of the drug into a nanoparticle prevents byside interactions is a very promising strategy in medicine2. Oxidative stress-induced activation of
NADPH oxidase and peroxisome proliferators-activated receptors, alterations of redox state of
binding proteins, DNA mutations and induction of early response genes and hematopoietic activation,
etc. seem to be common elements in the induction of hyperplasia, neoplasia, cancer metastasis, and
angiogenesis. In the present work we show application of different nano-preparations of 20 – 100 nm
size, nanoliposomes and solid nanoparticles loaded with Re-Pt system or with its components in
different ratios in the model of tumor growth. The cluster rhenium compounds dichlorotetra-isobutiratodirhenium(III) [Re2(i-C3H7CO2)4Cl2] (Re1) and cis-Re2(C10H15COO)2Cl4·2(CH3)2SO (Re2)
tetrachlorodi-µ-adamantylcarboxylatodirhenium(III) with dimethyl sulfoxide as axial ligands were
the matter of concern. Parameters of oxidative stress in blood of experimental animals were
measured. Intensity of peroxide oxidation process (POL), activity of catalase (C) and superoxide
dismutase (SOD) in plasma and red blood cells were very sensitive to tumor growth and to its
prevention by the system. Introduction of the Re-Pt system in nanoliposomes and nanoparticles did
not influence on the inhibition of tumor growth, except experiments, where quantity of cisplatin in
capsules were lower (1:8). The lowering of the size of the introduced liposomes and particles did not
influence on the intensity of POL: concentration of malonic dialdehyde was not changed. Activities
of SOD and C in plasma and erythrocytes were higher, especially in experiments with solid
nanoparticles (in 1.8 times in comparison with application of ordinary liposomes). This activation of
the antioxidant enzymes was independent from the size of the tumor and remained on the high level
even in those experiments, where ratio of introduced Rhenium compound : cisplatin was 1 : 8. In this
work we show also that influence of rhenium compounds on the enzymes activity is dependent from
the structure of organic radical in the investigated rhenium substance. Encapsulation of the rhenium
substances (first component) into lipid coating is effective as in form of liposomes, as in form of
nanoparticles; the Re-Pt system is effective in the form of nanoliposomes with mixed composition
inside (encapsulation of both components) that opens great opportunities to use medicines with
different properties and in ratio of personal inquire in one preparation. Elaboration of solid
nanoparticles formulations of the Re-Pt requires additional investigations as on this stage of
development of the idea it is clear that only one component of the system may be effectively included
into solid lipid coating. Encapsulation of both components is promising, but requires additional
procedures warranting prevention of the interactions between cisPt and rhenium compounds.
Encapsulation of the Re-Pt antitumor system in nanoparticles and nanoliposomes resulted in active
antyhemolytic properties of the systems and activated the specific antioxidant defence.
References
1. (a) N. Shtemenko, P. Collery, A. Shtemenko. Anticancer Res. 2007, 27, 2487-2492. (b) A.
Shtemenko, P. Collery, N. Shtemenko, K. Domasevitch, et al. Dalton Trans. 2009, 26, 5132 - 5136.
2. (a) C. Medina, M.J Santos-Martinez, A. Radomski. British Journal of Pharmacology, 2007, 150,
552-558. (b) K. N. J. Burger, R.W. H. M. Staffhorst. Nat. Med., 2002, 8, 81-84.
27
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
OP-12
The [CpM(CO)3] - Moiety (M = Mn, Tc, Re) as Phenyl Ring analog – a Promising
Strategy Towards New Drugs and Radiopharmaceuticals
D. Can, H.P. N'Dongo, P. Schmutz and R. Alberto*
University of Zurich, Faculty of Inorganic Chemistry, Winterthurerstrasse 190, 8057 Zurich,
Switzerland.
E-mail: daniel.can@aci.uzh.ch
Structural changes imposed on proteins or nucleic acids by metal cations such as Ca2+ or Zn2+ are
essential for the initiation of biological processes. Organometallic complexes are comparably rare as
structural recognition site in receptors, whereas exactly this is how most organic molecules and drugs
tend to work1.
As early as 1979 Hanzlik et al. studied the interaction of -Ferrocenylalanine with phenylalanine
hydroxylase and phenylalanine decarboxylase and showed that the ferrocene derivative behaved like
phenylalanine analogues2. Ongoing investigations by Jaouen et al. showed years later, that substitution
of a phenyl ring in tamoxifen by ferrocene similarly kept the biological activity of the lead compound
intact3.
As 99mTc is nowadays in the focus of the development of radiotracers, introducing group 7 transition
metals as [CpM(CO)3] into this analogy opens new directions not only towards new drugs but also
towards very promising radiopharmaceuticals.
O
O
N
H
N
H
N
Re
OC
N
CO
CO
Following this strategy we will present the analogy of different classes of bioactive compounds
containing [CpRe(CO)3]: sulphonamides acting as carbonic anhydrase inhibitors with high binding
affinities5, histone deacetylase inhibitors, amino acids transported by the LAT1 transporter and
melanoma imaging agents with melanin afiinity.
Herein we describe the synthesis and characterization of "cold" Re-compounds as surrogates to well
known pharmaceuticals and discuss their analogy. For the "hot" molecules, we followed a general
aqueous approach towards 99mTc(CO)3 labeled 5-Cp derivatives from their dimeric Cp species via
metal mediated retro-Diels-Alder reaction4 and show that the conditions used can be applied to a
variety of functional groups.
References
1. S. J. Lippard, J. M. Berg, Principles of Bioinorganic Chemistry, University Science Books, Mill
Valley, CA, 1994
2. R. P. Hanzlik, P. Soine, W. H. Soine, J. Med. Chem., 1979, 22, 424-428
3. G. Jaouen, S. Top, A. Vessière, Bioorganometallics, Wiley-VCH, Weinheim, 2006, p. 65
4. Y. Liu, B. Spingler, P. Schmutz et al, J. Am. Chem. Soc., 2008, 130, 1554-1555
5. C. T. Supuran, Nature, 2008, 7, 168-181
28
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
OP-13
Ferrocenyl Flavonoids: Synthesis and Antiproliferative Effects
Elizabeth A. Hillard,a Jean-Philippe Monserrat,a Guy Chabot,b Louis Hamon,c and Gérard Jaouenc
a
Chimie ParisTech (Ecole Nationale Supérieure de Chimie de Paris), Laboratoire Charles Friedel,
UMR CNRS 7223, 11 rue Pierre et Marie Curie, 75231 Paris cedex 05, France.b Chimie ParisTech
(Ecole Nationale Supérieure de Chimie de Paris), Département Friedel; Université Paris Descartes,
Faculté des Sciences Pharmaceutiques et Biologiques, Laboratoire de Pharmacologie Chimique,
Génétique et Imagerie (CNRS UMR 8151- INSERM U 1022), 4 avenue de l’Observatoire, 75006
Paris, France.c Institut Parisien de Chimie Moléculaire, UMR CNRS 7201, Université Pierre et Marie
Curie, CC47, 4 Place Jussieu, 75252 Paris Cedex 05, France.
Flavonoids, such as flavanones and flavones, are ubiquitous plant-based polyphenols. Their
importance in health was first reported in 1936,1 and numerous benefits have been reported for various
conditions including cancer, cardio-vascular diseases, asthma, and viral infections Several pathways
for chemoprevention have been elucidated, particularly protective antioxidant properties. However,
some flavonoids, such as quercetin, are also known to act as prooxidants because they can be
metabolized to o-quinones and quinone methides that subsequently produce ROS, which have been
proposed as a way to stimulate apoptosis in cancer cells.2 Because of the dual antioxidant/prooxidant
actions of flavonoids, we therefore became interested in modifying these compounds with redoxactive ferrocene and screening them against cancer cells.
OH
OH
O
HO
O
OH
O
O
chalcone
O
flavone
OH
O
quercetin
O
Fe
O
aurone
O
flavanone
O
ferrocenyl chalcone
It is remarkable, that, although ferrocenyl chalcones have been widely studied for over 50 years,3 there
is, to our knowledge, no report of the corresponding ferrocenyl flavones or flavanones. We have
recently discovered a novel reaction which gives easy access to the first ferrocenyl flavones, via a
ferricenium intermediate.4 The ferrocenyl flavones, furthermore, isomerize under basic conditions to
give access to a class of ferrocenyl aurones. We have also been able to graft ferrocene to the flavanone
skeleton via an acid-catalyzed condensation reaction. The synthesis of these new compounds and
preliminary in vitro antiproliferative results will be presented.
References
1. S. Rusznyak, A. Szent-Gyorgyi, Nature 1936, 138, 27.
2. H. Pelicano, D. Carney, P. Huang, Drug Resist. Update 2004, 7, 97-110.
3. C. R. Hauser, J. K. Lindsay, J. Org. Chem. 1957, 22, 482-485.
4. J-P Monserrat, G. G. Chabot, L. Hamon, L. Quentin, D. Scherman, G. Jaouen, E. A. Hillard, Chem.
Commun., 2010, in press.
29
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
OP-14
Preclinical Development of Metal-Based Compounds:
Set Up of a Plastic Mouse Model
A. Bergamo,a V. Vidimar,a D. Gallo,a G. Chiaruttini,a and G. Sava*a,b
a
Callerio Foundation Onlus, via A. Fleming 22-31, 34127, Trieste, Italy. b University of Trieste,
Faculty of Pharmacy, Department of Life Sciences, via L. Giorgieri 7, 34127, Trieste, Italy.
E-mail: a.bergamor@callerio.org
Nowadays the main goal of solid tumour chemotherapy is the treatment of metastases, primary cause
of death in most of the cancerous diseases.1,2 The anti-cancer drugs currently used in the clinic have
only limited success: to achieve effective therapeutic approaches, selectivity should be improved and
the new drugs should be designed to hit targets specific of metastatic cells. This work arises from the
need to renew the screening’s system of the anti-tumour drugs employed for the treatment of solid
tumour metastases, a field still lacking of a simple, handy, and easily controllable in vitro models to be
used for evaluating and measuring specifically the potential anti-metastatic activity of active
principles. This project would contribute to match this unmet need through a biotechnological device,
born from the collaboration between the Callerio Foundation Onlus and the Department of Materials
and Natural Resources of the University of Trieste, able to mimic some physio-pathological
conditions, typical of the metastatic process. This system constitutes a “bridge” between the “classic in
vitro study” and the “classic in vivo study”; in the device the tumour cells can migrate, through a
microcircuit, from a well representing the primary tumour, to a well representing the target organ of
metastases. The model we wish to validate is the metastasis from colo-rectal cancer, a great social
impact disease in western countries, which prognosis and life time expectancy are mainly determined
from the progression of the secondary tumours to the liver, and not from the primary tumour itself.3 In
order to recreate a metastatic colorectal tumour model, human colon adenocarcinoma HT-29 are
chosen as invasive and malignant cells, human non-malignant colon epithelial cell line HCEC is used
to mimic a normal colonic epithelial tissue, and immortalized human hepatocytes IHH to mimic the
healthy hepatic tissue. The first issue of this study is to set up the optimal environment to simulate the
physio-pathological process of metastatization and liver invasion through the development of a coculture system in which the three cell lines grow together. In parallel the effects of three reference
drugs for the treatment of colorectal cancer (irinotecan, 5-fluorouracil and oxaliplatin),4 are studied in
the same system. The results of theses series of experiments, propaedeutic to the extension of the coculture model in the biotechnological device, will be presented.
Acknowledgements
This work was carried out within the framework of COST Action D39.
References
1.
2.
3.
4.
P. Cairns, Nat. Rev. Cancer 2006, 7, 531-543.
http://www.nlm.nih.gov/medlineplus/cancer.html
J.M. McLoughlin, E.H. Jensen, M. Malafa, Cancer Control 2006, 13, 32-41.
M. Koopman, C.J. Punt, Eur. J. Cancer 2009, 45 Suppl. 1, 50-56.
30
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
OP-15
Arjunolic acid: The First Renewable-Nano Triterpenoid in Bioorganometallics
Braja G. Bag,*a Partha P. Dey,a Rakhi Majumdar,a Shaishab K. Dinda,a and Shib S. Dasa
a
Vidyasagar University, Department of Chemistry and Chemical Technolgy, Midnapore 721 102,
India. E-mail: bgopalbag@yahoo.co.in
Utilization of plant metabolites as renewables in various facets of bioorganic, bioorganometallic and
organic chemistry research has become significant in recent years because such investigations aim at
the development of sustainable chemical feedstocks.1 Ferrocene moiety has been utilized in the design
of peptide analogues, redox-responsive gelators, enhanced antimalarial drugs, etc.2 However, inspite
of the abundance of a large variety of triterpenoids, having nano-metric dimensions with varied
lengths of rigid and flexible parts,3 according to our knowledge, no ferroceno-triterpenoid has been
reorted so far. Availability of arjunolic acid 1, extractable from the heavy wood of Terminalia Arjuna
became the first choice for such investigations.4
Figure 1: (a) A redox-responsive organogel from ferrocenylidene arjunolic acid 2, (b) SEM image
reveals self-assembled fibrillar network having fibers of nano-meter diameters, (c) TEM image of CdS
nano-particles templated by self-assembled nano-fibers from arjunolic acid derivatives.
The ferrocenylidene arjunolic acid 2, synthesized in one-step from arjunolic acid 1 and formylferrocene in high yield, self-assembled in various organic media to form soft solid-like materials
(Figure 1a, Table 1). Scanning electron micrographs of the soft-solids showed fibrillar net-work
structures having fibers of nano-metric dimensions (Figure 1b).
Table 1: Gelation Test Results of 2
Detailed investigations on the self-assembly of arjunolic acid
or its derivatives revealed that most of these derivatives selfToluene
Gel
assemble in aqueous or organic liquids leading to the
o-Xylene
Gel
formation of fibers of nano-metric diameters.5,6 When H2S
m-Xylene
Gel
gas was diffused through a gel of an arjunolic acid derivative
p-Xylene
Gel
in ethanol saturated with Cd(OAc)2, then porous CdS
nanoparticles templated by the self-assembled nano-fibers were formed (Figure 1c). Recent results
from our laboratory will be presented describing various approaches towards bioorganometallic
chemistry for the utilization triterpenoids.
Acknowledgements: Financial assistance from AvH foundation Germany and DRDO India are
gratefully acknowledged.
Solvent
State
Conc.
(g/100 mL)
10
9
10
10
References
1. B.G. Bag, S.K. Dinda, Pure Appl. Chem. 2007, 79, 2031.
2. (a) D.R. van Staveren , N. Metzler-Nolte, Chem. Rev. 2004, 104, 5931; (b) F. Dubar, G. Anquetin,
B. Pradines, D. Dive, J. Khalife, C. Biot, J. Med. Chem. 2009, 52, 7954.
3. B.G. Bag, C. Garai, R. Majumdar, unpublished results.
4. B.G. Bag, P.P. Dey, S.K. Dinda, W.S. Sheldrick, I.M. Oppel, Beil. J. Org. Chem. 2008, 4, 24.
5. B.G. Bag, S.K. Dinda, P.P. Dey, A.V. Mallia, R.G. Weiss, Langmuir 2009, 25, 8663.
6. B.G. Bag, G.C. Maity, S.K. Dinda, Org. Lett. 2006, 8, 5457.
31
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
OP-16
Anticancer Activity of Multinuclear Ruthenium-Arene Complexes Coordinated
to Dendritic Poly(propyleneimine) Scaffolds
Gregory S. Smith*a and P. Govendera
a
University of Cape Town, Faculty of Science, Department of Chemistry, 7701, Cape Town,
South Africa. E-mail: Gregory.Smith@uct.ac.za
Dendrimers have found potential as molecular tools in biological applications, especially as nanocarriers, diagnostic agents and as chemotherapeutics.1-4 An advantage of using dendrimers is their
multivalency, which leads to increased interaction between a dendrimer-drug conjugate and a target
bearing multiple receptors, further improving the selectivity to cancer cells. Large macromolecules,
like dendrimers, can also specifically target tumours by exploiting the ‘enhanced permeability and
retention’ (EPR) effect, in which macromolecules can accumulate at the tumour site due to an increase
in blood vessel permeability within diseased tissues compared to normal tissues.5
In this presentation, we report a series of multinuclear ruthenium-arene complexes based on first- and
second-generation poly(propyleneimine) dendritic scaffolds (Fig. 1). Their cytotoxicity against the
A2780 human ovarian cancer cell line will also be discussed.
R
Cl
O
Cl Ru
Cl
N
N
N
N
O
Ru
Cl
Cl
N
Cl
O Ru
Cl
R
N
N
N
R
R
N
N
Ru
Cl Cl
Cl Cl
Ru
N
R
N
N
Ru N
Cl Cl
R
R
Ru
Cl Cl
Cl
Ru N
N
N
N
N Ru
Cl Cl
R
R
N
Cl
Cl Cl
N Ru
N
N
Cl
O Ru
N
4+
R
R
R
Cl Cl
Ru
N
=
O
N
O H
R
Fig. 1: Ruthenium-arene metallodendrimers based on a poly(propyleneimine) scaffold.
References
1. (a) U. Boas, J. B. Christensen, P. M. H. Heegaard: Dendrimers in Medicine and Biotechnology:
New Molecular Tools, RSC Publishing (2006). (b) C. C. Lee, J. A. MacKay, J. M. J. Fréchet, F. C.
Szoka, Nature Biotech. 2005, 23, 1517-1526.
2. F. Aulenta, W. Hayes, S. Rannard, Eur. Polym. J. 2003, 39, 1741-1771 and references therein.
3. J. B. Wolinsky, M. W. Grinstaff, Adv. Drug Deliv. Rev. 2008, 60, 1037-1055 and references therein.
4. (a) A. Agarwal, S. Saraf, A. Asthana, U. Gupta, V. Gajbhiye, N. K. Jain, Int. J. Pharm. 2008, 350,
3-13. (b) E. R. Gillies, J. M. J. Fréchet, Drug Discov. Today 2005, 10, 35- 43.
5. D.F. Baban, L.W. Seymour, Adv. Drug Delivery Rev. 1998, 34, 109-119.
32
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
OP-17
Biofunctionalization of a Generic Collagenous Triple Helix
with the Integrin α2β1 Binding Site
Stephan Niland,a Christoph Westerhausen,b Thilo Bracht,a Alletta Schmidt-Hederich,a Désirée Freund,a
Stephan W. Schneider,c Matthias F. Schneider,d and Johannes A. Eblea
a
Goethe University Frankfurt, University Hospital, Center for Molecular Medicine, Department of
Vascular Matrix Biology, Excellence Cluster Cardio-Pulmonary System, Theodor-Stern-Kai 7, 60590
Frankfurt/Main, Germany. b University of Augsburg, Faculty of Mathematics and Natural Sciences,
Department of Experimental Physics I, Universitaetsstrasse 1, 86135 Augsburg, Germany.
c
Heidelberg University, Mannheim University Hospital, Department of Experimental Dermatology,
Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany. d Boston University, Department of
Mechanical Engineering, Biological Physics, 590 Commonwealth Avenue, MA 02215, Boston, USA.
E-mail: niland@med.uni-frankfurt.de
Integrin  is a major collagen-binding receptor and widely distributed on different tissues. It plays
essential roles in elementary cell functions such as adhesion morphology, migration, proliferation,
gene activation, and differentiation. Therefore, it regulates various (patho)physiological situations,
such as thrombosis, tumor infiltration, and metastasis. It plays an essential role in liver micrometastasis formation.1
Integrin  recognizes triple-helical collagens, whose quaternary structure consists of three lefthanded polyproline-like chains supercoiled in a right-handed helix about a common axis, yielding a
characteristic triple helical coiled-coil, which provides the framework for the integrin 
recognition motif (GFOGER)3. Due to these structural requirements, chemical imitation of triplehelical  integrin recognition site is still a demanding feat. The aim of this study was to generate a
recombinant mini-collagen with a single binding site for integrin  and to use this collagenmimetic to characterize the role of integrin at both molecular and cellular level. Force
spectroscopy was used to determine at the molecular level the binding of integrin to its triplehelical recognition motif (GFPGER)3. To define and disclose the role of integrin in cell biology,
an integrin -specific and agonistic recombinant mini-collagen was used, as well as the snake
venom-derived highly specific integrin  antagonist rhodocetin.2
The strong binding of integrin to its ligand underlines its importance as cellular
mechanotransducer. On a substratum biofunctionalized with integrin binding mini-collagen FC3, cells
behave similar as on collagen I in terms of adhesion, spreading and migration. As recombinant minicollagen FC3 is unhydroxylated, and thus highly specific for integrin , this integrin is fully
sufficient to induce this behaviour, while the participation of other collagen receptors is at most
ancillary under this conditions.3
References
1. F. Rosenow, R. Ossig, D. Thormeyer, P. Gasmann, K. Schlüter, G. Brunner, J. Haier, J.A. Eble,
Neoplasia 2008, 10, 168-176.
2. J.A. Eble, S. Niland, T. Bracht, M. Mormann, J. Peter-Katalinic, G. Pohlentz, J. Stetefeld, FASEB J.
2009, 23, 2917-2927l.
3. S. Niland, C. Westerhausen, S.W. Schneider, M.F. Schneider, J.A. Eble, submitted to Biochem J.,
Bio-functionalization of a generic collagenous triple helix with the  integrin binding site allows
molecular force measurements.
33
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
OP-18
Organometallic Anticancer Drugs: From Simple Structures to Rational Drug
Design Based on a Mechanistic Approach
Paul J. Dyson
Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH
1015 Lausanne, Switzerland. E-mail: paul.dyson@epfl.ch
Organometallic chemistry has a strong tradition in the rational synthesis of compounds with
specific functions, whatever the nature of the required function. But how is rational synthesis
of organometallic pharmaceutical compounds currently achieved? The first part of the
presentation will discuss the relevant issues by considering examples from the literature as
well as from my own laboratory.1 The presentation then continue with a focus on
organometallic compounds based on the ruthenium(II)-arene unit developed in my laboratory
that exhibit excellent in vivo anticancer activity and overcome certain limitations of presently
used drugs.2 The elements of the drug design process and the relevant known drug targets will
be discussed. It will be shown that ligands with specific functions can be introduced into the
drug structure in order to endow the compound with specific properties allowing the metal to
perform a more classical role.
One of the overriding features of the compounds discussed during the presentation is that
targets other than DNA, i.e. enzyme and protein targets, are crucial for metal drugs, especially
for the ruthenium(II)-arene drugs emanating from my laboratory, and evidence to support this
notion will be provided.
References
1. C. G. Hartinger, P. J. Dyson, Chem. Soc. Rev., 2009, 38, 391–401.
2. W. H. Ang, L. J. Parker, A. De Luca, L. Juillerat-Jeanneret, C. J. Morton, M. Lo Bello, M. W.
Parker, P. J. Dyson, Angew. Chem. Int. Ed., 2009, 48, 3854–3857.
34
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
OP-19
Biological Activity of Gold and Silver Bis(Phosphino)Hydrazine Complexes
Frederik H. Kriel,*a and Judy Coatesa
a
AuTEK Biomed, Mintek, Private Bag X3015, Randburg, 2125, South Africa. E-mail:
erikk@mintek.co.za
The anti-tumour potential of gold(I) phosphine complexes was first identified at the time when
auranofin was shown to kill tumour cells in culture. This sparked the interest of Berners-Price et al.1,2
and led to the development of the bis-chelated gold(I) phosphine anti-tumour compound
[Au(bis(diphenylphospino) ethane)2]Cl and later [Au(bis(di-2-pyridalphosphino)ethane)2]Cl. Clinical
development of delocalised lipophilic cations has been hindered by severe toxicity, but several classes
of these compounds have demonstrated a relationship between anti-tumour selectivity and lipophilichydrophilic balance.1,2
Following on the work done by Berners-Price et al.; a series of hydrazine-bridged ligands have been
synthesised to modulate the lipophilic-hydrophilic balance of the resulting complexes.3,4 These include
the phenyl, p-methoxyphenyl and p-dimethylaminophenyl derivatives of the bis-phosphine. The main
focus of the research is on the group 11 transition metals and corresponding gold and silver phosphine
complexes. Here we describe the anti-tumour activity and NCI 60 cell line profile of these compounds.
Acknowledgements
The authors would like to thank the University of Pretoria for use of their facilities. Prof. Connie
Medlen, Dr. Gisella Joone and Mrs. Margo Nell for guidance. Prof. Denver Hendricks at the
University of Cape Town for reviewing the work. National Research Fund for the funding for training.
The NCI for the 60 cell line screen. AuTEK Biomed (Mintek and Harmony) for permission to publish
the results and financial support.
References
1 S. J. Berners-Price, Chem. Aust., 2004, 71, 10.
2 S. J. Berners-Price, P. J. Sadler, Struc. and Bond., 1988, 70, 27.
3 V. S. Reddy, K. V. Katti, Inorg. Chem., 1994, 33, 2695.
4 F. H. Kriel, M. Layh, H. M. Marques, J Coates, Ph.D. Thesis, University of the Witwatersrand,
2007.
35
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
OP-20
DNA and Protein Binding, Cleavage and Anticancer Activity of Organometallic
(M = Ru(II), Rh(III) and Ir(III)) Arene Complexes
R. Loganathan,a S. Ramakrishnan,a P. Kumar,c D. S. Pandey,c A. Riyasdeen,b
M. A. Akbarsha,b and Mallayan Palaniandavar*a
a
Centre for Bioinorganic Chemistry, School of Chemistry, bDepartment of Animal Science,
Bharathidasan University, Tiruchirapalli 620 024, India. cDepartment of Chemistry, Facult of
Science, Banaras Hindu University, Varanasi 221 005, India.
E-mail: palanim51@yahoo.com
The study of organometallic compounds as anticancer agents is receiving much attention now. These
compounds can be tuned by using suitable chelating ligands to facilitate their uptake into the cells or
for selectivity of reactions with DNA or proteins. However, the number of such studies is very limited.
This is because of the low solubility and instability in water and poor uptake by the cells. The
ruthenium complexes NAMI-A and KP1019, which show prominent anticancer activity, are currently
in clinical trials for the treatment of metastasis and colorectal cancers, respectively. Very recently, we
have shown that non-covalent interactions of certain water soluble Ru(II) complexes1,2 with DNA
enhances the cytotoxicity against several cancer cell lines. It is noteworthy that a family of
ruthenium(II)–arene complexes developed by Sadler, and Dyson et al. exhibits high in vitro and in
vivo anticancer activity. The titanocene dichloride has already completed phase II clinical trials and
ferrocifen, which is a ferrocenyl derivative of tamoxifen, appears set to enter clinical trials soon. More
recently, increasing interest has been focused on organometallic-arene compounds, which show
excellent antiproliferative properties in vitro and in vivo. In this work a series of water soluble
organometallic complexes of the type [{Ru(η6-arene)(L)Cl}](BF4)2 (arene = benzene; 1 and p-cymene;
2) and [{(η5- C10Me5)M(L)Cl}](BF4)2, (M = Rh; 3 and Ir; 4 and L = benzyl-di-pyridin-2-yl-amine) has
been isolated and the structures of 3 and 4 have been determined by X-ray crystallography. The
bidentate benzyl-di-pyridin-2-ylamine ligand is designed to provide hydrophobicity. Also, the present
compounds are equipped with a chloride leaving group in order to enable covalent interaction of the
complexes with biological targets. Further, the arene ligand provides hydrophobicity thus tuning the
DNA- and protein-binding and DNA- and protein-cleaving properties of the complexes. The
interactions of these metal complexes with CT DNA have been explored by using absorption,
emission and CD spectroscopy and electrochemical and viscosity measurements. DNA and protein
cleavage reactions have also been studied using agarose and polyacrylamide gel electrophoresis
respectively. The anticancer activities and the mode of cell death have also been established. The
results of our systematic investigations will be presented and discussed.
Cl
Cl
N2
N2
Ir
Rh
N3
N3
N1
N1
References
1. V. Rajendiran, M. Murali, E. Suresh, S. Sinha, K. Somasundaram, M. Palaniandavar Dalton Trans.
2008, 148-163.
2. V. Rajendiran, M. Murali, E. Suresh, M. Palaniandavar, V.S. Periasamy, M.A. Akbarsha
Dalton Trans. 2008, 2157-2170.
36
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
OP-21
Organometallic Pyrone and Pyridone Complexes as Anticancer Agents
Christian G. Hartinger,*a Wolfgang Kandioller,a Muhammad Hanif,a Andrea Kurzwernhart,a
Helena Henke,a Robert Trondl,a Caroline Bartel,a Gerhard Mühlgassner,a Michael A. Jakupec,a
Maria G. Mendoza-Ferri,a Alexey A. Nazarov,a,b Bernhard K. Kepplera
a
University of Vienna, Institute of Inorganic Chemistry, Waehringer Str. 42, A-1090, Vienna, Austria.
Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne (EPFL),
CH-1015 Lausanne, Switzerland. E-mail: christian.hartinger@univie.ac.at
b
Organometallic compounds have received growing interest as potential chemotherapeutics for the
treatment of cancer. Ru(II) compounds bearing ligands such as 1,3,5-triaza-7-phosphaadamantane,
ethylene-1,2-diamine or maltol-derived ligands have shown promising anticancer properties with in
vitro or in vivo anticancer activity comparable to or in some cases superior to cisplatin.1 Some of the
compounds are even active in cisplatin-resistant cell lines, probably due to different modes of action,
and potentially provide a means to overcome drug resistance.2
Organometallic Ru–arene compounds bearing a maltol ligand were shown to be nearly inactive in
vitro.3 In order to study their biological properties, compounds with different substitution pattern [e.g.
3-hydroxy-2-pyr(id)one vs. 3-hydroxy-4-pyr(id)one] of the pyrone-derived ligands were prepared, or
an oxygen donor of the chelating moiety was replaced by sulphur. Furthermore, polynuclear
compounds were obtained by linking pyridone moieties via aliphatic chains. The chemical properties
of the obtained compounds are very different from that of the parent maltolato complex with regard to
stability in aqueous solution, lipophilicity and, depending on the metal centre, reactivity with
biomolecules. For example, reactions with amino acids demonstrate higher stability of thiopyrone than
of pyrone complexes, which may explain their activity against human tumour cells. In general, the
compounds show affinity to nucleobases, but the polynuclear compounds form extremely rare types of
DNA and protein adducts and are efficient cross-linkers.4 Anticancer potencies of the arene complexes
are as divergent as their chemical behaviour, from compounds active in the low μM range to inactive
compounds. Based on the chemical and biological data, structure-activity relationships have been
elucidated, and further directions of development will be discussed.
References
1. G. Süss-Fink, Dalton Transactions 2010, 1673-1688.
2. (a) W. H Ang, P. J. Dyson, Eur. J. Inorg. Chem. 2006, 4003-4018. (b) A. F. A. Peacock, P. J.
Sadler, Chem. Asian J. 2008, 3, 1890-1899.
3. A. F. A. Peacock, M. Melchart, R. J. Deeth, A. Habtemariam, S. Parsons, P. J. Sadler, Chem. Eur. J.
2007, 13, 2601-2613.
4. O. Nováková, A. A. Nazarov, C. G. Hartinger, B. K. Keppler, V. Brabec, Biochem. Pharmacol.
2009, 77, 364-374.
37
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
OP-22
Metalloenzymes in the bacterial life on carbon monoxide:
A view from structural biology
Holger Dobbek,* and Jae-Hun Jeoung
Humboldt-Universität zu Berlin, Institute of Biology, Structural Biology/Biochemistry, Unter den
Linden 6, 10099, Berlin, Germany. E-mail: holger.dobbek@biologie.hu-berlin.de
The biological conversions of small substrates like N2, H2, and CO2 are vital for the biogeochemical
cycle and are typically catalyzed by metalloenzymes with complex iron-sulfur clusters. However, only
little is known about how these metalloclusters activate their substrates.
Carbon monoxide dehydrogenases (CODHases) catalyze the reversible oxidation of carbon monoxide
with water, to carbon dioxide, two protons and two electrons. Two principal types of CODHases have
been described, which differ in activity, metal composition, amino acid sequence and stability in the
presence of oxygen. The Ni, Fe-containing CODHases found in anaerobic microorganisms have a
unique Ni- and Fe-containing metal cluster called cluster C.1 A Cu- and Mo-containing metal site is
found in CODHases isolated from aerobic microorganisms.1
We used a crystallographic approach to gain further insights into the reaction mechanism of Ni, FeCODHases. Structural analysis of CODHII from Carboxydothermus hydrogenoformans in several
different states showed how substrates are activated by cluster C.2 Water is bound by an
asymmetrically coordinated Fe(II)-ion and carbon dioxide has been shown to act as a bridging ligand
between Ni and the Fe(II)-ion. Amino acids in the direct vicinity of the cluster may contribute to
catalysis by fast proton transfers and the stabilization of negatively charged intermediates. We further
tested the reactivity of cluster C with inhibitors3 and slow substrates, whose binding mode was
resolved at atomic resolution. The structural analysis of ligand binding to cluster C presents a
complementary approach to spectroscopic methods describing the electronic changes of cluster C
during catalysis. Both approaches converge to a mechanism in which substrate activation and catalysis
is mediated by a binuclear Ni-Fe sub site of cluster C.
References
1. S. W. Ragsdale, Crit. Rev. Biochem. Mol. Biol. 2004, 39, 165-195.
2. J.-H. Jeoung, H. Dobbek, Science 2007, 318, 1461-1464.
3. J.-H. Jeoung, H. Dobbek, J. Am. Chem. Soc. 2009, 131, 9922-9923.
38
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
OP-23
Models for the Active Site in [FeFe] Hydrogenase with Silicon-containing Ligands
Ulf-Peter Apfel,a Dennis Troegel,b Yvonne Halpin,c Stefanie Tschierlei,d Ute Uhlemann,d Helmar Görls,a
Michael Schmitt,d Jürgen Popp,d P. Dunne,e M. Venkatesan,e Michael Coey,e,* Manfred Rudolph,a,*
Johannes G. Vos,c,* Reinhold Tacke,b,* Wolfgang Weiganda,*
a
Institut für Anorganische und Analytische Chemie, Friedrich-Schiller-Universität Jena, August-BebelStraße 2, D-07743 Jena, Germany,wolfgang.weigand@uni-jena.de. b Institut für Anorganische Chemie,
Universität Würzburg, Am Hubland, D-97074 Würzburg, Germany. c Solar Energy Conversion SRC,
School of Chemical Sciences, Dublin City University, Dublin 9, Ireland. d Institut für Physikalische
Chemie, Friedrich-Schiller-Universität Jena, Helmholtzweg 4, D-07743 Jena, Germany. e SFI-Trinity
Nanoscience Laboratory, Physics Department, Trinity College, Dublin 2, Ireland.
A series of multifunctional (mercaptomethyl)silanes of the general formula type RnSi(CH2SH)4−n (n = 0–2;
R = organyl) was synthesized, starting from the corresponding (chloromethyl)silanes. They were used as
multidentate ligands for the conversion of dodecacarbonyltriiron, Fe3(CO)12, into iron carbonyl complexes
in which the deprotonated (mercaptomethyl)silanes act as m-bridging ligands. These complexes can be
regarded as models for the [FeFe] hydrogenase. They were characterized by elemental analyses (C, H, S),
NMR studies (1H, 13C, 29Si), and single-crystal X-ray diffraction. Their electrochemical properties were
investigated by cyclic voltammetry to disclose a new mechanism for the formation of dihydrogen
catalyzed by these compounds, whereby one sulfur atom was protonated in the catalytic cycle. The
reaction of the tridentate ligand MeSi(CH2SH)3 with Fe3(CO)12 yielded a tetranuclear cluster compound. A
detailed investigation by X-ray diffraction, electrochemical, Raman, Mössbauer, and susceptibility
techniques indicates that for this compound initially a [Fe2{MeSi(CH2S)2CH2SH}(CO)6] is formed. This
dinuclear
complex
is
however
slowly
transformed
into
the
tetranuclear
species
[Fe4{MeSi(CH2S)3}2(CO)8].
39
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
OP-24
DNA-Organometallic Hybrid Catalysts
Andres Jäschke,* Pierre Fournier,a Michaela Caprioara,a and Matthias Höhnea
a
Heidelberg University, Institute of Pharmacy and Molecular Biotechnology, Im Neuenheimer Feld
364, 69120 Heidelberg, Germany. E-mail: jaeschke@uni-hd.de
Hybrid catalysis combines homogeneous chemical catalysts with biopolymers to develop selective
catalysts for organic reactions. While proteins have been used as hosts for various transition metal
complexes,1 only few published examples are based on nucleic acids.2 In these reports high
stereoselectivities were obtained in Diels-Alder reactions, Michael additions and fluorinations, with
DNA as sole source of chirality, but all these systems relied on Lewis acid catalysis by CuII ions. Our
goal is the application of DNA-conjugated transition metal complexes in organometallic catalysis, as
this kind of catalysis is widespread among synthetically useful reactions.
We recently presented DNA-based systems that use IrI-diene chemistry to catalyze an allylic
substitution in aqueous medium.3 Towards this end, we covalently attach transition metal ligands, like
phosphinoxazoline and diene ligands, to specific positions of oligonucleotides.4
Our approach is based on a modular design where a 19mer oligodeoxynucleotide carrying a transition
metal ligand is combined with different DNA or RNA counterstrands, thereby forming perfect and
imperfect duplexes that provide subtle changes in the environment of the metal center. The covalent
attachment of the ligand guarantees its specific, reproducible positioning on nucleic acid structures.
We demonstrate that catalysis occurs in the presence of DNA and its numerous functional groups, and
that the structure of the DNA modulates the stereochemical outcome of the reaction.3
Recent work will be presented on the extension of our approach to other reactions, metals, and ligands,
and about rational and combinatorial strategies for improvement of performance and stereoselectivity.
Iridium(I)-catalyzed allylic amination using DNA-based ligands
References
1. (a) J. Steinreiber, T. R. Ward, Coord. Chem. Rev. 2008, 252, 751. (b) M. E. Wilson, G. M.
Whitesides, J. Am. Chem. Soc. 1978, 100, 306. (c) M. T. Reetz, M. Rentzsch, A. Pletsch, M. Maywald,
P. Maiwald, J. J. P. Peyralans, A. Maichele, Y. Fu, N. Jiao, F. Hollmann, R. Mondiere, A. Taglieber,
Tetrahedron 2007, 63, 6404. (d) A. Pordea, M. Creus, J. Panek, C. Duboc, D. Mathis, M. Novic, T. R.
Ward, J. Am. Chem. Soc. 2008, 130, 8085.
2. (a) G. Roelfes, B. L. Feringa, Angew. Chem. Int. Ed. 2005, 44, 3230. (b) N. S. Oltra, G. Roelfes,
Chem. Comm. 2008, 6039. (c) D. Coquière, Ben L. Feringa, G. Roelfes, Angew. Chem. Int. Ed. 2007,
46, 9308. (d) N. Shibata, H. Yasui, S. Nakamura, T. Toru, Synlett 2007, 1153.
3. P. Fournier, R. Fiammengo, A. Jäschke, Angew. Chem. Int. Ed. 2009, 48, 4226.
4. M. Caprioara, R. Fiammengo, M. Engeser, A. Jäschke, Chem. Eur. J. 2007, 13, 2089.
40
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
OP-25
Construction of Organometalloenzymes
Yoshihito Watanabea
a
Nagoya University, Graduate School of Science, Department of Chemistry, Chikusa, 464-8602,
Nagoya, Japan. E-mail: yoshi@nucc.cc.nagoya-u.ac.jp
A variety of protein structures are employed in nature as frameworks for the deposition of metal
cofactors to provide metalloenzymes. Very recently, we have designed a myoglobin mutant as a
model for a substrate bound form of cytochrome P450 and site
specific aromatic hydroxylation was found to proceed by a
stochiometric amount of H2O2 in a few seconds.1 As an
extension of our efforts for the construction of
organometalloproteins, we have replaced the heme prosthetic
group with a series of M(salophen) complexes, Rh(Phebox) (Fig
1), and Cu complexes.2 Instead of these small protein cavities,
we have also employed a protein having a large cavity, i.e., apoferritin (apo-Fr). Ferritin is an iron storage protein and its apoFig.1 Apo-Mb•Rh(Phebox) composite
form has been employed as nano-reactors. We have also structure.
prepared a zero-valent palladium cluster by chemical reduction
of palladium ions in the apo-ferritin cage and examined its catalytic hydrogenation activity. The
palladium clusters catalyzes size-selective olefin hydrogenation because substrates must penetrate into
the ferritin cavity through the size restricted channels.3 Through the Pd•apo-Feritin study, we have
found that there are Pd ion binding sites in the apo-ferritin to capture as many as 300 Pd ions. Thus,
we have examined crystal structures of apo-ferritin containing various amounts of Pd ions. The crystal
structures of Pd•apo-Fr has been refined to 1.65Å resolution (Fig 2).4 We have further found that
PdII(allyl) ion utilizes
different binding sites
bearing
different
coordination
structures
(Fig 3). The Pd(allyl)•
apo-Fr composites show
catalytic activities for the
Fig.3 The crystal structure of apo-Fr•Pd(allyl).
Suzuki coupling reaction Fig.2 The crystal structure of apo-Fr•Pd.
as shown below.5
References
1) T. D. Pfister, et al., J. Biol. Chem. 280, 12858 (2005). 2) M. Koshiyama, et al., J. Am. Chem. Soc.
127, 6556 (2005). 3) M. Suzuki, et al., Angew. Chem. Int. Ed. 43, 2527 (2004). 4) T. Ueno, et al., J.
Am. Chem. Soc. 131, 2094 (2009). 5) T. Ueno, et al., J. Am. Chem. Soc. 130, 10512 (2008).
41
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
OP-26
CO Releasing Properties of cis-trans-[ReII(CO)2Br2L2]n Complexes: A Feature
Modulated by Ligand Variation for a True Chance at Medicinal Applications.
Fabio Zobi*a and Alois Degondaa
a University of Zürich, Institute of Inorganic Chemistry, Winterthurerstr. 190, CH-8057, Zürich,
Switzerland. E-mail: fzobi@aci.uzh.ch
In recent years carbon monoxide (CO) has been acknowledged as a fundamental small-molecule
messenger in humans.1 The tissue specific distribution of heme oxigenases and their action-derived
CO have been linked to several effects. For example, carbon monoxide acts as a signaling molecule in
the inducible defensive system against stressful stimuli.1 It plays a fundamental role in the circulatory
system by improving vasorelaxation and cardiac blood supply and it suppresses arteriosclerotic lesions
associated with chronic graft rejection.1,2 As the importance of CO is been increasingly recognized,
there is a steadily growing interest in the in pharmacological and medicinal applications of CO. Direct
inhalation of carbon monoxide has been viewed as a novel therapeutic approach but reports on
tolerance to CO exposure are contradictory.
An alternative approach to the administration of carbon monoxide is the use of CO-releasing
molecules (CORMs). An obvious choice for CORMs are transition metal carbonyl complexes with
one or more CO ligands. Several complexes have been evaluated to date, but the pioneering work of
Motterlini and Mann has resulted in the discovery of the fac-[RuCl(glycinato)(CO)3] complex
(CORM-3) as the most promising compound for the CO release in vivo.3
In here we show that complexes of the type cis-trans-[ReII(CO)2Br2L2]n (where L = monodentate
ligand)4 act as CO-releasing molecules and that under physiologically relevant conditions the rate of
CO release is comparable to that of CORM-3. The complexes represent a first example of metal-based
CORMs in which the central metal ion is not found in a d6 or d8 configuration. The open shell d5
configuration of the Re system herein described represents an advantage over the more robust d6 or d8
systems for which physical stimuli (e.g. UV radiation) are often needed in order to elicit dissociation
of carbon monoxide from the metal core. The rate of CO release of cis-trans-[ReII(CO)2Br2L2]n
complexes is pH dependent and can be modulated by ligand variation. These features offer a true
chance for the application of these molecules in medicinal chemistry.
References
1. Wu, L.; Wang, R., Pharmacol. Rev. 2005, 57, 585-630.
2. Otterbein, L. E.; Zuckerbraun, B. S.; Haga, M.; Liu, F.; Song, R. P.; Usheva, A.; Stachulak, C.;
Bodyak, N.; Smith, R. N.; Csizmadia, E.; Tyagi, S.; Akamatsu, Y.; Flavell, R. J.; Billiar, T. R.; Tzeng,
E.; Bach, F. H.; Choi, A. M. K.; Soares, M. P., Nature Med. 2003, 9, 183-190.
3. Foresti, R.; Bani-Hani, M. G.; Motterlini, R., Intensive Care Med. 2008, 34, 649-658.
4. Zobi, F.; Kromer, L.; Spingler, B.; Alberto, R., Inorg. Chem. 2009, 48, 8965-8970.
42
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
OP-27
Nitric Oxide Synthase Targeting with 99mTc(I)/Re(I) Complexes
João D. G. Correia,*a Bruno L. Oliveira,a Filipa Mendes,a Paula D. Raposinho,a Isabel Santos,a
António Ferreira,b Carlos Cordeiro,b Ana P. Freireb
a ITN, Unidade de Ciências Químicas e Radiofarmacêuticas, Estrada Nacional 10, 2686-953
Sacavém, Portugal. b Universidade de Lisboa, Faculdade de Ciências, Departamento de Química e
Bioquímica, Lisbon, Portugal. E-mail: jgalamba@itn.pt
Nitric oxide (NO), a key signaling mammalian mediator in several physiophatolological processes, is
biosynthesized in vivo by oxidation of L-arginine to L-citrulline catalalyzed by Nitric Oxide Synthase
(NOS).1 This enzyme has two constitutive isoforms (neuronal, nNOS; endothelial, eNOS) and one
inducible isoform (iNOS). Noninvasive imaging of NOS expression in vivo by nuclear techniques,
namely by Single Photon Emission Tomography (SPECT) or Positron Emission Tomography (PET),
holds great potential for providing new insights in understanding NO/NOS-related diseases, and may
facilitate the development of novel therapeutic approaches.2,3 Aiming to find 99mTc(CO)3-based tracers
for probing NOS levels in vivo, we will report on the synthesis and characterization of novel
Re(I)/99mTc(I) organometallic complexes containing pendant bioactive units for recognition of NOS
active site.4 The enzymatic studies with isolated murine iNOS have shown that some Re(I) compounds
could inhibit the enzyme, being the first examples of organometallic complexes able to inhibit NOS.
Such effect was also observed in LPS-stimulated murine macrophages. Interestingly, a few complexes
could also be used as NOS substrates by the same cell model. The biological assessment of the 99mTccomplexes in different cell lines and in mice will also be presented.
References
1. S. Moncada, R. M. J. Palmer, E. A. Higgs, Pharmacol. Rev. 1991, 43, 109-142.
2. D. Zhou, H. Lee, J. M. Rothfuss, D. L. Chen, D. E. Ponde, M. J. Welch,R. H. Mach, J. Med.
Chem.2009, 52, 2443–2453.
3. H. Hong, J. Sun, W. Cai, Free Radic. Biol. Med. 2009, 47, 684–698.
4. B. L. Oliveira, J. D. G. Correia, P. D. Raposinho, I. Santos, A. Ferreira, C. Cordeiro, A. P. Freire,
Dalton Trans. 2009, 1, 152-162.
Acknowledgements
We thank the Fundação para a Ciência e Tecnologia (FCT) for financial support (POCI/SAUFCF/58855/2004). Mallinkrodt-Tyco Inc. is acknowledged for providing the IsoLink® kits. B. L. O.
thanks FCT for a BD grant (SFRH/BD/38753/2007). J. Marçalo is acknowledged for the ESI-MS
analyses, which were run on a QITMS instrument (FCT Contract REDE/1503/REM/2005 - ITN).
43
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
OP-28
Mechanistic and Synthetic Studies of Bio-compatible
Carbon Monoxide-Releasing Molecules
Anthony J. Atkin,a Ian J. S. Fairlamb,a Jason M. Lynam,*a and Wei-Qiang Zhanga
Department of Chemistry, University of York, Heslington, York, YO10 5DD, UK
E-mail: jml12@york.ac.uk
Carbon monoxide – releasing molecules (CO-RMs) have become an exciting target for therapeutic
intervention.1 CO generated in mammals is responsible for a variety of important physiological
functions and is a fundamental signalling mediator. CO gas also elicits a range of beneficial
therapeutic effects, although the associated toxicity and inherent poor selectivity of CO in its naked
form is clearly not ideal. The method of choice for taking advantage of the beneficial role of CO is to
utilise a CO-RM, such as a metal carbonyl complex, which act as a source of CO in biological
systems.
Although the biological effects of CO (and CO-RMs) are now well established, there is little
understanding of the precise requirements needed for transition metal carbonyl compounds to act as
effective therapeutic agents. We have therefore undertaken a systematic study in order to elucidate the
factors that may control CO-release.2 This has allowed us to determine which metal-carbonyl scaffolds
have the greatest potential to act as CO-RMs which has in turn informed a synthetic programme
designed to prepare a library of novel complexes with bio-compatible ligands. For example, we have
prepared a range of Group 6 compounds which contain both natural and non-natural amino acids
incorporated into the coordination sphere of the metal through a range of binding modes (Figure 1).
This presentation will detail the key results from the findings of our synthetic and mechanistic studies
into the CO-release process, as well as the behaviour of the new bio-compatible CO-RMs. For
example, we have demonstrated how the CO-release behaviour of the amino ester derivatives 1 may
be simply modulated by the choice of the substituent on the organic ligand. A mechanistic study has
demonstrated that this process is controlled by loss of the amino ester and therefore supply of the
“M(CO)5” (M = Cr, Mo, W) fragment is crucial to CO-release in aqueous systems. For the CO-RMs
with structure 2 the rate of CO-release correlates with the electrophilicity of the carbene carbon,
consistent with a mechanism in which nucleophilic attack of water initiates the CO-release process.
The scope of biologically-relevant ligands which can be introduced into the coordination sphere of the
metal will also be detailed.
References
1. (a) T. T. Johnson, B. E. Mann, J. E. Clark, R. Foresti, C. J. Green, R. Motterlini, R. Angew. Chem.
Int. Ed. 2003, 42, 3722-3729. (b) I. J. S. Fairlamb, A.-K. Duhme-Klair, J. M. Lynam, B. E. Moulton,
C. T. O’Brien, P. Sawle, J. Hammad, R. Motterlini, Bioorg. & Med. Chem. Lett. 2006, 16, 995-998.
(c) P. Sawle, J. Hammad, I. J. S. Fairlamb, B. E. Moulton, C. T. O'Brien, J. M. Lynam, A.-K. DuhmeKlair, R. Foresti, R. Motterlini, J. Pharmacol. Exp. Ther. 2006, 318, 403-410. (d) I. J. S. Fairlamb, J.
M. Lynam, B. E. Moulton, I. E. Taylor, A. K. Duhme-Klair, P. Sawle, R. Motterlini, Dalton Trans.
2007, 3603-3605.
2. W.-Q. Zhang, A. J. Atkin, R. J. Thatcher, A. C. Whitwood, I. J. S. Fairlamb, J. M. Lynam, Dalton
Trans. 2009, 4351-4358.
44
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
OP-29
Peptide-carbenes and peptide-phosphines transition metal catalysts for “Green”
solid phase catalysts.
Morten Meldal,*a Kasper Worm-Leonhard,a and Christian A. Christensena
a
Carlsberg Laboratory, SPOCC-Centre, Gamle Carlsberg Vej 10, 2500 Valby, Denmark,
E-mail: mpm@crc.dk
In Nature metalloproteins play a crucial role in complex biochemical transformations while displaying
exquisite regio- and enantio-selectivity. More importantly the protein framework coordinates the
catalytic metal and ensure substrate match and lower activation energy of the reaction to provide very
high turnovers, which in turn facilitates the efficient biochemical transformation at low concentration
of the catalytic protein.
These properties can advantageously be mimicked in the field peptide and peptide-organic chemistry
to putatively create catalysts for “green” chemistry. By engineering the peptide scaffold with one or
several ideal ligands for a variety of transition metals, e. g. Pd, Zn or Cu. artificial enzyme like
compounds, displaying selectivity and turnover for general organic chemistry transformations may be
obtained.
This presentation describes the synthesis and application of carbene- and phosphine-precursors for
incorporation into peptide frameworks that folds around a transition metal and forms relatively
compact and stable globular structures with an enzyme like binding cavity for substrate binding and
catalysis. The strategy is modular and well suited for a Split/Mix approach where a large number of
catalysts may be generated in a single combinatorial synthesis.
Backbone phosphinylated peptides (1) were synthesized on polar PEGA supports and in solution and
the catalytic activity was compared. The solid supported catalysts were very efficient and could be
recycled at least 5 times without loss of activity. The palladium coordination of the phosphine could
furthermore be combined with folding and complexation with other dedicated functional groups in the
peptide.
Backbone carbenes (2) formed extremely stable palladium-peptido carbene complexes that did not
loose any activity with time or use. These solid phase catalysts could be used in microwave assisted CC and C-N couplings in water with good selectivities and quantitative yields.
References
1.
2.
(a) C. A. Christensen and M. Meldal. Efficient Solid-Phase Synthesis of Peptide Based
Phosphine Ligands: Towards Combinatorial Libraries of Selective Transition Metal Catalysts.
Chem. Eur. J. 2004, 11, 4121-4131; (b) C. A. Christensen and M. Meldal. Solid-phase
synthesis of a P,S-ligand system designed for generation of combinatorial peptide-based
catalyst libraries. J. Comb. Chem. 2007, 9, 79-85.
(a) J. F. Jensen, K. Worm-Leonhard, and M. Meldal. Optically active (peptido-carbene)
palladium complexes: towards true combinatorial solid phase libraries of transition metal
catalysts. Eur. J. Org. Chem. 2008, 3785-3797 (b) K. Worm-Leonhard and M. Meldal. Green
catalysts: Solid-phase peptide carbene ligands in aqueous transition metal catalysis. Eur. J. Org.
Chem. 2008, 5244-5253.
45
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
OP-30
Construction of an Immunosensor via Copper-Free ‘Click’ Reaction Between
Azido SAMs and Alkynyl Fischer Carbene Complex. Application to the detection
of Staphyloccal Enterotoxin A
Pratima Srivastava,a Amitabha Sarkar,b Sudeshna Sawoo,b Amarnath Chakraborty,b Pinak Dutta,b
Othman Bouloussa,c Claire-Marie Pradier;d Souhir Boujday,d and Michelle Salmain*a
a
Ecole Nationale Supérieure de Chimie de Paris, Laboratoire Charles Friedel (UMR CNRS 7223),
11, rue Pierre et Marie Curie, 75231 Paris cedex 05, France. b Indian Association for the Cultivation
of Sciences, Department of Organic Chemistry, 700032, Kolkata, India. c Institut Curie, laboratoire
Physico-chimie Curie (UMR CNRS 168), 26 rue d’Ulm, 75248, Paris , cedex 05, France. d Université
Pierre et Marie Curie, Laboratoire de réactivité de surface (UMR CNRS 7197), 4 place Jussieu,
75252, Paris cedex 05, France. E-mail: pratima-srivastava@chimie-paristech.fr
Keywords: Immunosensor, IRRAS, ‘click’ reaction, Fischer carbene, antibody-antigen reaction.
A copper-free « click » reaction between azido-terminated self-assembled monolayers (SAMs) on gold
and an alkynyl Fischer carbene complex yielded functionalized surfaces on which facile and swift
grafting of amine-containing molecules was achieved via aminolysis of the Fischer carbene moieties
(Figure).1
W(CO)5
MeO
Ph
Au S
N3
+
Au S
N
N N
NH
(OC)5W
NH2
Au S
Ph
N
N N
W(CO)5
OMe
This 3-step process could be conveniently monitored by Infrared Reflection-Absorption Spectroscopy
(IRRAS). An extensive study of the different parameters involved in the covalent grafting of proteins
on the Fischer carbene modified SAMs was carried out. As an application, an antibody against
Staphylococcal Enterotoxin A (SEA) was immobilized onto gold chips so as to ultimately construct an
optical immunosensor for the detection of this toxin in food samples.
References
1. S. Sawoo, P. Dutta, A. Chakraborty, R. Mukhopadhyay, O. Bouloussa, A. Sarkar, Chem. Commun.
2008, 5957-5959.
46
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
OP-31
Polypeptides Induced Self-Association and Emission Properties of
Platinum(II) and Gold(I) Complexes
Toshiyuki Moriuchi,*a Masahiro Yamada,a Kazuki Yoshii,a and Toshikazu Hiraoa
a
Department of Applied Chemistry, Graduate School of Engineering, Osaka University,
Yamada-oka, Suita, Osaka 565-0871, Japan. E-mail: moriuchi@chem.eng.osaka-u.ac.jp
Highly-ordered molecular assemblies are constructed in bio-systems to fulfill unique functions as
observed in enzymes, receptors, etc. Introduction of functional complexes into highly-ordered
biomolecules is considered to be a convenient approach to novel biomaterials, bio-inspired systems,
etc. Recently, the field of bioorganometallic chemistry has drawn great attention and undergone rapid
development. Conjuction of organometallic compounds with biomolecules such as peptides and
nucleobases is envisioned to afford such bioconjugates. The non-covalent bond is a powerful tool in
the construction of architectural molecular assemblies. We have already demonstrated the chirality
organization of ferrocene-peptide bioconjugates to induce highly-ordered molecular assemblies.1
Poly-L-glutamic acid (P(Glu)) is known to exist in a -helix form at around pH 4.3. The carboxyl
groups of side chains are expected to assemble cationic metal complexes along the exterior of poly-Lglutamic acid through the electrostatic interactions. On the other hand, poly-L-Lysine (P(Lys)) exists
as a random coil conformation at a neutral pH due to repulsion between positively charged side chains,
and an -helical conformation at above pH 10.6 due to the reduced charge on the side chains at a pH
above the pKa (10.5). P(Lys) bearing multiple positively charged side chains is envisioned to serve as a
polymeric spatially aligned scaffold for the aggregation of negatively charged metal complexes. From
these points of view, we embarked upon the assembling and self-association of luminescent metal
complexes spatially along the cationic or anionic polypeptides to form the luminescent aggregates.
The
cationic
organoplatinum(II)
complexes
[Pt(trpy)C≡CR]+ (trpy = 2,2',6',2''-terpyridine; R = Ph
M
M
(PtH), PhC12H25 (PtC12)) were introduced into the anionic
M
M
M
poly-L-glutamic acid (P(Glu)) through electrostatic
interactions. An emission based on metal-metal-to-ligand
M
charge transfer (MMLCT) transition was observed in the
M
M
M
case of P(Glu)-PtC12. However, such synergistic effect
M
was not observed in the case of P(Glu)-PtH. Poly-Lglutamic acid was found to serve as an efficient molecular scaffold, wherein the platinum(II)
complexes might be accommodated.
The assembling and self-association of anionic dicyanoaurate(I), [Au(CN)2], spatially around the
cationic poly-L-Lysine (P(Lys)) through electrostatic interactions was also demonstrated to form the
luminescent [Au(CN)2] aggregates.
References
1. (a) Chem. Commun. 1998, 1963. (b) J. Organomet. Chem. 1999, 589, 50. (c) J. Am. Chem. Soc.
2001, 123, 68. (d) Organometallics 2001, 20, 1008. (e) Organometallics 2001, 20, 3101. (f) J.
Organomet. Chem. 2001, 637-639, 75. (g) Org. Lett. 2003, 5, 4285. (h) Org. Lett. 2005, 7, 5265. (i)
Org. Lett. 2006, 8, 31-34. (j) Dalton Trans. 2009, 4286.
47
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
OP-32
Homogeneous and Bio-Catalysis in Concert:
Hybrids of ECE-pincer Organometallics and Lipases
Gerard van Koten*a
a
Organic Chemistry and Catalysis, Faculty of Science, Utrecht University, The Netherlands
g.vankoten@uu.nl
Bis-ortho-chelated aryl-metal complexes, the socalled ECE-pincer metal complexes, exist in great
varieties. Several novel strategies for anchoring these ECE-pincer metal complexes to soluble and
insoluble supports have been developed. Novel synthetic routes have been developed for the direct
introduction of functional para-substituents onto the pre-formed ECE-pincer metal complexes.1 This
allows, for example the introduction of anionic tethers which can non-covalently bind the ECE-pincer
metal complex to the core of multicationic core-shell dendrimers.
Recently, we concentrated on the covalent anchoring of ECE-pincer metal complexes to proteins.2
This approach, involving the inhibitory activity of nitrophenyl phosphonate esters to the catalytic triad
(serine, histidine and asparagine) of lipases, has great potential for future applications in the fields of
protein structure elucidation (NMR, X-Ray, mass spectrometry), medicinal chemistry (biomarkers,
MRI contrast agents, radiopharmaceuticals), biomaterials and catalysis (enantioselectivity, catalysis in
aqueous media). Crystal structures of these novel ECE-pincer metal-lipase hybrids show in detail how
the ECE-pincer metal unit is covalently attached to the enzyme.3 The photophysical (biomarker),
coordinative and catalytic (dynamic kinetic resolution) properties of these and related rutheniumlipase hybrid materials will be discussed.
Fig 1. Structure in the solid state of the NCN-pincer platinum bromide-cutinase hybrid.
References
1. M.Gagliardo, D.J.M. Snelders et al., Angew. Chem. 2007, 46, 8558.
2. C.A. Kruithof et al., Chem. Eur. J. 2005, 11, 6869.
3. B. Wieczorek et al., Chem. Eur. J. 2009, 15, 4270.
48
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
OP-33
Chemo-Genetic Optimization of DNA Recognition by Metallodrugs using a
Presenter Protein Strategy
Jeremy M. Zimbron,a A. Sardo,a T. Heinisch,a,b T. Wohlschlager,c J. Gradinaru,d C. Massa,b
T. Schirmer,*b Marc Creus,*a and Thomas R. Ward*a
a
University of Basel, Department of Chemistry, Spitalstrasse 51, Basel 4056, Switzerland, bUniversity
of Basel, Biozentrum, Klingelbergstrasse 50/70, Basel 4056, Switzerland, cUniversity of Neuchâtel,
Institute of Chemistry, Avenue de Bellevaux 51, Neuchâtel 2009, Switzerland
DNA is a privileged target of anticancer metallodrugs like cisplatin. However, such drugs often suffer
from high toxicity and drug-resistance due to non-selective binding to other than oncogenic DNA.1
To increase selectivity of small molecule drugs for macromolecular targets, “surface borrowing” can
be used to provide additional surface contacts via a presenter protein, which modulates the specificity
and affinity of ligand–macromolecule interaction.2 The use of bifunctional molecules based on biotinstreptavidin technology has been used for targeting RNA, in which a contribution for protein contacts
to the anti-tobramycin RNA aptamer was suggested.3 Inspired by these presenter protein strategies and
our previous experience of enantioselective artificial metalloenzymes,4 we synthesized a biotinylated
metallodrug (compound 1, Fig.1) inspired on promising anticancer Ru(II) piano-stool complexes,4 for
incorporation into streptavidin (Sav).
Here we shown that a supramolecular assembly of a drug with a presenter protein can modulate
selectivity through provision of additional non-covalent interactions with the target that are not
typically available to small molecule drugs, thus allowing selectivity toward macromolecules such as
DNA telomeres.
Fig.1 Presenter protein strategy for targeting telomeric DNA with ruthenium metallodrugs.
References
1. L. Kelland, Nat. Rev. Cancer 2007, 7, 573.
2. R. Briesewitz, G. T. Ray, T. J. Wandless, G. R. Crabtree, Proc. Natl. Acad. Sci. U. S. A. 1999, 96,
1953.
3. I. Harvey, P. Garneau, J. Pelletier, Proc. Natl. Acad. Sci. U. S. A. 2002, 99, 1882.
4. M. Creus, A. Pordea, T. Rossel, A. Sardo, C. Letondor, A. Ivanova, I. Letrong, R. E. Stenkamp, T.
R. Ward, Angew. Chem. Int. Ed. 2008, 47, 1400.
5. P. C. Bruijnincx, P. J. Sadler, Curr. Opin. Chem. Biol. 2008, 12, 197.
49
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
OP-34
RAPTA-T interacts with 11 integrin at the molecular level
Alletta Schmidt-Hederich,a Michael Grössl,c Alessia Masi,b Alberta Bergamo,b Gianni Sava,b Paul J.
Dyson,c and Johannes A. Eble*a
a
Goethe University of Frankfurt, Faculty of Medicine, Center for Molecular Medicine, Vascular
Matrix Biology, Excellence Cluster CardioPulmonary System, Theodor-Stern-Kai 7, 60590
Frankfurt/Main, Germany. b Callerio Foundation, Via Fleming 31, 34127 Trieste, Italy. c Ècole
Polytechnique Fedèrale de Lausanne, Department of Chemistry and Chemical Engineering, 1015
Lausanne, Switzerland. E-mail: Eble@med.uni-frankfurt.de
Metal-based compounds, such as cisplatin and ruthenium complexes have been used as cytostatic
drugs in cancer treatment. These compounds are generally thought to target DNA and hence interfere
with the growth of highly proliferative tumor cells. However, recent experiments have suggested that
ruthenium compounds, such as RAPTA-T, additionally affect cellular interactions with the
extracellular matrix (ECM). Among cell adhesion molecules, integrins form a numerous and most
versatile family. They bind to ECM proteins in a divalent cation-dependent manner and thus mediate
cell-matrix interactions and regulate tissue-specific cell morphology, migration, cell survival and
proliferation. Therefore, they play key roles in various physiological situations and diseases, such as
tumor progression and metastasis.
To analyse the effects of ruthenium-based compounds, in particular RAPTA-T, on integrins at both
cellular and molecular level, we used cell attachment studies as well as cell-free protein interaction
assays with recombinant human integrins. Moreover, a test system to determine the binding of metal
organic compounds to integrins was established.
At the cellular level, RAPTA-T affected cell adhesion especially to the basement membrane collagen
IV and to fibronectin, which is mediated via the integrins 11 and 51, respectively. The isolated
integrins were affected in their binding properties towards their cognate ligands, depending on the
incubation time with RAPTA-T. Bioanalytical studies, such as gel filtration of 11 integrin with the
ruthenium compound followed by an on-line detection of ruthenium by inductively coupled plasma
mass spectrometry (ICP-MS), demonstrated that RAPTA-T binds to 11 integrin and alters its ability
to form higher aggregates. In parallel, the binding activity of 11 integrin is compromised.
Additional studies will be necessary in the future to elucidate the molecular mechanism.
50
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
OP-35
Advances in Organometallic Chemistry for the Preparation of Molecular Imaging
and Therapy Agents
John F. Valliant*,a,b Anika Louie,a Alla Darwish,a Michael Cooke,a Antonio Toppino,a Karin
Stephenson,b Ryan Simmsb
a McMaster University, Faculty of Science, Department of Chemistry, 1280 Main St. West, L8S 4M1,
Hamilton, Canada. b The Centre for Probe Development and Commercialization, McMaster
University, BSB-B231, 1280 Main St. West, L8S 4K1, Hamilton, Canada. E-mail:
valliant@mcmaster.ca
Medical isotopes that are metallic in nature are playing an increasingly important role in modern
nuclear medicine and basic biological research.1 Delivering these radioisotopes to specific
biochemical targets while minimizing non-specific binding requires the development of new
prosthetic groups that form robust metal complexes in high yield under conditions that do not
degrade or modify sensitive targeting vectors. These prosthetic groups or ligands must also be
versatile with respect to how they are linked to targeting vectors and structurally modified in
order to meet the lipophilicity needs of the agent under development. With these requirements in
mind, organometallic complexes of Tc and Re are attractive platforms for developing new
imaging and therapy agents in that inert complexes can be formed in high yield using an array of
unique chelates and organometallic ligands. The work to be presented will include the
development of isostructural Re and Tc complexes that can be imaged in vitro and in vivo using
fluorescence microscopy and radioimaging methods respectively.2 Complexes will include novel
chelates for the [M(CO)3]+ core, which can be labeled at room temperature and incorporated into
peptide vectors as if they were natural amino acids. In addition, a new generation of isostructural
organometallic probes derived from carboranes will be presented. New labeling strategies for
tagging these molecules that go beyond conventional bulk solution methods will also be
discussed.
References
1. R. Alberto, J. Organomet. Chem. 2004, 692, 1179-1186.
2. K. Stephenson, S.R. Banerjee, T. Besanger, O.O. Sogbein, M.K. Levadala, N. McFarlane, J.
Lemon, D. R. Boreham, K. P. Maresca, J. D. Brennan, J. W. Babich, J. Zubieta, J. F. Valliant, J. Am.
Chem. Soc. 2004, 126, 8598-8599.
51
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
OP-36
Syntheses of New Isomeric Analogues of HYNIC for Evaluation
as a Bifunctional Chelator for Technetium-99m
Anica Dose,a L. K. Meszaros,b S. C. G. Biagini*a and P. J. Blower*b
a
University of Kent, Functional Materials Group, School of Physical Sciences, Canterbury CT2 7NH,
UK. b Kings College London, Division of Imaging Sciences, Rayne Institute 4th Floor Lambeth Wing,
St. Thomas’ Hospital, London SE1 7EH, UK. E-mail: ad308@kent.ac.uk
Introduction: Technetium, as a meta-stable isotope is extensively used in
nuclear medicine. It is a transition metal of the 7th subgroup with all formal
N
N
N
N
oxidation states between -1 and +7 accessible and therefore possesses a large
Tc
N
N
range of coordination structures.1 Since the first use of radiolabelled
Tc
1
2
antibodies with the bifunctional chelator 6-hydrazinonicotinamide (6-HYNIC)
3,2 the use of radiopeptides with the metastable isotope of technetium 99mTc as
Fig 1: possible monodentate 1
3
and chelating 2 structures of Tc- an imaging agent for cancer cells has increased significantly until today.
HYNIC complex
However, robust structural data for these conjugates is lacking. The HYNIC
and 99mTc coordinating sphere is still not fully determined and previous studies provide ambiguous
results about the complex.4 To radiolabel a peptide with HYNIC and 99mTc also requires one or more
co-ligands to fulfil the coordination sphere around the metal. Different co-ligands can have different
effects on the homogeneity and stability of the complex and its biodistribution. Finally they are
responsible for the formation of more than one end product. The latest results gives a clear insight that
there is one chelating HYNIC per metal site and the oxidation state of Tc is formally +5.5 The question
as to which mode of the HYNIC coordination, monodentate 1 or chelating 2 is operating, remains
uncertain.
Aims: The aim of this project is to assess the specific binding of the complex between HYNIC and Tc,
Tc and co-ligands and a further investigation of potential direct interactions between Tc and the
peptide.6
HO
O
HO
O
O
HO
O
Results: Isomeric HYNIC analogues HO
H
H
4-7 were synthesised. These syntheses
N
N
Cl
HO
O
NH ·HCl
NH ·HCl
are related to the synthesis of 62
H
N
N
N
N
N
HYNIC-Boc. The preparation of
HCl·H N
HYNIC-rhenium crystals, will provide
HN
HN
HN
N
NH ·HCl
NH ·HCl
NH
new data about the binding structure
4
7
3
6
5
and this will be followed by the
Fig 2: HYNIC analogues
preparation of analogous HYNIC-Tc
crystals. The novel synthesis of Fmoc-Lysine-NHS-2-HYNIC-Boc was also succesfully accomplished.
This will allow for its use in solid phase peptide synthesis (SPPS) to synthesise the “nanogastrin”
peptide [Lys(R)-Glu-Ala-Tyr-Gly-Trp-Met-Asp-PheNH2] where R= HYNIC, which binds to the
CCK-2 receptor overexpressed on certain tumours.7
Further work will evaluate the new ligands for labelling with Tc-99m and investigate the structural
chemistry of the rhenium and technetium-99m complexes.
2
2
2
2
2
2
References
1. U. Abram, R. Alberto, J. Braz. Chem. Soc. 2006, 17, 1486-1500.
2. M. J. Abrams, M. Juweid, C. I. Tenkate, D. A. Schwartz, M. M. Hauser, F. E. Gaul, A. J. Fuccello,
R. H. Rubin, H. W. Strauss, A. J. Fischman, J. Nucl. Med. 1990, 31, 2022-2028.
3. M. L. Bowen, C. Orvig, Chem. Commun. 2008, 41, 5077-5091.
4. L. K. Meszaros, A. Dose, S. C. G. Biagini, P. J. Blower, Inorg. Chim. Acta 2010,
DOI:10.1016/j.ica.2010.01.009
5. R. C. King, M. Surfraz, S. Biagini, P. J. Blower, S. J. Mather, Dalton Trans. 2007, 43, 4998-5007.
6. M. Surfraz, R. King, S. J. Mather, S. Biagini, P. J. Blower, J. Inorg. Biochem. 2009, 107, 971-977.
7. R. King, M. B. U. Surfraz, C. Finucane, S. C. G. Biagini, P. J. Blower, J. Nuc. Med. 2009, 50, 591598.
52
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
OP-37
Fluorescent Conjugates Between Dinuclear Rhenium(I) Complexes and Peptide
Nucleic Acids (PNA) for Cell imaging and DNA Targeting
Emanuela Licandro,*a S. Maiorana,a C. Baldoli,b G. Prencipe,a E. Ferri,a D. Donghi,c M. Panigati,c
G. D’Alfonso,c and L. D’Alfonsod
a
Dipartimento di Chimica Organica e Industriale, Università degli Studi di Milano, Via Venezian 21,
I-20133, Milano, Italy. bIstituto di Scienze e Tecnologie Molecolari, C.N.R., Via C. Golgi 19, I-20133
Milano, Italy. cDipartimento di Chimica Inorganica, Metallorganica e Analitica, Università degli
Studi di Milano, Via Venezian 21, I- 20133, Milano, Italy. dDipartimento di Fisica, Università di
Milano-Bicocca, P.za Scienze 6, I-20126 Milan. Italyo.
E-mail: emanuela.licandro@unimi.it
Peptide nucleic acids (PNA) are structural analogues of DNA, with pseudo-peptide backbone based on
N-(2-aminoethyl)glycine, which show high binding affinity and specificity for the complementary
DNA and RNA.1 The conjugation of organometallic complexes to biomolecules finds applications
both in diagnostic and therapeutic fields. The incorporation of Re(I) complexes into PNA, can offer a
double advantage, due both to its radiochemical and photo-emitting properties.
In this communication we describe the set up of the synthesis of new PNA-rhenium organometallic
bioconjugates as luminescent compounds for DNA targeting. In particular, we utilized two novel
rhenium complexes, namely [Re2(CO)6(-Cl)2(-4-COOH-pyridazine)] and Re2(CO)6(-Cl)2(-4(CH2)3COOH-pyridazine)], belonging to a recently developed family of dimeric luminescent
rhenium(I) complexes,2 which were conjugated with the tymine PNA monomer and decamer. The
second complex was prepared in order to check the influence of the n-propyl chain spacer on the
lifetime and quantum yields of the emission of the PNA-rhenium bioconjugate. The most fluorescent
Re-PNA conjugate also showed two photon absorption properties as assessed by “in cell” experiments,
that revealed that it permeates the cell membrane, staining both the cytoplasm and the nucleus.
Although more detailed experiments are needed, in order to establish the kinetics of the process and to
set a lower limit to the sample concentration to be used, these preliminary results indicate that the RePNA conjugate is viable as a fluorophore for cell imaging.
References
1. Peptide Nucleic Acids; 2nd Ed.; P. E. Nielsen, Ed.; Horizon Bioscience: Norfolk, UK, 2004.
2. D. Donghi, G. D’Alfonso, M. Mauro, M. Panigati, P. Mercandelli, A. Sironi, P. Mussini, L.
D’Alfonso, Inorg. Chem. 2008, 47, 4243-4255.
53
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
OP-38
Design of Cyclometalated Iridium(III) Polypyridine Complexes as Luminescent
Biological Labels and Probes
Kenneth Kam-Wing Lo
Department of Biology and Chemistry, City University of Hong Kong, Tat Chee Avenue, Kowloon,
Hong Kong, P. R. China. E-mail: bhkenlo@cityu.edu.hk
+
R1
R2
N
C
N
Ir
C
R1
N
N
Emission Intensity (A. U.)
Many cyclometalated iridium(III) polypyridine complexes exhibit intense and long-lived emission that
is very sensitive to the molecular structures and local environments of the complexes. These
interesting properties allow the complexes to serve as useful probes for various biological molecules
including oligonucleotides, peptides, and proteins. We have attached amine- and sulfhydryl-specific
reactive functional groups such as isothiocyanate, aldehyde, and iodoacetamide to cyclometalated
iridium(III) polypyridine complexes of the type [Ir(N^C)2(N^N)]+ to yield new luminescent labels for
biomolecules. Additionally, we have designed related iridium(III) polypyridine complexes appended
with various biological substrates including indole, -estradiol, biotin, and lipids, and utilized the
complexes as luminescent probes for indole-binding proteins, estrogen receptors, avidin, and lipidbinding proteins, respectively. Some of these complexes show interesting dual-emissive properties
that enable the biological binding event to be reflected by a change of emission profiles of the probes.
Furthermore, we have recently developed DNA-metallointercalators, dendrimers, and PEGylation
reagents derived from luminescent iridium(III) polypyridine complexes. We have focused on the
molecular design, photophysical properties, biomolecule-binding behavior, cytotoxicity, and cellularuptake characteristics of these luminescent probes.
500
+ ER
550 600 650 700
Wavelength / nm
750
References
1. K. K.-W. Lo, K. Y. Zhang, C.-K. Chung, K. Y. Kwok, Chem. Eur. J. 2007, 13, 7110 – 7130.
2. K. K.-W. Lo, P.-K. Lee, J. S.-Y. Lau, Organometallics 2008, 27, 2998 – 3006.
3. K. K.-W. Lo, K. Y. Zhang, S.-K. Leung, M.-C. Tang, Angew. Chem. Int. Ed. 2008, 47, 2213 –
2216.
4. J. S.-Y. Lau, P.-K. Lee, K. H.-K. Tsang, C. H.-C. Ng, Y.-W. Lam, S.-H. Cheng, K. K.-W. Lo,
Inorg. Chem. 2009, 48, 708 – 719.
5. K. Y. Zhang, S. P.-Y. Li, N. Zhu, I. W.-S. Or, M. S.-H. Cheung, Y.-W. Lam, K. K.-W. Lo, Inorg.
Chem. 2010, 49, 2530 – 2540.
54
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
OP-39
Subcellular Imaging of a Re(CO)3 Complex by Photothermal Infrared
Spectromicroscopy (PTIR).
Anne Vessières,a Clotilde Policar,b Marie-Aude Plamont, a Sylvain Clède, b Alexandre Dazzi c
a
ENSCP, CNRS-UMR 7223, 11 rue P. et M. Curie, F-75231 Paris Cedex 05, France, bDépartement
Chimie de l’ENS, CNRS-UMR 7203, 24 rue Lhomond, F-75231 Paris Cedex 05, cLaboratoire de
Chimie Physique, CNRS-UMR 8000, Université Paris-Sud 11, F-91405 Orsay Cedex,
E-mail: a-vessieres@chimie-paristech.fr
The most widely developed techniques for bio-imaging are those based on fluorescence
spectroscopy, however vibrational techniques including infra-red (IR) are also valuable. However, in
classical optical microscopy, sub-micrometric resolutions are not attainable in the mid-IR-range, as the
diffraction criterion imposes resolution higher than /2 (i.e. 2.5 µM at 2000 cm-1) which is not well
suited for intracellular mapping. To reach sub-micrometric resolution, near-field techniques are
mandatory. Photothermal induced resonance (PTIR) is a cutting edge technique using a set-up recently
patented by Dazzi et al.,1 coupling atomic force microscopy (AFM) and a tunable infrared laser to
make spatially resolved absorption measurements in the IR-range. It has been successfully used to
map a single air-dried E. coli cell by irradiation in the amide I and II bands.2 The next challenge is the
identification and localization of exogeneous diluted compounds inside single cells. The Re(CO)3 unit
grafted to a hydroxy-tamoxifen-like molecule has been selected for this study as it is stable in
biological environments and displays intense absorption in the 1850 – 2100 cm-1 region where
biological samples are transparent.
Figure : left: AFM-set up. middle: PTIR mapping at 1925 cm-1 of a single cell incubated 1h with 10
µM of the Re(CO)3 complex (red = high concentration) right : spectromicroscopy at the nucleus
We will present the results of the chemical imaging of this Re complex, inside a single cell,
using PTIR. Cells are initially located on the surface of a ZnSe prism by using the AFM topology.
Then the complex is localized thanks to its two characteristic CO bands at 1925 and 2017 cm-1. Cells
showed an uneven distribution of the complex with one hot spot (red area on the picture above) and
cold regions (blue zones). Interestingly, this location seems to correspond to cell nucleus located using
irradiation at 1240 cm-1 (phosphate band) and 1650 cm-1 (amide I of proteins). In addition, a spectrum
recorded inside the hot spot shows the two characteristic bands of the complex at 1925 and 2017 cm-1,
thus confirming its presence (right part of the figure).
References
1. A. Dazzi, M. Reading, P. Rui, K. Kjoller, Patent 2008, WO/2008/143817 A. B. Lastname, C. D.
2. A. Dazzi, R. Prazeres, F. Glotin, J.-M. Ortega, Infrared Physics Techn. 2006, 49, 113.
55
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
OP-40
Dynamical Studies of Bioconjugated Luminescent Ruthenium Complexes in
Lipid Vesicles
Edward Rosenberg,a Ayesha Sharmin,a J. B. Alexander Rossa
a
Department of Chemistry and Biochemistry
University of Montana, Missoula, MT 59812, USA Email: edward.rosenberg@mso.umt.edu
A detailed analysis of the time-resolved anisotropy decay of the emission from luminescent molecules
can provide useful information about molecular dynamics in a given media. To obtain such
information, the excited-state lifetime must match the time scale of the process being examined and it
is desirable that the time-zero emission anisotropy be in the range of 0.1 or greater. In our prior work,
we designed a series of phosphorescent ruthenium complexes that have the longer lifetimes, higher
quantum yields and the lower symmetry required for studying the dynamics of these probes in lipid
vesicle bilayers.1 Starting with the complexes [Ru(H)(trans-PPh3)2(dcbpy)CO][PF6] (1) and [Ru(
dppene) (5-amino- phen)CO(TFA)][PF6] (2) (dcbpy = 4,4’-dicarboxy bipyridine, dppene = 1,2diphenylphosphino ethene, 5-amino phen = 5-amino phenanthroline, TFA = trifluoroacetic acid) we
have used standard techniques to covalently conjugate these molecules to two and one phosphatidyl
ethanolamine molecules, respectively. Complex 2 has also been conjugated to cholesterol via reaction
with cholesterol chloroformate. Analyses of the anisotropy decay as a function of temperature from
the conjugated probes in vesicles—made from both naturally occurring and synthetic lipids—reveal
that the lipid conjugates are located within the lipid bilayer while the cholesterol conjugated complex
is at the bilayer-water interface. The rotational correlation times for the complexes are responsive to
the nature of the lipid vesicle used and analyses of this parameter allowed a detailed picture of the
kinds of motions of the conjugated complex in the vesicle. The lipid conjugates with 1and 2
incorporated into vesicles via extrusion through a size-selective membrane, showed an unexpected
blue-shift in the emission spectra and a corresponding short excited-state lifetime in the range of 10 ns;
the lifetimes in solvents are in the range of 0.1-2 s. This unusual phenomenon will be discussed in
terms of the properties of the excited states in the lipid vesicle environment in contrast to in bulk
solvents. For comparison with complexes 1and 2, related complexes have been conjugated to lipids
and cholesterol via the phosphine ligands, and their photophysical properties in lipid vesicles will also
be presented
References
1. Ayesha Sharmin , Reuben C. Darlington ,Kenneth I. Hardcastle, Mauro Ravera, Edward Rosenberg,
J. B. Alexander Ross “Tuning Photophysical Properties with Ancillary Ligands in Ru(II) MonoDiimine Complexes,” J. Organometal. Chem. 2009, 694, 988-1000.
56
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
OP-41
Multi-Organometallic-Containing Peptide Nucleic Acids: Preparation and
Biological Applications
Gilles Gasser,*a,b Antonio Pinto,b Sebastian Neumanb and Nils Metzler-Nolte*b
a
University of Zurich, Institute of Inorganic Chemistry, Winterthurerstrasse 190, CH-8057 Zurich,
Switzerland. E-mail: gilles.gasser@aci.uzh.ch; b Ruhr-University Bochum, Faculty of Chemistry and
Biochemistry, Department of Bioinorganic Chemistry, Universitätstrasse 150, D-44780 Bochum,
Germany.
Peptide nucleic acids (PNAs) are non-natural nucleic acid analogues. Their neutral pseudopeptide
backbone is made of N-(2-aminoethyl)glycine units which are ligated via a methylene carbonyl to the
four nucleobases (Figure 1).1 In comparison to double-stranded DNA (dsDNA), corresponding
PNA•DNA hybrids are thermally more stable due to the missing electrostatic repulsion between the
strands. Moreover, PNA is much more mismatch sensitive than DNA enabling sensitive and selective
mismatches discrimination. All these favourable features led to application of PNAs in various
research areas such as antisense and antigene therapies or biosensing.
Base
Base
O
P
HO
O
O
O
O
P
O
O
O
O
O
P
O
O
O
n
Base
Base
O
O
OH
HO
DNA
Base
O
O
N
N
H
Base
O
O
N
N
H
O
N
NH2
n
PNA
Figure 1. Structure comparison between DNA and PNA.
In order to modify the intrinsic properties of PNAs or in order to add new functionalities and/or
spectroscopic properties to PNA oligomers, organometallics have been synthetically attached to these
non-natural DNA analogues. During this talk, we will present our recent advances on the preparation
of multi-organometallic-containing PNA monomers and oligomers as well as their potential for
biological purposes (see Figure 2 for an example of application of metal-containing PNAs).2-6
Figure 2. Re-containing PNA oligomer mediated the silencing of enhanced green fluorescent protein
(eGFP) in HeLa-eGFP cells 48 h after cellular delivery by electroporation. (200 x magnification in all
images)
References
1.
2.
3.
4.
P.E. Nielsen, P., M. Egholm, R.H. Berg, O. Buchardt, Science 1991, 254, 1497-1500
G. Gasser, N. Hüsken, S.D. Köster and N. Metzler-Nolte, Chem. Comm. 2008, 3675-3677.
N. Hüsken, G. Gasser, S.D. Köster and N. Metzler-Nolte, Bioconjugate Chem. 2009, 20, 1578–1586.
G. Gasser, O. Brosch, A. Ewers, T. Weyhermüller and N. Metzler-Nolte, Dalton Trans. 2009, 43104317.
5. A. Sosniak, G. Gasser and N. Metzler-Nolte, Org. Biomol. Chem. 2009, 7, 4992 – 5000.
6. M. Patra, G. Gasser, D. Bobukhov, K. Merz, A.V. Shtemenko and N. Metzler-Nolte, 2010, submitted.
57
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
Poster presentations
58
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
P-01
In Vitro and In Vivo Anti-tumor Activities of Five Coordinated Cyclometallated
Organoplatinum(II) Complexes Containing Biphosphine Ligands
Hamidreza Samouei,a Mehdi Rashidi,*a Q. Ping Dou,*b Michael Frezza,b Yan Xiao,b
amd Frank W. Heinemannc
a
Chemistry Department, College of Sciences, Shiraz University, Shiraz 71454, Iran. b Department of
Pathology, School of Medicine, Wayne State University, 540.1 HWCRC, 4100 John R Road, Detroit,
USA.c Institut fuer Anorganische Chemie, Universitaet Erlangen-Nuernberg, Egerlandstrasse 1, D91058 Erlangen, Germany. E-mail:samouei@gmail.com
Ever since Rosenberg in late 1960s discovered the anti-tumor activity of cisdiamminedichloroplatinum(II), cis-[Pt(NH3)2Cl2] known as cisplatin,1 many other Pt complexes have
been designed, synthesized and tested in order to circumvent the cisplatin acquired resistance, side
effects, toxicity and low water solubility in order to increase the efficacy of the drug.2 Most platinum
complexes being used as therapeutic agents usually contain amine (with at least one N-H bond)
ligands,3 but the analogous complexes containing phosphine ligands are not unusual in these kinds of
applications.3b,4 Many attempts have been made during the past 3 decades to synthesize new
complexes of platinum and other transition metals (such as Ru) to overcome the difficulties associated
with cisplatin. For example some cyclometallated Pt(II) complexes have recently been used as active
cytotoxic anticancer drugs.4,5 The use of phosphine ligands instead of amines has recently been
envisaged, in particular because a large number of gold complexes containing phosphine ligands have
successfully been used as therapeutic agents.4,6
In the present study, we report two novel cyclometallated Pt(II) complexes containing biphosphine
ligands with unique structural features that are more potent than cisplatin in relation to their anti-tumor
activity and have also been found to exhibit proteasome-inhibitory activities in vitro and in vivo. We
also have suggested a potential relationship between the structure of the complexes and their cytotoxic
effects.
References
1. B. Rosenberg, L. VanCamp, J.E. Trosko and V.H. Mansour, Nature 1969, 222, 385-386.
2. K. S. Lovejoy, S. J. Lippard, Dalton Trans. 2009, 10651-10659.
3. (a) P. J. Miguel, M. Roitzsch, L. Yin, P. M. Lax, L. Holland, O. Krizanovic, M. Lutterbeck, M.
Schurmann, E. C. Fusch, B. Lippert, Dalton Trans. 2009, 10774-10786; (b) J.C. Shi, C.H. Yueng,
D.X. Wu, Q.T. Liu, and B.S. Kang, Organomet. 1999, 18, 3796-3801.
4. R. W.Y. Sun, D. Ma, E. L. M. Wong, C. M. Che, Dalton Trans. 2007, 4884-4892.
5. T.Okada, I.M.El-Mehasseb, M.Kodaka,, T.Tomohiro, K.Okamoto, H.Okuno, J. Med. Chem. 2001,
44, 4661-4667.
6. (a) L. C. Eiter, N. W. Hall, C. S. Day,G. Saluta, G. L. Kucera, U. Bierbach, J. Med. Chem. 2009, 52,
6519-6522; (b) C. P. Bagowski, Y. You, H. Scheffler, D. H. Vlecken, D. J. Schmitz, I. Ott, Dalton
Trans, 2009, 10799-10805.
59
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
P-02
Degradation of Platinum-Based Anticancer Drugs by Thiosulfate Ions:
an EXAFS Study
Diane Bouvet- Muller,a A. Michalowicz,a S.Crauste-Manciet,b,c and K. Provosta
a
Institut de Chimie et des Matériaux Paris Est, ICMPE/SAX, UMR 7182 CNRS-Paris Est, 2 à 8 rue
Henri Dunant, 94320 Thiais, France, bLaboratoire de Pharmacie Galénique, Université Paris V,
75006 Paris, France, c Service de Pharmacie, CHI Poissy Saint Germain en Laye, 78105 Saint
Germain en Laye, France. E-mail: muller@u-pec.fr
Three platinum complexes are currently used worldwide: cisplatin, carboplatin and oxaliplatin.1
Cisplatin is the most common, and its reactivity has been widely studied. On the contrary, derivatives
of carboplatin and oxaliplatin deserve to be structurally characterized in order to understand their
mode of action and stability in solution. This study takes place in the work carried out by our group on
the behavior of these platinum complexes in presence of various halogen and sulfur ligands.2-4
These drugs react rapidly with nucleophilic species in solution. Their degradation has two
consequences: in vitro, it can compromise the stability of the drug in solution before administration; in
vivo, the structural modification of these molecules can induce notable changes in their modes of
action. Sulfur nucleophilic ligands are particularly interesting:5 they play a major role in the
6
detoxification of the drugs. Particularly, thiosulfate ions are used to prevent nephro- and ototoxicity.
This study deals with the reaction of carboplatin and oxaliplatin with thiosulfate. For both drugs, the
reaction products remain in solution. Thus we used X-ray absorption spectroscopy in order to
characterize their structures. Spectra have been recorded for different reaction times (from one hour to
one month) and for different drug/thiosulfate ratios (from 1/2 to 1/40). For a 1/2 ratio at one month of
reaction, we observe the displacement of the carboxylate ligand for both drugs,and a strong similarity
of the signal between 3 and 4 Å. This EXAFS signal can be used as a signature of the Pt-Thiosulfate
binding, in order to model the complete reaction products structures in solution.
On this basis, the spectral and structural evolution as a function of the reaction time on one hand and
of the drug/thiosulfate ratio on the other hand are discussed.
References
1. L.R. Kelland, Nat. Rev. Cancer 2007, 7, 573-584.
2. D.Bouvet, A. Michalowicz, S. Crauste-Manciet, D. Brossard, K. Provost. Inorg. Chem 2006,
45, 3393-3398.
3. D. Bouvet et al. J. Synchr. Rad. 2006, 13, 477-483.
4. K. Provost et al. Biochimie 2009, 91, 1301-1306.
5. J. Reedjik, Chem. Rev. 1999, 99, 2499-2510.
6. D.J. Leitao, B.W. Blakley. Journal of Otolaryngology 2003, 32, 146-150.
60
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
P-03
Biological Activity of Enantiomeric Complexes [PtCl2L2]
(L2 = Aromatic Bisphosphanes and Aromatic Diamines)
Luca Gaviglio,a Sophie Bombard,b Marzia Bruna Gariboldi,c Elena Monti,c Elisabetta Gabano,a
Mauro Ravera,a amd Domenico Osellaa
a
University of Piemonte Orientale “A. Avogadro”, Department of Environmental and Life Sciences,
Viale Michel 11, 15121, Alessandria, Italy. bUniversité Paris Descartes, Laboratoire de Chimie et
Biochimie Pharmacologiques et Toxicologiques, 45, Rue des Saints-Pères, 75006 Paris, France.
c
Department of Structural and Functional Biology, University of Insubria, Section of Pharmacology,
Via A. da Giussano 10, 21052 Busto Arsizio (VA), Italy. E-mail: luca.gaviglio@mfn.unipmn.it
Enantiomeric complexes of formula [PtCl2L2] (L2 = R-(+)- and S-(-)-BINAP, where BINAP = 2,2’bis(diphenylphosphane)-1,1’-binaphthyl, and R-(+)- and S-(-)-DABN, where DABN = 1,1'binaphthyl-2,2'-diamine, were tested for their cytotoxic activity against three cancer cell lines and for
their ability to bind to the human telomeric sequence folded in the G-quadruplex structure. Similar
experiments were carried out on prototypal complexes cisplatin and cis-[PtCl2(PPh3)2] for comparison.
Pt-complexes containing phosphanes proved less cytotoxic against cancer cell lines and less likely to
interact with the nucleobases of the G-quadruplex than those containing amines; in both cases the S-()-isomer was more active than the R-(+)-counterpart. More specifically, whereas all the platinum
complexes were able to platinate the G–quadruplex structure from the human telomeric repeat, the
extent and sites of platination depended on the nature of the ligands. Complexes containing (bulky)
phosphanes interacted only with the adenines of the loops, while those containing the less sterically
demanding amines interacted with adenines and some guanines of the G-quartet.1
References
1. S. Bombard, M. B. Gariboldi, E. Monti, E. Gabano, L. Gaviglio, M. Ravera, D. Osella, J. Biol.
Inorg. Chem., 2010, in press, doi: 10.1007/s00775-010-0648-8.
61
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
P-04
Organometallic Palladium(II) Complexes Containing Tridentate [C,N,S]
Thiosemicarbazone Ligands: Synthesis, Structure and Antimalarial activity
Prinessa Chellan,a Kelly Chibale,a,b and Gregory S. Smith*a
a
University of Cape Town, Faculty of Science, Department of Chemistry, Private Bag, Rondebosch
7701, South Africa, b Institute of Infectious Disease and Molecular Medicine, University of Cape
Town, Rondebosch 7701, South Africa. E-mail: prinessa.chellan@uct.ac.za
Thiosemicarbazones (TSCs) are Schiff base type compounds that are noted for their pharmacological
properties, particularly as antiparisital,1 antibacterial 2 and antitumoral agents.3 The antiplasmodial
activity of thiosemicarbazones against Plasmodium falciparum strains has been reported.4 However,
reports on the use of thiosemicarbazone metal complexes as antimalarial agents are sparse.
In this presentation, we report the synthesis, characterisation and antimalarial study of mono-, di- and
tetrameric cyclopalladated [C,N,S] Pd(II) complexes prepared from two thiosemicarbazone ligands,
3,4-dichloroacetophenone thiosemicarbazone (1, Scheme 1) and 3,4-dichloropropiophenone
thiosemicarbazone (2), which have previously been screened for biological activity.5 Attendant
questions to be addressed in this presentation are, whether coordination of these compounds to
palladium enhances their inhibitory effects and if the number of thiosemicarbazone Pd(II) complex
moieties per molecule would increase antiplasmodial activity.
R
H
N
Cl
NH2
1: R = CH3
2: R = CH2CH3
N
S
Cl
K2[PdCl4] / EtOH-H2O
R.T.
R
5
Cl
3
Cl
NH2
N
6
N
4
Pd
1
2
4
PPh3 / Acetone
P
R
Cl
NH2
N
Cl
3
2
1
H2N
N
Pd
4
S
Pd
P
1
6
N
R
2
5
PPh3
5: R = CH3
6: R = CH2CH3
S
3
N
4
P / Acetone
Cl
5
Cl
3: R = CH3
4: R = CH2CH3
S
P
Pd
R
N
Cl
NH2
Scheme 1
Cl
S
N
P
7, 9, 11: R = CH3
8, 10, 12: R = CH2CH3
P = bis(diphenylphoshino)ferrocene (7 and 8);
trans-bis(diphenylphosphino)ethylene (9 and 10);
bis(diphenylphosphino)benzene (11 and 12)
References
1. K. J. Duffy, A. N. Shaw, E. Delorme, S. B. Dillon, C. Erickson-Miller, L. Giampa, Y. Huang, R. M. Keenan,
P. Lamb, N. Liu, S. G. Miller, A. T. Price, J. Rosen, H. Smith, K. J. Wiggall, L. Zhang and J. I. Luengo, J.
Med. Chem. 2002, 45, 3573-3578.
2. X. Du, C. Guo, E. Hansel, P.S. Doyle, C.R. Caffery, T.P. Holler, J. H. McKerrow and F.E. Cohen, J. Med.
Chem. 2002, 45, 2695-2707.
3. D. Kovala-Demertzi, M.A. Demertzis, E. Filou, A.A Pantazaki, P.N. Yadav, J.R. Miller, Y. Zheng and D.A.
Kyriakidis, Biometals 2003, 16, 411-418.
4. For example, A. Walcourt, M. Loyevsky, D. B. Lovejoy, V. R. Gordeuk and D. R. Richardson, Int. J.
Biochem. Cell Biol. 2004, 36, 401-407.
5. For example, N. Fujii, J. P. Mallari, E. J. Hansell, Z. Mackey, P. Doyle, Y. M. Zhou, J. Gut, P. J. Rosenthal,
J. H. McKerrow and R. K. Guy, Bioorg. Med. Chem. Lett. 2005, 15, 121-123.
62
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
P-05
Solid-State Synthesis of Peptide-Tethered Pt(IV) Complexes
and Their Cytotoxic Properties
Sergey Abramkin,a Markus Galanski,a and Bernhard Keppler*a
a
University of Vienna, Faculty of Chemistry, Department of Inorganic Chemistry, Währingerstrase
42, 1090, Vienna, Austria. E-mail: sergey.abramkin@univie.ac.at
Platinum-based drugs play an essential role in cancer treatment since the discovery of the anticancer
drug cisplatin. Subsequent development of complexes resulted in three generations of drugs, the last
one to be approved by the FDA was oxaliplatin. Side effects remain one of the main shortcomings of
chemotherapy, arising from lack of specificity and inefficient cell entry.
Short peptides can be used for targeting and transportation of drug molecules. They can change not
only the basic parameters like lipophilicity or water solubility, but even more complex interactions of
drugs with the microenvironment can be influenced. The axial ligands of Pt (IV) are the optimal site
for derivatization: upon reduction they are cleaved from the prodrug, and the Pt(II) complex is
released.
Inefficient cell entry is the reason for higher dosage of drugs, however stimulated uptake will increase
the amount of the drug, reaching the intracellular target. Cell-penetrating peptides can be used for
intracellular delivery of Pt complexes; the TAT peptide is the best studied example of this group.
Selectivity can be achieved using the peptides as delivery vectors. High expression of the GRP
receptor in many tumors (prostate, lung, breast) makes it an interesting target for platinum conjugates.
The short peptide bombesin was chosen for conjugation to Pt to investigate its influence on cytotoxic
properties.
O
O
OH
OH
O
O
O
H2
N
R
O
O
O
O
O
O
R
OH
O
O
O
N
H2
O
O
O
O
O
O
Pt
+
O
N
H2
O
H2
N
O
Pt
Pt
N
H2
R
O
O
H2
N
O
O
O
O
R
O
R = TAT47-57(YGRKKRRQRRR) or Bombesin(QWAVGHLM)
Solid-phase synthesis is a commonly used method for the preparation of peptides and their conjugates.
Oxaliplatin was oxidized and two uncoordinated carboxyl groups were introduced, thereafter the
complex was reacted with polymer-bound TAT and bombesin. Cleavage with TFA and purification
afforded mono- and bisconjugates, characterized with ESI-MS, NMR and analytical HPLC. Synthesis
and cytotoxic properties will be presented.
The support of COST, the FWF, the FFG and the Austrian Council for Research and Technology
Development is gratefully acknowledged.
63
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
P-06
Response Profile of Cancer Cells to Cisplatin Treatment
Hamed Alborzinia,a Pavlo Holenyaa and Stefan Wölfl*a
a
Ruprecht-Karls-Universität Heidelberg, Institute of Pharmacy and Molecular Biotechnology,
Im Neuenheimer Feld 364, D-69120 Heidelberg, Germany
E-mail: hamed.alborzinia@uni-heidelberg.de, wolfl@uni-hd.de
The cell based sensor chip system BIONAS® 2500 offers the ability to measure three important
parameters of cellular metabolism on line in living cell cultures: (i) glycolytic flux measured as pH
change; (ii) cellular respiration (mitochondrial activity) measured as oxygen consumption; and (iii)
cellular morphology, adhesion and membrane function measured as cellular impedance. These
parameters are analyzed with metabolic sensor chips (SC1000) that feature the following analytical
tools: (i) ion-sensitive field effect transistors (ISFETs) to record pH changes; (ii) oxygen electrodes to
monitor oxygen consumption; and (iii) interdigitated electrode structures (IDES) to measure
impedance under the cell layer. Cells are grown on the chip surface and all parameters are measured
continuously with the electrodes on the chip surface. To work under stable conditions the medium is
exchanged in short cycles with an automated fluidic system.
We use this system to measure changes in cellular metabolism and morphology in response to
treatment with cisplatin in different cell lines on line. Cisplatin treatment shows a well defined onset
of change in acidification and impedance at about 7h and 10h respectively after treatment is started. At
these time points we collected cells for further analysis of specific signalling pathways and gene
expression. Protein phosphorylation of growth related signalling pathways was analyzed with a
phosphoprotein ELISA micro array. Gene expression was analyzed using whole genome Affymetrix
Gene Expression micro arrays.
This work was in part supported by the BMBF (FKZ 01 EA 0509: “Nutrition.Net”) and the DFG
Forschergruppe FOR630.
64
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
P-07
Development of Novel [Diarylsalene]- and [Salophene]platinum(II) Complexes
as Cytotoxic Agents
Maria Proettoa amd Ronald Gust*a
a
Institute of Pharmacy, Freie Universität Berlin, Königin-Luise-Str. 2 + 4, 14195 Berlin, Germany
Breast cancer is the most common cancer in women.1 Platinum-based drugs are widely used against
various solid tumours, but they are inactive against breast cancer.
In this project, new platinum analogues have been synthesized in an attempt to overcome this problem.
The complexes were tested in vitro for growth inhibitory activity on both hormone dependent MCF-7
(ER+) and hormone independent MDA-MB-231 (ER-) breast cancer cells to determine possible
selective effects.
Based on the experience of the coordination chemistry of Schiff base ligands with different metals,2, 3
we chose diarylsalene and salophene as ligands and synthesized two types of platinum complexes
(Figure 1). Variations of the substituents in the aromatic rings were made to evaluate their significance
for the cytotoxic profile. In order to understand the mode of action of these [diarylsalene]platinum(II)
and [salophene]platinum(II) complexes, they were tested in vitro for DNA-binding and DNAintercalation.
R
R
R'''
N
N
N
O
N
Pt
Pt
O
O
R'
O
R''
R'
[diarylsalene]Pt(II) complexes
R''
[salophene]Pt(II) complexes
Figure 1
References
1. World Health Organization International Agency for Research on Cancer. "World Cancer Report"
2003.
2. R. Gust, I. Ott, D. Posselt, K. Sommer, J. Med. Chem. 2004, 47, 5837-5846.
3. A. Hille, I. Ott, A. Kitanovic, I. Kitanovic, H. Alborzina, E. Lederer, S. Wölfl, N. Metzler-Nolte, S.
Schäfer, W.S. Sheldrick, C. Bischof, U. Schatzschneider, R. Gust, J. Biol. Inorg. Chem. 2009, 14, 711725.
65
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
P-08
Following Investigations of Antiradical and Bioconjugative Properties of
Cluster Rhenium Compounds
Alexander V. Shtemenko,a Alexander A. Golichenko,a and Nataliia I. Shtemenkob
a
Department of Inorganic Chemistry, Ukrainian State Chemical Technological University, Gagarin
Ave. 8, Dnipropetrovs’k 49005, Ukraine., bDepartment of Biophysics and Biochemistry,
Dnipropetrovs’k National University, 72 Gagarin avenue, Dnipropetrovs’k 49010, Ukraine, E-mail:
shtemenko@ukr.net
Antiradical and bioconjugative properties of the five structural types of cluster dirhenium(III)
compounds with halide, carboxylate and phosphate ligands were described. Antiradical properties of
these substances occurred by δ-component of quadruple Re-Re bond ( 2 bonds ) and was welldetectable in electronic absorption spectra (EAS) due to * transition (20000 - 14000 cm-1). It has
been shown that the binuclear cluster fragment Re26+ actively reacts with artificial radicals in vitro,
however the rate of such interaction strongly depended from the ligand environment of the cluster
Re26+-centre. The reaction rate decreased with an increase of induction effects of alkyl groups in the
carboxylic ligands. The mechanism of antiradical action of Re26+-derivatives may be explained by the
transition of an unpaired electron of a synthetic radical to a δ-orbital of the Re26+ fragment, thus
decreasing the Re-Re bond order. Cluster rhenium compounds revealed their antiradical properties in
the model of tumor growth. We consider that antiradical properties of the rhenium compounds may
also play a leading role in their antitumor properties. Recent investigations showed that the antiradical
properties of rhenium compounds in vivo depended from the structure of the compounds, but this
dependence did not coincide with that obtained from the investigations with artificial radicals shown
herein and was more complex due to multidirectional interactions in living cells. Presented data
showed positive future prospects for Re26+-substances applications as therapeutic agents due to their
low toxicity and antiradical activity.
Very important was the fact that EAS gave information about the quadruple rhenium - rhenium bond
mode of substitution that was used in the bioconjugative investigations. Different structural types of
Re26+-derivatives had the characteristic absorption maxima, which position were dependent from the
quantity of hyperconjugated cycles around Re26+-centre. The effect of hyperconjugation is realized
due to the interaction of the delocalized -bond of -carboxylic ligands group and the -component
of the Re-Re bond. Bidentate coordinated tetra--phosphates [Re2(HPO4)4(H2O)2]2- and
[Re2(HPO4)2(H2PO4)2(H2O)2]..4H2O had the δ→δ* absorption band in the area 15625 см-1, that
corresponded to the existence of two hyperconjugated cycles around Re26+- centre. These facts were
used by us to show what was happened to the quadruple bond during formation of liposomes and
interactions with lipids. The mechanism of interaction between nucleic bases and rhenium(III)
compounds was studied and another mechanism of the interactions in comparison with platinides was
demonstrated. Some experiments with proteins were also discussed. Thus, quadruple Re-Re bond
offers unique opportunities to study processes of bioconjugation.
66
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
P-09
Lead Structure Development of Cytotoxic ([9]aneS3)Rh(III) Compounds
Containing Polypyridyl and Related Ligands
Ruth Bieda,a Andreas Meyer,b Ingo Ott,band William S. Sheldrick*a
a
Ruhr Universität Bochum, Faculty of Chemistry and Biochemistry, Department of Analytical
Chemistry, Universitätsstraße 150, 44780 Bochum, Germany. b Technische Universität Braunschweig,
Institute of Pharmaceutical Chemistry, Beethovenstraße 55 ,38106 Braunschweig, Germany.
E-mail:ruth.bieda@rub.de
Various compounds of the type [RhCl(LL)([9]aneS3)]2+ (LL = bpy, bpm, phen, tap, dpq, dppz)
containing the tridentate ligand [9]aneS3 were prepared with the goal of establishing structure-activity
relationships with regard to their DNA interaction and cytotoxic activity.1 Polypyridyl ligands of
different size and length were used as well as diamine and thiaether ligands. Recently published data
have revealed that rhodium(III) complexes containing polypyridyl ligands, which were previously well
known for their intercalating DNA binding properties, also exhibit pronounced cytotoxic activity.2
For the determination of structure-activity relationships, modified ligands similar to 2,2’-bipyridine
were also investigated. For instance, the organometallic compound containing the ligand 2phenylpyridine reduces the overall charge of the compounds to +1, a change that could lead to an
improvement in the cellular uptake. The biological properties of this complex were compared with
those of the analogous 2,2’-bipyridine and 2,2’- bipyrimidine compounds.
Interactions of the cytotoxic ([9]aneS3)Rh(III) complexes with DNA were investigated by CD, UV/Vis
and NMR spectroscopy and by gel electrophoresis. Peptide interaction due to covalent binding
following chloride exchange were also established by ESI-MS. IC50 values toward the cancer cells
MCF-7 and HT-29 as well as toward the human embryonic kidney cells HEK-293 were determined
using the crystal violet assay. Apoptosis induction was ascertained for non-adherent BJAB lymphoma
cells and healthy leukocytes. The studies indicate dramatic differences in cytotoxic activity and cell
selectivity within the ligand series LL = bpm, bpy, 2-phenylpyridine. A very high cell selectivity
towards malign lymphoma cells was established for LL = bpm. The complexes induce apoptosis by
the intrinsic mitrochondrial pathway and cause negligible necrosis.
+
2+
S
S
N
S
S
Rh
S
N
N
N
N
Rh
S
Cl
2-phenylpyridine
Cl
2,2’-bipyrimidine
References
1. R. Bieda, I. Ott, M. Dobroschke, A. Prokop, R. Gust, W. S. Sheldrick, J. Inorg. Biochem. 2009,
103, 698-708.
2. (a) M. Harlos, I. Ott, R. Gust, H. Alborzinia, S. Wölfl, A. Kromm, W. S. Sheldrick, J. Med. Chem.
2008, 51, 3924-3933. (b) R. Bieda, I. Ott, R. Gust, W. S. Sheldrick, Eur. J. Inorg. Chem. 2009, 38213831.
67
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
P-10
Octahedral Ruthenium Complexes as Protein Kinase Inhibitors
Sebastian Blancka and Erik Meggers*a
a
Philipps-Universität Marburg, Fachbereich Chemie, Hans-Meerwein-Straße, 35043 Marburg,
Germany. E-mail: sebastian.blanck@chemie.uni-marburg.de
Protein kinases are an important target in the field of medicinal chemistry. Since protein
phosphorylation represents a key step in many crucial cellular processes, the synthesis of potent and
selective kinase inhibitors has become more and more important. The ATP competitive
indolocarbazole alkaloid staurosporine is a potent but rather unselective inhibitor. Meggers et al. have
pioneered the design of inert and rigid organometallic complexes using staurosporine as a lead
structure (Figure 1).1
Figure 1: Staurosporine as lead structure for octahedral metal complexes as kinase inhibitors.
By varying the ligands A-D around the metal center the preference for certain kinases can be
changed.2 Thus it is possible to synthesize a variety of different kinase inhibitors using combinatorial
chemistry. The octahedral complex 1 has been found to be a good inhibitor for the protein kinase
GSK-3. GSK-3 has been shown to be a key component of the signal transduction in the insulin and
wnt signalling pathways.3 1 is significantly more potent for the α-isoform (IC50 = 8 nM) over the βisoform (IC50 = 50 nM), which is astonishing because GSK-3α and GSK-3β show 97% sequence
identity in the ATP-binding pocket. By using molecular modeling and structure based drug design it
was possible to increase the potency against GSK-3α by almost an order of magnitude (IC50 = 1 nM),
while the isoform selectivity remained the same. The amino group of the complex is very important
for the binding to the kinase since a protection of the functional group results in a complete loss of
inhibition as in metal complex 3 (Figure 2).
Figure 2: 2-(Aminomethyl)pyridine complexes as kinase inhibitors.
References
1. E. Meggers, G. E Atilla-Gokcumen, H. Bregman, Synlett 2007, 8, 1177.
2. H. Bregman, P. J. Carroll, E. Meggers, J. Am. Chem. Soc. 2006, 128, 877.
3. N. Pagano, J. Maksimoska, E. Meggers, Org. Biomol. Chem. 2007, 5, 1218
68
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
P-11
Synthesis, Characterizatiotion and Biological Evaluation of New Organometallic
Rhenium(I) Complex with Ferulic Acid
Dmytro Bobukhov,a Maksym Izumsky, a and Alexander Shtemenko*a
a
Ukrainian State Chemical Technological University, Department of Inorganic Chemistry, Gagarin
Avenue 8, 49005, Dnipropetrovs’k, Ukraine. E-mail: dbobukhov@googlemail.com
The aqueous chemistry of the organometallic cation [Re(CO)3(H2O)3]+ has received much attention
over the past decade, due to its relevance to the design of 186/188Re radiopharmaceuticals as well as its
ability to act as a surrogate for the chemistry of [99mTc(CO)3]+. In many cases, these investigations
have focused on reactions between biomolecules and [Re(CO)3(H2O)3]+. The attractiveness of this
low-valent precursor results from its particularly high thermodynamic stability, that is, high
substitution stability of CO ligands and substitution lability of water molecules, which can be easily
replaced by a variety of mono, bis, and tridentate ligands of different size, shape, and donor atom sets.1
Here we report the synthesis, characterization and biological evaluation of new rhenium(I) complex
with ferulic acid (3-(4-hydroxy-3-methoxyphenyl)-2-propenoic acid, C10H10O4). Ferulic acid is a
phenolic acid of low toxicity, it can be absorbed and easily metabolized in the human body. Ferulic
acid has been reported to have many physiological functions, including antioxidant, antiinflammatory, antithrombosis, and anticancer activities.2 Because of these properties and its low
toxicity, we decided to study interaction between trans-ferulic acid and [Re(CO)3(H2O)3]+ cation, and
possibility of using phenolic acid – rhenium(I) complexes in biomedicine. The corresponding complex
was synthesized in a stepwise manner from [Re(CO)3(H2O)3]Br and trans-ferulic acid in methanol.
The compound has been characterized by 1H NMR, ESI-MS and IR spectroscopy. Crystal structure
and biological activity of the corresponding complex will be discussed.
References
1. S. Alves, A. Paulo, J. D. G. Gorreia, L. Gano, C. J. Smith, T. J. Hoffman, I. Santos, Bioconjugate
Chem. 2005, 16, 438-449.
2. S. Ou, K.-C. Kwok, J. Sci. Food Agric. 2004, 84, 1261-1269.
69
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
P-12
Synthesis of Ferrocene Peptide Conjugates and their Application as Inhibitors of
Peptide Association
Samaneh Beheshti,a and Heinz-Bernhard Kraatza
a
The University of Western Ontario, Faculty of Science, Department of Chemistry, 1151 Richmond St,
N6A 5B7, London, Ontario, Canada. Email: sbehesh@uwo.ca
The amyloid beta peptide (Aβ) with 40-42 amino acids is the major constituent of plaques found in
the brain of people affected with Alzheimer’s disease.1 There is a hypothesis that conformational
switching from α-helical to β-sheet ultimately leads to amyloid fibril formation . On this basis, finding
compounds that are able to destabilize the β-sheet structure and to interfere with the assembly of
peptide strands is a useful strategy to prevent peptide aggregation and fibril formation. Synthetic
peptides have been reported as β-sheet breakers that preclude amyloid formation.2 For example, a
novel pentapeptide inhibitor that has a proline in place of valine and an aspartic acid in place of
alanine in the Aβ17-21 (Leu-Val-Phe-Phe-Ala) fragment has been reported with the ability to inhibit the
formation of amyloid fibrils.3 In this work, a series of Fc-peptide conjugates is prepared of the type
FcCO-Val-Phe-Phe-OR (1:R = Me, 2:R = H), Fc[CO-Val-Phe-Phe-OR]2 (3:R = Me, 4:R = H), Fc[COVal-Phe-OR]2 (5:R = Me, 6:R = H) and Fc[CO-Leu-Val-OR]2 (7:R = Me, 8:R = H) . Conformational
properties of these ferrocene peptide conjugates and their interaction with several sequences of Aβ
have been studied in solution by circular dichroism and scanning electron microscopy. In addition, the
interaction of Aβ attached on the gold surface with these ferrocene peptide conjugates has been
studied by using electrochemical methods.
References
1. L. O. Tjernberg, J. Naslund, F. Lindqvist, J. Johansson, A.R. Karlstrom, J.Thyberg, L. Terenius,C.
Nordstedt, J. Biol. Chem. 1996, 271, 8545-8548.
2. C. Soto, E.M. Sigurdsson, L. Morelli, R.A. Kumar, E.M. Castano, B. Frangione, Nat. Med. 1998, 4,
822-826.
3. C. Adessi, M.J. Frossard, C. Boissard, S. Fraga, S. Bieler, T. Ruckle,F. Vilbois, S.M. Robinson, M.
Mutters, W.A. Banks, C. Soto, J. Biol. Chem. 2003, 278, 13905-13911.
70
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
P-13
Synthesis, Characterization, and Biological Study of Functionalized
Cyclopentadienylmanganese and Rhenium Tricarbonyl Complexes
and Their Peptide Bioconjugates
Wanning Hu,a Katrin Splith,b Ines Neundorf,b and Ulrich Schatzschneider*a
a
Ruhr-Universität Bochum, Lehrstuhl für Anorganische Chemie I - Bioanorganische Chemie,
Universitätsstr. 150, D-44801 Bochum, Germany.
b
Institut für Biochemie, Universität Leipzig, Brüderstr. 34, D-04103 Leipzig, Germany.
wanning.hu@rub.de
rel. cell viability [%]
125
100
75
O
Cym1-sC18
Cyr1-sC18
Cyr5-sC18
50
25
L
OC
0
0
50
100
150
200
M
COOH
CO
CO
250
M = Mn, Re
csubstance [mol]
Several functionalized cyclopentadienyl manganese and rhenium tricarbonyl half-sandwich complexes
were prepared and coupled to the sC18 carrier peptide to investigate whether the structural
modification of the linker and the change of the metal center would influence the biological properties
of the metal-peptide-bioconjugates. Two new cymantrene complexes with a 1,3- and 1,4-phenylene
linker were prepared and were fully characterized with 1H-NMR, 13C-NMR, IR, ESI-MS, elemental
analysis, and X-ray crystallography.1 In addition, three novel related CpRe(CO)3 complexes showed
good purity in 1H-NMR, IR and ESI-MS. Four of the compounds were successfully coupled to the
sC18 peptide and the cytotoxicity of the conjugates was studied with the resazurin assay on MCF-7
human breast cancer cells. The CpMn(CO)3 conjugates showed IC50 values of about 55 µM on MCF-7
human breast cancer cells, which is comparable to other cymantrene-sC18 conjugates already studied.2
In contrast, the rhenium analogue of the cymantrene complex with the 1,2-phenylene linker is inactive
at up to 150 µM. However, a CpRe(CO)3 complex with the 1,4-phenylene linker but a methylene
group between the Cp and phenyl rings gave a bioconjugate with an activity very similar to the
cymantrene- sC18-bioconjugates. The cellular internalization of these conjugates was studied with
confocal fluorescence microscopy on MCF-7 cells.
References
1. K. Splith, I. Neundorf, W. Hu, H. W. Peindy N'Dongo, V. Vasylyeva, K. Merz, U. Schatzschneider,
Dalton Trans. 2010, 39, 2536-2545.
2. I. Neundorf, J. Hoyer, K. Splith, R. Rennert, H. W. Peindy N'dongo, U. Schatzschneider, Chem.
Commun. 2008, 5604-5606.
71
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
P-14
Coordination of a Peptide -Turn Mimetic to Tungsten:
Possible Applications for the Study of -Sheets
Adam N. Boyntona and Timothy P. Curran*a
a
Department of Chemistry, Trinity College, Hartford, CT 06106 USA
Email: timothy.curran@trincoll.edu
In 1995 Kemp and Li described the synthesis of 2-amino-2'-carboxyphenylacetylene (1) and its use as
a peptide turn mimetic.1,2 Their work showed that 1 does function as a -turn mimetic, and that
OH
O
1
NH2
peptide derivatives incorporating 1 adopted -sheet structures. A key structural element in 1 is the
alkyne group that links both phenyl rings. Because of our ongoing interest in the use of tungstenalkyne coordination for generating constrained peptides,3,4,5 we have begun investigations into whether
peptide derivatives of 1 can be reacted with W(CO)3(dmtc)2 to yield tungsten-bis(alkyne) complexes
(like 2), and whether the peptides maintain a -sheet structure after coordination to tungsten. If the
peptides do maintain their sheet structure, then it would be of interest to know whether the two sheets interact with each other via stacking arrangements. Owing to solubility and oligomerization
issues, there are very few model systems for investigating -sheet stacking interactions.
O
2
N
H
H
N
O
O
N
H
H
N
O
S
S
S
W
S
H
N
O
N
H
O
O
H
N
O
S
S
=
H3C
H3C
S
N
S
N
H
This presentation will detail the status of our efforts to prepare and study these novel
bioorganometallic species.
References
1.
2.
3.
4.
5.
D. S. Kemp, Z. Q. Li, Tetrahedron Lett., 1995, 36, 4175-4178.
D. S. Kemp, Z. Q. Li, Tetrahedron Lett., 1995, 36, 4179-4180.
T. P. Curran, A. L. Grant, R. L. Lucht, J. C. Carter, J. Affonso, Org. Lett., 2002, 4, 2917-2920.
T. P. Curran, R. S. H. Yoon, B. R. Volk, J. Organometallic Chem., 2004, 689, 4837-4847.
T. P. Curran, A. B. Lesser, R. S. H. Yoon, J. Organometallic Chem., 2007, 692, 1243-1254.
72
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
P-15
Synthesis and Characterisation of Palladium Bioconjugates
Jan Dittricha and Nils Metzler-Nolte*a
aRuhr-University Bochum, Faculty of Chemistry and Biochemistry, Department of
Inorganic Chemistry I, Universitätsstr. 150, 44801 Bochum, Germany
E-mail: Jan.Dittrich@rub.de
Some transition metals like gold and platinum play a major role in anti-tumor research.1,2 Palladium is
a homologue element of platinum with related chemical behaviour, but is not in focus of cancer
research until now. The ligand exchange rate of palladium is much higher than the one of platinum,
consequently cispalladium would not work as an anticancer drug. The goal we are striving for are
palladium bioconjugates like 1. A suitable metal complex is formed from a cyclometallated palladiumazide3 and methyl 2-isocyanoacetate, which undergo a [3+2] cycloaddition reaction to yield after
rearrangement an ester functionalised palladium-tetrazole. After saponification this compound can be
linked to an amino acid or peptide, both in solution and on solid phase. The compounds were
characterized by multidimensional and multinuclear NMR techniques, mass spectrometry and IR
spectroscopy.
N
N
Pd
N
N
N N
H
N
O
O
N
H
H
N
O
O
N
H
H
N
O
OH
O
OH
1
References
1. I. Ott, Coord. Chem. Rev. 2009, 52, 763-770.
2. Z. Guo, P.J. Sadler, Angew. Chem. Int. Ed. Engl. 1999, 38, 1512-1531.
3. Y.J. Kim, X. Chang, J.T. Han, M.S. Lim, S.W. Lee, Dalten Trans. 2004, 3699-3708.
73
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
P-16
Conjugation of Rheniumtricarbonyl Bisimine Complexes to Polylactides Fluorescent Polymers for in vivo Tumour Diagnostics
Nadine E. Brückmanna and Peter C. Kunz*a
a
Heinrich-Heine-University of Düsseldorf, Department of Inorganic Chemistry I,
Universitätsstr. 1, 40225, Düsseldorf, Germany. E-mail: peter.kunz@uni-duesseldorf.de
In order to improve current cancer pharmaceuticals, new polymer-based transport systems are being
developed that deliver the drug directly to the tumour, where it can subsequently be released.
Macromolecules can accumulate in tumours due to the EPR-effect.1 Although polymers are now
widely used in therapeutic approaches, only a few examples of diagnostically applied polymerconjugates exist.2 Rheniumtricarbonyl bisimines e.g. are useful as dyes for fluorescence microscopy.
Their fluorescence emission lies in the visible light spectrum, resulting from a metal-to-ligand-chargetransfer (MLCT). These transitions typically have large Stokes shifts, which makes the fluorescence
easily destinguishable from tissue autofluorescence.3 Attachment of these rhenium cores to ligandfunctionalised polylactides leads to biodegradable fluorescent polymers.
In particular, rheniumtricarbonyl complexes of 2,2’bipyridine (bipy), 1,10-phenanthroline (phen) as
well as dipyrido[3,2-a:2’,3’-c]phenazine (dppz) were prepared. Absorption and emission data were
ascertained, cytotoxicity was determined on A2780 ovarian cancer cell lines and the in vivo
localisation was examined by confocal microscopy. Investigations into their degradation kinetics are
currently ongoing.
References
1. H. Maeda, J. Wu, T. Sawa, Y. Matsamura, K. Hori, J. Cont. Rel. 2000, 65, 271-284.
2. A. Mitra, A. Nan, H. Ghandehari et al., Pharm. Res. 2004, 21(7), 1153-1159.
3. A. Amoroso, M. Coogan, J.E. Dunne et al., Chem. Commun. 2007, 29, 3066-3068.
74
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
P-17
Organometallic Complexes Coupled to Cell-Penetrating Peptides: Generation of
Promising New Cytostatic Compounds
K. Splith,a Jan Hoyer,a Wanning Hu,b Ulrich Schatzschneider,b Yvonne Geldmacher,c
Malte Kokoschka,c William S. Sheldrick,c and Ines Neundorf*a
a
Leipzig University, Faculty of Biosciences, Pharmacy and Psychology, Department of Biochemistry,
Brüderstr. 34, 04103, Leipzig, Germany. b Ruhr-University Bochum, Faculty of Chemistry and
Biochemistry, Department of Inorganic Chemistry I, Universitätsstr.150, 44801, Bochum, Germany.
c
Ruhr-University Bochum, Faculty of Chemistry and Biochemistry, Department of Analytical
Chemistry, Universitätsstr.150 ,44801, Bochum, Germany. E-mail: splith@uni-leipzig.de
Bioorganometallic chemistry has become more and more important in several fields, especially in the
development of new drugs for cancer treatment. A number of metal-based building blocks have
promising features for applications in therapy and diagnosis. Introduction of a metal centre could add
new features which might help to overcome some problems in cancer treatment. However the low
water solubility and bioavailability of these organometallic compounds inhibits their therapeutic use in
medicine. Recently, so called cell-penetrating peptides (CPP) have emerged as potent tools to
introduce substances into cells. CPP are an inhomogenic group of peptides that share the ability to
translocate in a large number of different cell-lines without the need of a receptor or transporter
molecule. Thereby they are capable to transport various cargos inside cells, like proteins,
oligonucleotides, nanoparticles or small organic drugs.1,2
This work describes the coupling of metal-based building blocks to cell-penetrating peptides based on
an antimicrobial peptide cathelicidin CAP18.3 Synthesis was achieved by solid phase peptide synthesis
using standard Fmoc chemistry and activation by HOBt/DIC. Several different metal complexes have
been investigated, e.g. half-sandwich-complexes of different metals. Cellular uptake of the new
bioconjugates was investigated with different methods and high accumulation in different tumour cells
could be observed. Furthermore, cell viability assays showed that those organometallic peptide
conjugates are very potent and possess promising cytotoxic properties.4,5,6
References
1. K. M. Stewart, K. L. Horton, S. O. Kelley, Org. Biomol. Chem. 2008, 6, 2242-2255.
2. I. Neundorf, R. Rennert, J. Franke, I. Közle, R. Bergmann, Bioconjugate Chem. 2008, 8, 1596-603.
3. I. Neundorf, R. Rennert, J. Hoyer, F. Schramm, K. Löbner, I. Kitanovic, S. Wölfl, Pharmaceuticals 2009, 2,
49-65.
4. I. Neundorf, J. Hoyer, K. Splith, R. Rennert, H.W. Peindy N’dongo, U. Schatzschneider, Chem. Commun.
2008, 43, 5604-5606.
5. K. Splith, I. Neundorf, W. Hu, H.W. Peindy N'dongo, V. Vasylyeva, K. Merz, U. Schatzschneider, Dalton
Trans. 2010, 39, 2536-2545.
6. K. Splith, W. Hu, U. Schatzschneider, R. Gust, I. Ott, I. Neundorf, manuscript submitted.
75
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
P-18
Interaction between [Ru(6-p-cym)(H2O)3]2+ and (O,O) Donor Ligands of
Biological Importance in Aqueous Solution
Péter Buglyó,*a Linda Bíró,a and Etelka Farkasa
a
University of Debrecen, Faculty of Science and Technology, Department of Inorganic and Analytical
Chemistry, P. O. Box 21, H- 4032 Debrecen, Hungary. E-mail: buglyo@delfin.unideb.hu
Numerous Ru(III) and Ru(II) complexes have been synthesized, characterized in the solid state and
tested for antitumor activity. The most promising candidates are shown to act differently both in vitro
and in vivo from the antitumor platinum complexes currently used in the therapy. Beside Ru(III)
complexes with octahedral geometry half-sandwich organometallic Ru(II) complexes with typical
“piano stool” geometry are also investigated intensively.1
Recently we have shown that one class of important biomolecules, monohydroxamates (being also
(O,O) chelators), are capable to form stable complexes with the [Ru(6-p-cym)(H2O)3]2+ core both in
the solid state and in aqueous solution.2 We have also explored in detail the hydrolysis of the metal ion
using different (pH-potentiometry, NMR, UV-VIS and ESI-MS) techniques and estimated the stability
constants of the hydroxo complexes formed in the H+–[Ru(6-p-cym)(H2O)3]2+ system. Taking into
consideration the hydrolysis we were able to obtain the pH dependent speciation of the H+–[Ru(6-pcym)(H2O)3]2+–meaha system (meaha = N-methyl-acetohydroxamate) and to determine the
composition and stability constants of the complexes formed with the monohydroxamate.
In order to compare the [Ru(6-p-cym)(H2O)3]2+ binding strength of meaha with that of other (O,O)
donors partly used as building blocks in ruthenium complexes with potential anticancer activity or
present in biofluids a systematic study has been carried out. Ligands capable to form five membered
(oxalic acid, lactic acid, kojic acid, maltol, 3-hydroxy-1,2-dimethylpyridin-4(1H)-one, 1,2dihydroxybenzene-3,5-disulfonate)
and
six-membered
(cyclobutane-1,1-dicarboxylic acid,
acetylacetone, salicylic acid) chelates in which the donor atoms exhibit different basicity were choosen
and the interaction of these chelators with [Ru(6-p-cym)(H2O)3]2+ was investigated. This contribution
summarises the results of a detailed solution equilibrium work. During this study our goal was to
estimate the speciation and to compare the composition and stabiliy constants of Ru-(O,O) type
complexes formed applying different (pH-potentiometry, 1H-NMR, ESI-MS) experimental techniques.
References
1. (a) P. C. A. Bruijnincx, P. J. Sadler, Adv. Inorg. Chem., 2009, 61, 1-62. (b) W. Kandioller, C. G.
Hartinger, A. A. Nazarov, M. L. Kuznetsov, R. O. John, C. Bartel, M. A. Jakupec, V. B. Arion, B. K.
Keppler, Organometallics, 2009, 28, 4249-4251.
2. P. Buglyó, E. Farkas, Dalton Trans., 2009, 8063-8070.
Acknowledgement: We thank the members of the EU COST Action D39 for motivating discussions.
This work was supported by the Hungarian Scientific Research Fund (OTKA K76142).
76
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
P-19
Organometallic Osmium Arene Complexes with Potent Cancer Cell Cytotoxicity
Ying Fu, aAbraha Habtemariam,a Ana M. Pizarro,a Sabine H. van Rijt, a Guy J. Clarkson,a
and Peter J. Sadler*a
University of Warwick, Department of Chemistry, Gibbet Hill Road, Coventry, CV4 7AL,
U.K, E-mail: fuyingpku@gmail.com
Arene complexes of the heavier congener osmium(II) display similar
structures in the solid state to those of RuII but are subtly different
Arene
with regard to their chemical reactivity. For example, OsII arene
ethylenediamine chlorido complexes hydrolyze ca. 40x more slowly
and the related aqua adducts have pKa values for OsOH2/OH which
are ca. 1.5 pKa units lower (more acidic) than those of the analogous
RuII complexes.1,2 Faster ligand exchange in OsII complexes can be
achieved by incorporating oxygen-containing chelating ligands, e.g.
picolinates.3,4 In general they show a different cytotoxicity profile and
have a larger reactivity window compared to Ru arene complexes.
The synthesis of a range of osmium complexes of the general
structure shown will be discussed including the X-ray crystal
structures of five complexes. Surprisingly, several of these OsII
[Os(Arene)(NN)X]+
complexes with iodide as the X ligand are an order of magnitude
more potent than the clinically-used drug cisplatin towards a range of human cancer cell lines.
We thank Dr. Michael Khan (Biological Sciences) for provision of facilities for cell culture, and the
MRC, EPSRC (Knowledge Transfer Network), ERC and EU EDRF/AWM (APOC) for funding, and
members of COST Action D39 for discussion.
Os
X
N
N
References
1. Peacock, A. F. A.; Habtemariam, A.; Fernandez, R.; Walland, V.; Fabbiani, F. P. A.; Parsons, S.;
Aird, R. E.; Jodrell, D. I.; Sadler, P. J. J. Am. Chem. Soc. 2006, 128, 1739-1748.
2. Wang, F.; Habtemariam, A.; van der Geer, E. P.; Fernandez, R.; Melchart, M.; Deeth, R. J.; Aird,
R.; Guichard, S.; Fabbiani, F. P.; Lozano-Casal, P.; Oswald, I. D.; Jodrell, D. I.; Parsons, S.; Sadler, P.
J. Proc Natl Acad. Sci.U.S.A. 2005, 102, 18269-18274.
3. Peacock, A. F. A.; Sadler, P. J. Chem.--Asian J. 2008, 3, 1890-1899.
4. van Rijt, S. H.; Peacock, A. F. A.; Johnstone, R. D. L.; Parsons, S.; Sadler, P. J. Inorg. Chem. 2009,
48, 1753-1762.
77
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
P-20
Cytotoxic Apoptosis-Inducing Organometallic Rhodium Complexes with
Substituted Polypyridyl Ligands
Yvonne Geldmacher,a Riccardo Rubbiani,b Ingo Ott,b and William S. Sheldricka*
a
Ruhr-Universität Bochum,Faculty of Chemistry and Biochemistry, Department of Analytical
chemistry, Universitätsstr. 150, 44780 Bochum, Germany, bTechnical University of Braunschweig,
Department of Pharmaceutical Chemistry, Beethovenstr. 55, 38106 Braunschweig, Germany
E-mail: yvonne.geldmacher@rub.de
apoptotic cells [%]
The complexes of the type [(η5-C5Me5)RhCl(pp)]CF3SO3 (with pp= dpq, dppz, dppn) represent a new
class of cytotoxic substances. Cytotoxicity and cellular uptake studies on the HEK-293, MCF-7 and
HT-29 cell lines have been employed to establish relationships between the structure and the activity
of the complexes. UV/Vis kinetic, thermal denaturation and CD studies have shown, that the prefered
binding mode of the complexes to DNA is intercalation. [(η5-C5Me5)RhCl(dppz)]CF3SO3 invokes the
largest increase in Tm with a value 12 °C being recorded for a 1:10 complex/DNA mixture in the
denaturation experiment. In contrast, complexes containing the smaller chelate ligands with pp = en,
bpy and phen exhibit negative ΔTm values, which indicates the presence of a covalent binding mode.
CD spectra for the complex/DNA mixtures with pp = dpq and dppz contain a negative ICD-signal in
the range 280-300 nm, which also indicates intercalation. Viscosity measurements also confirm the
conclusions from UV/Vis and CD studies.1 100
75
50
25
0
Co DMSO 0.1
1
5
10
25
50
75 100
concentration [µM]
Figure 1: crystal structure of
5
[(η -C5Me5)RhCl(5,6- Me2phen)]CF3SO3
Figure 2: DNA-fragmentation after a 72 h treatment of
5
BJAB cells with [(η -C5Me5)RhCl(5,6- Me2phen)]CF3SO3 at different
concentrations
The biological activity also correlates with the lipophilicity and thereby with the size of the
polypyridyl ligand. The IC50 values decrease in the series en, bpy>> phen,dpq > dppz > dppn. One
goal of our ongoing studies is to improve the cell selectivity and identify lead substances by varying
the ligands L and pp in complexes [(η5-C5Me5)RhL(pp)](CF3SO3)n. It has previously been shown that
there are significant differences between the cytotoxicities of Pt(II) complexes with methylated 1,10phenanthroline ligands.2 We now report studies of the biological activity of [(η5C5Me5)RhCl(pp)]CF3SO3 complexes containing methylated phenanthroline ligands and other
substituted polypyridyl ligands. Measurements of the LDH release for lymphoma (BJAB) cells after
1h incubation with phen, 5,6-Me2phen and dppz complexes demonstrated that unspecific necrosis is
negligible. Specific cell death apoptosis via DNA fragmentation was detected for BJAB cells after 72
h (Figure 2).
References
1. M.A. Scharwitz, I. Ott, Y. Geldmacher, R. Gust, W.S. Sheldrick, J. Organomet. Chem. 2008, 693,
2299-2309.
2. C.R. Brodie, J.G. Jollins, J.R. Aldrich-Wright, Dalton Trans. 2004, 1145.
78
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
P-21
Antiproliferative Activity of Cationic and Neutral Heterobimetallic
Ferrocene-(Vinyl)Ru(CO)Cl(PiPr3)2 Complexes
Konrad Kowalski,*a Ingo Ott,*b Rainer. F. Winter,c and Ronald Gustd
a
University of Łódź, Faculty of Chemistry, Department of Organic Chemistry, Tamka 12, 91-403
Łódź, Poland. b Technische Universität Braunschweig, Institute of Pharmaceutical Chemistry,
Beethovenstraße 55, 38106 Braunschweig, Germany. c Universität der Regensburg, Institut für
Anorganische Chemie, Universitätsstraße 31, D-93040 Regensburg, Germany. d Freie Universität
Berlin, Institute of Pharmacy, Königin-Luise-Str. 2+4, 14195 Berlin, Germany.
E-mail: kondor15@wp.pl
Recently, some of us reported1 on the mixed ferrocene ruthenium organometallic species 1 and 2 with
the main focus on measuring the degree of electron delocalization in mixed-valent 2 and its medium
dependence. In the bioorganometallic chemistry field the cytotoxic activity of some ferrocenium salts
and the lack of activity of the corresponding ferrocenes is well known2. On the other hand the
anticancer activity of mixed ferrocene/ruthenium complexes has been recently reported3. Considering
these data, complexes 1 and 2 along with their monometallic counterparts 3-8 have been subjected
toward biological studies4. Antiproliferative activity of 1-8 was carried out in HT-29 colon carcinoma
and MCF-7 breast cancer cells. Both bimetallic derivatives 1 and 2 exhibited IC50 values between 4.8
μM and 16.8 μM. These values are within the range of common cytostatics such as cisplatin and 5fluorouracil investigated as control in the same assay. In addition our tests show higher
antiproliferative activity of cationic 2 than of neutral 1. In order to rationalize this observation the
cellular uptake of 1, 2 and 4 was determined by measurement of the ruthenium content of cells
exposed to the complexes by atomic absorption spectroscopy. Unexpectedly, the cellular uptake of
cationic 2 exceeded those of neutral 1 and were comparable to those exhibited by 4. This results
suggest that 2 might be effectively transported across cellular lipid membranes by an active transporter
system. Such a transporter systems are known to be crucial factors for cellular metal biodistribution.
However, they haven’t been identified for any cationic ferrocenes yet.
Fe
1
PiPr3
Cl
Ru
CO
PiPr3
PiPr3
i
P Pr3
Ru
Fe
+
Cl
CO
PiPr3
Ru
PF6-
R
i
Cl
CO
P Pr3
Fe
2
3
R = -OCH3
-F
-CF3
-N(CH3)2
-CHO
4
5
6
7
8
Acknowledgements: KK is grateful to the Alexander von Humboldt-Stiftung for a research
fellowship at the group of Prof. Dr. R. F. Winter, University of Regensburg
References
1. K. Kowalski, M. Linseis, R. F. Winter, M. Zabel, S. Záliš, H. Kelm,; H-J. Krüger, B. Sarkar, W.
Kaim, Organometallics 2009, 28, 4196.
2. G. Tabbi, G. Cassino, G. Cavigiolio, D. Colangelo, A. Ghiglia, I Viano, D. Osella, J. Med. Chem.
2002, 45, 5786.
3. M. Auzias, B. Therrien, G. Süss-Fink, P. Stepnicka, W.H. Ang, P. J. Dyson, Inorg. Chem. 2008, 47,
578.
4. I. Ott, K. Kowalski, R. Gust, J. Maurer, P. Mücke, R.F. Winter, Bioorg. Med. Chem. Lett. 2010, 20,
866-869.
79
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
P-22
Green Chemistry in the Production of Ferrocene Derivatives Using Recyclable
Solid Heteropolyacids as Catalysis
Jorge Jios,a Gustavo Romanelli,b and Nils Metzler-Nolte*c
a
Laseisic (CIC-CONICET-UNLP), Departamento de Química, Facultad de Ciencias Exactas, UNLP.
Camino Centenario e/505 y 508, CP1897, Gonnet, Argentina. b Centro de Investigación y Desarrollo
en Ciencias Aplicadas “Dr. J. J. Ronco” (CINDECA), Departamento de Química, Facultad de
Ciencias Exactas, UNLP-CONICET. Calle 47 Nº 257, B1900AJK La Plata, Argentina. c Lehrstuhl für
Anorganische Chemie I, Bioanorganische Chemie, Fakultät für Chemie und Biochemie, RuhrUniversität Bochum, Universitätsstrasse150, D-44801 Bochum, Germany. E-mail:
jljios@quimica.unlp.edu.ar
Dihydropyrimidinone are known to exhibit a wide range of biological activities such as antiviral,
antitumour, antibacterial, and anti-inflammatory properties.1 Several reagents/methods have been
reported for their preparation under milder and more efficient procedures such as Amberlyst-15,
Nafion-H, KSF clay with dry acetic acid under microwave irradiation, ionic liquids, cerric ammonium
nitrate under ultrasonication, Lewis acids with transition metals, lanthanides, and indium chloride.2 In
this work we present an improved procedure for the obtention of dihydropyrimidinones bearing
ferrocene in a three component one-pot condensation reaction using heteropolyacid catalysts (Figure
1).
O
C
Fe+2
Fe+2
H
NH2CONH2
+
O
R
O
Superacid Catalyst
O
R'
R´
NH
R
N
H
O
The results are discussed in terms of the catalyst used, their selectivity and the reaction conversion
degree. The aim of this work is investigate a convenient synthesis for the production of new
metallocene carrying heterocyclic compounds with biological activities. The spectral data are
discussed in detail.
References
1. C. O. Kappe, Tetrahedron 1993, 49, 6937-6963, and references cited therein.
2. (a) F. Bigi, S. Carloni, B. Frullanti, R. Maggi, G. Sartori, Tetrahedron Lett. 1999, 40, 3465-3468.
(b) J. Peng, Y. Deng, Tetrahedron Lett. 2001, 42, 5917-5919. (c) J. S. Yadav, B. V. S. Reddy, K. B.
Reddy, K. S. Raj, A. R. J. Prasad, Chem. Soc. Perkin Trans. 1 2001, 1939-1941. (d) E. H. Hu, D. R.
Sidler, U. H. Dolling, J. Org. Chem. 1998, 63, 3454-3457. (e) Y. Ma, C. Qian, L. Wang, M. Yang, J.
Org. Chem. 2000, 65, 3864-3868. (f) J. Lu, Y. Bai, Z. Wang, B. Yang, H. Ma, Tetrahedron Lett. 2000,
41, 9075-9078. (g) B. C. Rannu, A. Hajra, U. Jana, J. Org. Chem. 2000, 65, 6270-6272. (h) H. N.
Karade, M. Sathe, M. P. Kaushik. Molecules 2007, 12, 1341-1351.
80
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
P-23
Antiproliferative Activity of Diphenylmethylidenyl-[3]ferrocenophanes on Breast
and Prostate Hormone-independent Cancer Cell Lines
Meral Gormen,a Pascal Pigeon,a Siden Top,* a Elizabeth A. Hillard,a Marie-Aude Plamont,a
Anne Vessières,a amd Gérard Jaouena
a
ENSCP, Laboratoire Charles Friedel, UMR 7223, 11, Rue Pierre et Marie Curie, 75231, Paris,
Cedex 05, France. E-mail: meral-gormen@chimie-paristech.fr
Breast cancer is the leading cause of cancer death among women in the Western world and accounts for
23% of all female cancer cases worldwide.1 In terms of incidence rate, breast cancer touches one woman in
eight in Western countries.
Tamoxifen, whose active metabolite is hydroxytamoxifen (1), is currently the most widely used antiestrogen
in the adjuvant therapy of hormone-dependent breast cancers.2 However, it is known that one-third of these
cases are hormone-independent cancers, and don’t respond to tamoxifen therapy. We found that
hydroxyferrocifen (2) and ferrocifenol (3) exhibit strong antiproliferative activities against both hormonedependent MCF-7 cancer cells and hormone-independent MDA-MB-231cancer cells.3
OH
OH
HO
R1
OH
Fe
Fe
O(CH 2)2N(CH 3)2
1
R2
Fe
OR
4
2. R = (CH2)3N(CH3)2
3. R = H
5
R1,R2= H,OH,NH2,NHAc
It has recently been shown that dihydroxy [3]ferrocenophane 4 is 7 times more potent than ferrocifenol 3 on
MDA-MB-231 cells.4 We now extend our work on this new and interesting series by synthesizing other
compounds by varying the nature of the substituents R1 and R2 (5).5 These new compounds show high
activity compared to that of classical ferrocene analogues. The inhibitory concentrations (IC50) of 5 on
MDA-MB-231 cells range from 50 to 90 nM.
Our work was extended to prostate cancer which is one of the most frequently diagnosed cancers and is the
second leading cause of cancer death in men after lung. We found that [3]ferrocenophane derivatives are also
active against PC3 hormone-independent prostate cancer cells with IC50 ranging from 20 to 140 nM.
Synthesis and antitumor activities of [3]ferrocenophane derivatives will be presented.
References
1. (a) J. Ferley, F. Bray, P. Pisani, D. M. Parkin. GLOBOCAN 2002: Cancer Incidence, Mortality and
Prevalence Worldwide. IARC CancerBase No. 5 version 20. IARCPress, Lyon, France, 2004. (b) A.
Jemal, R. Siegel, E. Ward, T. Murray, J. Xu, M. J. Thun, CA Cancer J Clin 2007, 57, 43-66. (c) R. Y.
Wood, N.R. Della-Monica. Int. J. Older People Nursing, 2006, 1 (2), 75-84.
2. (a) V. C. Jordan, J. Med. Chem., 2003, 46 (6), 883-908 (b) V. C. Jordan, J. Med. Chem., 2003, 46 (7),
1081-1111.
3. S. Top, A. Vessières, G. Leclercq, J. Quivy, J. Tang, J. Vaissermann, M. Huche, G. Jaouen.
Chem. Eur. J., 2003, 9, 5223-5236. (b) A. Vessières, S. Top, P. Pigeon, E. Hillard, L. Boubeker,
D. Spera, G. Jaouen J. Med. Chem., 2005, 48, 3937-3940
4. D. Plazuk, A. Vessieres, E.A. Hillard, et al. J. Med. Chem., 2009, 52, 4964-4967.
5. M. Gormen, P. Pigeon, E.A. Hillard, et al. Tetrahedron Lett., 2010, 51, 118-120.
81
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
P-24
Cell Uptake and Cytotoxicity of Metal-Peptide-Bioconjugates
Annika Großa and Nils Metzler-Nolte*a
aRuhr-University Bochum, Faculty of Chemistry and Biochemistry, Department of
Inorganic Chemistry I, Universitätsstr. 150, 44801 Bochum, Germany
E-mail: Annika.Gross@rub.de
Organometallic conjugates of cell-invasive peptides are proposed as interesting candidates for a future
generation of novel cancer therapies since they are structurally unique compared to other classes of
routinely used cytotoxic drugs. We therefore aimed to synthesise various metal compounds linked to
peptides.
Solid and solution phase methods were used to generate peptides and their fluorescent and metal
containing analogs. Cell uptake, and the effect of the metal was investigated by comparison of
metallocene-peptide conjugates to acetylated peptides using fluorescence microscopy. Intracellular fate
was examined in co-localisation studies using compartment-specific dyes.
Cytotoxicity studies of functionalised peptides were performed using the Resazurin and Crystal Violet
proliferation assays on different cell lines.
Peptides containing acetyl, ferrocene, ruthenocene, cobaltocene and cobalt carbonyl moieties were
successfully synthesised, purified and characterised. All bioconjugates were cell permeable and colocalised with a lysosome-specific dye. Metallocene and reference compounds were not toxic in the range
100-1000 µM. However, depending on the cell line, the cobalt carbonyl gave IC50 values down to 10 µM
in these assays. Ferrocene, ruthenocene and cobaltocenium show no cytotoxicity, but cobalt carbonyl
renders the conjugate cytotoxic.
82
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
P-25
On the Mechanism of Hydroxyferrocifen Cytotoxicity
Didier Hamels,a Patrick M. Dansette,b Elizabeth A. Hillard,a Siden Top,a Anne Vessières,a Gérard
Jaouen,a and Daniel Mansuy.b
a
Chimie ParisTech, Laboratoire Charles Friedel, UMR 7223; 11, rue Pierre et Marie Curie
75231 Paris Cedex 05, France. b Université Paris Descartes, Laboratoire de Chimie et Biochimie
Pharmacologiques et Toxicologiques, UMR 8601; 45, rue des Saints Pères 75006 Paris, France.
E-mail : didier-hamels@chimie-paristech.fr
Breast cancer is one of the most common cancers of women in the Western World. When the estrogen
receptor (ER) is expressed in tumor cells, the breast cancer is categorized as hormone-dependent
(ER+). ER+ breast cancer is the most commonly diagnosed (2 out of 3 cases), and can be treated with
the help of selective estrogen receptor modulators (SERMs). Some SERMs act as ER antagonists in
the cancer cell, thus preventing cell division. Unfortunately, SERMs are not active against ER breast
cancer cells, and alternative molecules have to be found.
In 1996, Jaouen et al. designed and synthesized “hydroxyferrocifen”, a compound in which one of the phenyl groups of
Me
hydroxytamoxifen had been replaced by a ferrocene moiety.1
The original idea was to combine the antiestrogenic effect of
R
hydroxytamoxifen with the potentially cytotoxic effect of
Fe
N
ferrocene. Our expectations were rewarded by the discovery
O
that hydroxyferrocifen is indeed active against ER+ (MCF-7)
A hydroxyferrocifen
R = Ph : hydroxytamoxifen
derivative QM (QM-1)
R = Fc : hydroxyferrocifen
and ER (MDA-MB-231) breast cancer cells.2 When the side
chain was extended to three carbon atoms, the resulting Fc-OHTam[3] molecule was found to be even
more cytotoxic.
We thus decided to investigate the mechanism of action of the
hydroxyferrocifens and related molecules. We hypothesized that
their cytotoxicity is due to the in situ formation of highly
cytotoxic quinone methide (QM) species. This interpretation was
supported by electrochemical experiments3 but neither
hydroxytamoxifen4 nor hydroxyferrocifen QMs had ever been
isolated this far. Metabolic and chemical oxidation of FcOHTam[3] and three related conjugated ferrocene phenols
allowed us to isolate and characterize the QMs by 1H and 13C
QM-1 X-ray crystal structure
NMR spectroscopy, and by X-ray crystallography in one case.
The obtained QMs were then tested against ER breast cancer
cells (MDA-MB231) and were found to be cytotoxic.5 This strongly supports the hypothesis that QMs
are indeed relevant intermediates in the cytotoxicity of hydroxyferrocifens and related molecules
against breast cancer cells. We are currently investigating the reactivity of such QMs in order to identify potential biological targets.
OH
Me
O
References
1. Top et al., Chem. Com. 1996, 955-956.
2. Top et al., Chem. Eur. J. 2003, 9, 5223-5236.
3. Hillard et al., Angew. Chem. Int. Ed. 2006, 45, 285-290.
4. Fan et al., Chem. Res. Toxicol. 2000, 13 (1), 45-52.
5. Hamels et al., Angew. Chem. Int. Ed. 2009, 48, 9124-9126.
83
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
P-26
Influence of Cisplatin and Other (Bio-)organometalic Compounds on Changes in
Cellular Signaling Using Novel Phosphoprotein Microarray Elisa Assays
Pavlo Holenya,a Igor Kitanovic,a and Stefan Wölfl*a
Institute of Pharmacy and Molecular Biotechnology, University Heidelberg, Germany
Im Neuenheimer Feld 364, D-69120 Heidelberg, Germany
E-mail: wolfl@uni-hd.de
Understanding aspects of the regulatory network of signaling pathways and their role in the
development of the diseases is one of the crucial starting points in drug research. Signal transduction
in cells is regulated, among other things, by phosphorylation and dephosphorylation of numerous
signaling proteins. In many cases, phosphorylation reflects the activation state of those proteins within
pathways that control various biological responses. In order to understand how drugs influence cells
by modulating different pathways, it is highly desirable to simultaneously measure the
phosphorylation states of diverse signaling proteins and temporarily monitore their levels in cells.
For this we used a novel technology based on protein microarray platforms ArrayTubeTM and
ArrayStripTM developed by CLONDIAG Chip Technologies, Jena. Both platforms represent less
expensive and easy to handle systems for the development of protein arrays. The heart of the device is
a chemically modified glass surface assembled to form the bottom of a 1.5 ml plastic polystyrol
microtube or a standard well of a 96-well plate. Capture antibodies are deposited onto agarose-film
coated glass surface by contact spotting. Handling of the protein chip is easy and rapid and involves
the simple steps of an ELISA in a sandwich format. Specific interactions of antibody and antigen are
simply revealed by colorimetric detection. Acquisition and analysis of processed chip images are
performed by optical transmission microscopy in combination with image analysis software.
Using the ArrayTubeTM and ArrayStripTM platforms and commercially available capture and detection
antibodies, we established a protocol to quantitatively analyze changes in protein phosphorylation
upon treatment with diverse organometallic compounds. We demonstrate high sensitivity and
specificity of the microarrays and show quantitative analysis of several phosphorylated proteins,
among them phospho GSK-3β, phospho RSK1, phospho Akt1, phospho p38α, phospho Erk1, phospho
Erk2, phospho CREB, phospho TOR, phospho Src, phospho JNK, phospho p53, phospho STAT3,
phospho ATM.
Our results show that these newly developed arrays enable reliable evaluation of multiple target
protein phosphorylation in a single sample. The method requires minimal sample volumes (~10 μl)
and minimal amount of total protein (~1 μg) to obtain quantitative data, and it enables rapid evaluation
of multiple analytes.
We thank Clondiag GmbH, Jena, Germany for providing the microarray technology and the
colleagues from the DFG-Forschergruppe FOR630 for bioorganometallic substances.
84
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
P-27
Variable Binding of Heterodinuclear (Cu, Fe) Organometallics to N and O Donor
Functions of Guanine, Pterin, Lumazine and Alloxazine Heterocycles
Rajkumar Jana,a Biprajit Sarkar,a Jan Fiedler,b and Wolfgang Kaim*a
a
Institut für Anorganische Chemie, Universität Stuttgart, Pfaffenwaldring 55, D-70550, Stuttgart,
Germany; b J. Heyrovský Institute of Physical Chemistry, v.v.i., Academy of Sciences of the Czech
Republic, Dolejškova 3, 182 23 Prague 8, Czech Republic. E-mail: jana@iac.uni-stuttgart.de
Co-ordination compounds of the first row transition elements with small biorelevant heterocycles such
as coenzymes, vitamins, and also nucleobases are frequently labile, precluding the isolation and
structural identification of species present in solution equilibria. In contrast, complexes of the heavier
d block elements are often inert as exemplified by the platinum and platinum metal coordination
chemistry of nucleobases1 and coenzymes2. Herein we wish to report a number of first row transition
metal compounds which owe their stability to the use of a particular kind of organometallic complex
fragments, viz., [(dopf)Cu]+, dopf = 1,1`-bis(diorganylphosphino)ferrocene.
Fe
Fe
R2 P
R2 P
O
H
ButOC
PR 2
N
N
Me
O
H
N
N
N
H
+
Cu
But OC
N
H
+
Cu
Fe
PR 2
O
Me
N
N
N
R 2P
O
N
+
Cu
N
N
N
Me
N
Fe
R2 P
PR 2
O
Me
O
N
N
+
Cu
PR 2
N
Me
N
Me
Me
The dopf ligands are being extensively used as scaffolding chelate ligands in catalysis3, 4, sometimes
using their propensity for reversible one-electron oxidation at the ferrocene iron site. Our experience
especially with the dppf ligand (dppf = 1,1`-bis(diphenylphosphino)ferrocene) in heterobimetallic
[(dppf)Cu]+ to stabilize complexes with unreduced strong acceptors such as α-azoimines5 or oquinones6 has prompted us to explore the coordination of [(dppf)Cu]+ and [(dippf)Cu]+, dippf = 1,1`bis(diisopropylphosphino)ferrocene, with other small biorelevant unsaturated molecules containing the
lumazine, isoalloxazine, pterin and guanine heterocyclic structures. Synthesis and structural
characterization will be reported as will be electrochemical studies on oxidation (ferrocene) and
reduction (heterocycles).
References
1. (a) D. Montagner, E. Zangrando, B. Longato, Inorg. Chem. 2008, 47, 2688-2695. (b)
Cisplatin: Chemistry and Biochemistry of a Leading Anticancer Drug; B. Lippert, Ed.; Wiley-VCH,
Weinheim, 1999.
2. Bioorganometallics: Biomolecules, Labelling, Medicine; G. Jaouen, Ed.; Wiley-VCH, Weinheim,
2006.
3. L. M. Alcazar-Roman, J. F. Hartwig, A. L. Rheingold, L. M. Liable-Sands, I. A. Guzei, J. Am.
Chem. Soc. 2000, 122, 4618-4630.
4. M. S. Driver, J. F. Hartwig, J. Am. Chem. Soc. 1997, 119, 8232-8245.
5. S. Roy, M. Sieger, B. Sarkar, B. Schwederski, F. Lissner, T. Schleid, J. Fiedler, W. Kaim, Angew.
Chem. Int. Ed. 2008, 47, 6192-6194.
6. S. Roy, B. Sarkar, D. Bubrin, M. Niemeyer, S. Zalis, G. K. Lahiri, W. Kaim, J. Am. Chem. Soc.
2008, 130, 15230-15231.
85
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
P-28
Synthesis, Structure and Anticancer Activity of new Complexes of Copper
with Pyridoxal-semicarbazone
Violeta Jevtovic,*a Dragoslav Vidovic,b Radmila Kovacecic,c and Sonja Kaisarevicc
a
University of Novi Sad, Faculty of Sciences, Department of Chemistry, D. Obradovica 3, 38121,
Novi Sad, Serbia
b
University of Oxford, Chemical Research Laboratory,Masfield Road ,OX1 3TA, City, UK.
c
University of Novi Sad, Faculty of Sciences, Department of Biology, D. Obradovica 3, 38121, Novi
Sad, Serbia. E mail: violeta.jevtovic@dh.uns.ac.rs
With reaction of ligand pyridoxal-semicarbazone PLSC.2H2O1 and appropriate chloride, sulphate
and thiocyanate salts Cu(II) in alcohol and water mixtures which were given in three new copper(II)
complexes: [Cu(PLSC)Cl2](1),[Cu(PLSC)(H2O)(SO4)]2.3H2O(2), [Cu(PLSC)2(NCS)2](NCS)2 (3)
(see Fig.1). Cytototoxic activity was evaluated by colorimetric sulforhodamine B (SRB) assay, after
exposure of cells to tested compounds for 24 h and 72 h. (see Fig 2.) shows effect of different
concentrations of tested compounds on two cell lines after 24 h and 72 h incubation times. The results
suggest that compound (A) exibit no antiproliferative effect. Compound (B) exibit cytotoxic effects
on both cell lines only after 72h treatment by the highest tested concentrations. Similar cytotoxicity
patern was observed for compound (C) with aditional cytotoxic effect on MDA-MB-231 after 24 h
treatment with the highest concentration.
(1)
(2)
Figure 1. The molecular structure of complexes
(3)
Figure 2. Effects of compounds (1), (2) and (3) on cell proliferation of MCF7 and MDA-MB-231
References
1. V. Leovac, V.S. Jevtovic, Lj. Jovanovic, G.A. Bogdanovic, J. Serb. Chem. Soc. 2005, 70, 393-422.
86
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
P-29
Transcriptional Profile of HT-29 Cells upon Treatment with Different
Organometallic Compounds
Igor Kitanovic,a Ana Kitanovic,a Hamed Alborzinia,a Suzan Can,a Pavlo Holenya,a Elke Lederer,a
Hans-Günther Schmalz,b Annegret Hille,c Ronald Gust,c Ingo Ott,d Aram Prokop,e Melanie Oleszak,f
Yvonne Geldmacher,f William S. Sheldrick,f Gilles Gasser,g Nils Metzler-Nolte,h and Stefan Wölfl*a
a
Institute of Pharmacy and Molecular Biotechnology, University Heidelberg, Germany, b Institute of
Inorganic Chemistry, University of Cologne, Germany, c Institute of Pharmacy, Department of
Pharmaceutical Chemistry, Freie Universität Berlin, Germany, d Institute of Pharmaceutical
Chemistry, Technische Universität Braunschweig, Germany, e Cologne City Hospital, Department of
Oncology, Cologne, Germany, f Faculty of Chemistry and Biochemistry, Department of Analytical
Chemistry, University Bochum, g Institute of Inorganic Chemistry, University of Zurich, h Faculty of
Chemistry and Biochemistry, Department of Bioinorganic Chemistry, University of Bochum
email: Igor.Kitanovic@urz.uni-heidelberg.de, wolfl@uni-hd.de
In the past several decades metal compounds containing platinum became an essential part of many
clinical protocols for anti-cancer therapy. Considered to be relatively unspecific compounds that block
DNA-replication and cell cycle progression, metal-containing compounds were not in the research
focus of medicinal chemistry. New developments in the chemistry of (bio-)organometallic compounds
however lead to the discovery of several unexpected highly specific activities of new organometallic
compounds and opened new important perspectives in this field.
For cancer therapy cancer cell specific toxicity and apoptosis induction are highly desirable features of
new potential drugs. Within our collaborative network a wide range of new (bio-)orgamometallic
compounds were developed that show very distinct cytotoxic properties suggesting that rather than
acting through a common mechanism different cellular targets are responsible for cytotoxicity and cell
death induction.
We will present a comprehensive analysis of the cellular response of human colorectal
adenocarcinoma cells HT29 with very diverse organometallic compounds: ranging from FeIIsalophenes, through more classical bioorganometallic compounds to bioorganometallic compounds
derived from established (non-metal containing) drugs. To elucidate their specific activity profile,
standard cell based assays were combined with genome wide gene expression profiling using
affymetrix gene expression arrays. Although the substances represent a wide range of different
structures and metal cores, they all are highly cytotoxic and clearly induce apoptosis in HT-29 cells.
For gene expression profiling concentrations just below the IC50 (cytotoxicity) were chosen to obtain
more compound specific alterations in gene expression rather then common cytotoxicity profiles, in
addition mRNAs were collected at different time points critical in the cellular response upon
treatment.
The results obtained show similar response characteristics, but also very compound specific changes.
This clearly indicates very distinct biological properties and suggests common response mechanisms
as well as high selectivity and target specificity.
List of compounds: Hi41, CoASS (AG Gust), MH1 (AG Scheldrick), MeN69 (AG Schmaltz),
FcOHTAM3, ReGG1 (AG Metzler-Nolte)
This work is supported by the DFG as part of the Forschergruppe FOR630.
87
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
P-30
Organoiridium(III) and -rhodium(III) Bis-Intercalators: Influence of the
Bridging Ligand on Cytotoxicity
Malte Kokoschka,a Andreas Meyer,b Ingo Ott,b and William S. Sheldrick*a
a
Ruhr-Universität Bochum, Faculty of Chemistry and Biochemistry , Department of Analytical
Chemistry, Universitätsstraße 150, 44801, Bochum, Germany. b Technische Universität
Braunschweig, Institute of Pharmaceutical Chemistry, Beethovenstraße 55, 38106, Braunschweig,
Germany. E-mail: malte.kokoschka@rub.de
As we have recently shown, dinuclear iridium(III) polypyridyl complexes bridged by flexible ligands
are capable of sequence selective intercalation into a synthetic DNA oligomer.1 Induced structural
changes in DNA – which have been proposed to account for the cytotoxicity of cisdiamminedichloroplatinum(II) – should be closely related to the molecular shape of the employed
bridging ligand. Taking advantage of our findings from NMR assisted structure calculations on a
double-stranded decanucleotide bis-intercalator adduct, we have started a systematic investigation of
bis-intercalative compounds incorporating bridging ligands such as 1,3-benzenedithiol, 1,3- and 1,4benzenedimethanethiol with the ability to induce stronger distorsions into DNA. The resulting
compounds have being studied with respect to their cytotoxicity and DNA interaction, respectively.
[{(η5-C5Me5)Ir(dppz)}2(µ-2,9-dithiadecane)]4+ bis-intercalated into the double-stranded decanucleotide
d(5’-GCGCATCGGC-3’) as determined by NOESY NMR spectroscopy
References
1. M. Kokoschka, J.-A. Bangert, R. Stoll, W. S. Sheldrick, Eur. J. Inorg. Chem. 2010, 1507-1515.
88
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
P-31
Synthesis, Structures, Characterization and Biological Activities of Some
Diorganotin(IV) Complexes
See Mun Lee,*a H. Mohd. Ali,a and K. M. Loa
a
University of Malaya, Faculty of Science, Department of Chemistry, 50603 Kuala Lumpur,Malaysia.
E-mail: smlee@um.edu.my
Metal complexes are widely prepared and have been successfully used in the treatment of numerous
human diseases including cancer. Organotin(IV) complexes have been widely studied for their
biological activities such as anticancer, antihistamine, antifungal and many others. Schiff base derived
from substituted salicylaldehyde has been widely used as polydentate ligands in the preparation of
metal complexes. In our present studies, a series of Schiff base ligands were prepared by reacting 3hydroxy-2-naphthoic hydrazide with substituted 2-hydroxyacetophenone. The diorganotin complexes
were subsequently prepared by adding the ligands with diorganotin dichloride or oxide in 1:1 molar
ratio and were characterized by various spectroscopic methods including IR, NMR spectroscopies.
The X-ray structures of some of the diorganotin complexes namely
{[1-(5-Bromo-2-oxidophenyl)ethylidene]-3-hydroxy-2-naphthohydrazidato}dimethyltin(IV)
{[1-(5-Bromo-2 oxidophenyl)ethylidene]-3-hydroxy-2-naphtho-hydrazidato}dibutyltin(IV)
{[1-(5-Chloro-2-oxidophenyl)ethylidene]-3-hydroxy-2-naphtho-hydrazidato}dimethyltin(IV) and
{[1-(5-Chloro-2-oxidophenyl)ethylidene]-3-hydroxy-2-naphtho-hydrazidato}dimethyltin(IV)
have been determined using single crystal X-ray diffractometry. The in vitro cytotoxic activity of the
Schiff base ligands and diorganotin complexes has been evaluated against several cancer cell-lines
such as HT-29, SKOV-3 and MCF7.
References
1. M. Gielen, Coord. Chem. Rev. 1996, 151, 41-51.
2. A. J. Crowe, P. J. Smith, C. J. Cardin, H. E. Parge, F. E. Smith. Cancer Lett. 1984, 24 45-48.
89
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
P-32
Organometallic Iridium Anticancer Complexes
Zhe Liu, Abraha Habtemariam, Ana Pizarri, Sally Fletcher, Guy Clarkson and Peter J. Sadler
Department of Chemistry, University of Warwick, Coventry CV4 7AL, U.K.
E-mail: Z.Liu.2@warwick.ac.uk
Cisplatin has been used to treat various types of cancers for over 30 years, however, a number of
serious side-effects of cisplatin have stimulated the long quest for other metal-based anticancer agents,
especially drugs which possess a wider range of anticancer activity and with fewer side effects than
cisplatin. There is much current interest in the design of ruthenium1 and osmium2 complexes as
anticancer agents, but only a small amount of work has been done to investigate the antitumour
activity of iridium complexes.3
Here we report the synthesis and characterization of a wide range of Ir(III) cyclopentadienyl
complexes. We have studied their solid state structures, hydrolysis rates, reactivity towards
nucleobases and acidity of aqua complexes. Their cell uptake and distribution and toxicity towards
cancer cells have been studied and correlated with their chemical properties. Both the chemical and
biological activity of these complexes show a strong dependence on the nature of the substituents on
the cyclopentadienyl and the other ligands in the complexes.
Acknowledgements: We thank WPRS (scholarship for Z.L), ERC (award for P.J.S.), EDRF and
AWM for Science City funding, and members of COST Action D39 for stimulating discussions.
References
1. (a) A. Habtemariam, M. Melchart, R. Fernndez, S. Parsons, I. D. H. Oswald, A. Parkin, F. P. A.
Fabbiani, J. E. Davidson, A. Dawson, R. E. Aird, D. I. Jodrell, P. J. Sadler, J. Med. Chem., 2006, 49,
6858-6868. (b) J. M. Redemaker-Lakhai, D. van den. Bongard, D. Pluim, J. H. Beijnen, J. H. M.
Schellens, Clin. Cancer Res. 2004, 10, 3717–3727. (c) I. Bratsos, S. Jedner, T. Gianferrara, E. Alessio,
Chimia 2007, 61, 692-697.
2. (a) A. F. A. Peacock, S. Parsons, P. J. Sadler, J. Am. Chem. Soc. 2007, 129, 3348-3357. (b) P.C. A.
Bruijnincx and P. J. Sadler, Adv. Inorg. Chem. 2009, 61, 1-62.
3. S. Schäfer, I. Ott, R. Gust, W. S. Sheldrick, Eur. J. Inorg. Chem. 2007, 3034-3046.
90
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
P-33
The Research of the Interaction between Quercetin and Zirconium (IV) in
Water-Ethanol Medium
Olessya Loiko,a A.Khalitova,a B.Tuleuov,b A.Mashentseva*c
a
Karaganda State University, Faculty of Chemistry, Department of Chemistry, Universitetskaya 28,
100000, Karaganda, Kazakhstan. b ISPH “Phytochemistry”,Gasalieva str.4 , 100000, Karaganda,
Kazakhstan. c L.N.Gumilev Eurasian national university, Faculty of Chemistry, Department of
Chemistry, Munajtpasova 5, 010008, Astana, Kazakhstan.
E-mail: olessya0905@gmail.com
It’s known, that the search of new compounds with radioprotective, antioxidant and hepatoprotective
activities is carried out among flavonoids;1 because of their structural molecule uniqueness they can
hamper not only oxidising processes, but also make transfer of energy and migration of elementary
particles at the irradiation. At the same time, examples of individual flavonoids (rutin and quercetin)
and their derivatives’ usage in the medical practice are single, despite their wide variety, accessibility
of their production sources and relative availability.
It is suggested that the biological activity of an organic ligand can be increased when co-coordinated
or mixed with suitable metal ion, because of its ability to act as a free radical acceptor.2 From the
pharmacology point of view zirconium (IV) complexes are noted for their significant biological
properties, namely antibacterial and antifungal activities. Information about mechanism of interaction
between zirconium (IV) and quercetin will help to explain and predict biochemical activity of these
components’ mixture in the medical product.
The ability to form complex between quercetin and zirconium (IV) was studied in this work using
spectrophotometer method. Quercetin zirconium (IV) complex is characterized by 3 absorption bands:
in UV and visible parts of spectrum at 360 nm, 395 nm and 475 nm; the extension coefficients (ε)
were calculated for these bands: 1042, 1045 and 2966 correspondingly. In the presence of metal ions,
a bathochromic shift on 55 nm is observed in the absorption spectra of complex. Such bathochromic
shift can be explained by the interaction of cobalt chloride with the free C3-oxo group of quercetin.
Investigated complex was synthesized in the solid state. IR spectra of ligand and complex present
evidence of the coordination between zirconium ions and oxo-group of quercetin. It can be noted that
Zr-O frequencies appear at 559.78, 538.53 and 472.02cm-1.
As the result of made researches of complex formation between zirconium (IV) and quercetin, the
influence of time, solvent and organic reagent concentration were studied. Studying the complex
solubility, it was determined that the compound sufficiently dissolves in water-ethanol mixture. It has
been shown, that if the content of ethanol is under 15%, the complex will fall in a precipitation. Using
Jobs method it was established, that made compound has content, which formula is C30H18O15Zr. The
stability constant of complex is (9,56 ± 0,01)·109, this number shows that the complex is averagely
stable. Complex forms at the room temperature.
According to the PASS biocsreening calculation follow activities for the synthesized complex are
antiparkinsonian, nootropic, cardioprotectant and creatine kinase inhibitor.
References
1. I.S. Vasil’eva, V.A. Paseshnichenko, The achievements of Biological Chemistry, 2000, 3, 153-156.
2. M.Y. Morandi, J. Pourahmad, Free Radic. Biol. Med. 2003, 34, 243‐250. 91
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
P-34
Photocytotoxicity and DNA Cleavage Activity of 2-Ferrocenyl Adducts having
Imidazophenanthroline and Imidazophenanthrene Moieties
Basudev Maity,a Mithun Roy,a Sounik Saha,a Ritankar Majumdar,b Rajan R. Dighe,b and Akhil R.
Chakravarty*a
a
Indian Institute of Science, Department of Inorganic and Physical Chemistry, bDepartment of
Molecular Reproduction, Development and Genetics, Sir C V Raman avenue, 560012, Bangalore,
India. E-mail: basudev@ipc.iisc.ernet.in
Ferrocene is an important constituent in the field of bioorganometallic chemistry related to nucleic
acids in spite of having any effective anticancer activity.1 It is the ferrocenium cation, the oxidized
form of ferrocene, which is responsible for the anticancer activity.2 The designing of new ferrocenebased molecules showing photo-induced DNA cleavage and/or photocytotoxic activities are of
interests for their potential applications in the field of molecular biology, biotechnology and
particularly in medicine. This presentation includes the synthesis, characterization, interactions with
DNA, photo-induced DNA cleavage activity and photocytotoxicity of 2-ferrocenylimidazophenanthroline (1)3 and 2-ferrocenyl-imidazophenanthrene (2). To understand the role of the
ferrocenyl moiety, 2-phenyl-imidazophenanthroline (3)4 has been studied as a control species.
Compound 2 has been characterized by X-ray crystallography. The interaction of the compounds with
DNA has been studied by UV-visible absorption titration and thermal denaturation methods. All the
compounds show good binding affinity to calf thymus DNA with intrinsic binding constant values of
~105 M-1. The thermal denaturation data suggest DNA groove binding nature of the compounds. They
show poor chemical nuclease activity in the presence of H2O2 as an oxidizing agent and are inactive in
the presence of cellular reducing agent glutathione. Compound 1 shows significant photo-induced
DNA cleavage activity in UV-A light of 365 nm and visible light of 488 (blue light) and 530 nm
(green light). The mechanistic investigations of the DNA cleavage activity reveal the involvement of
reactive oxygen species. The photocytotoxicity of the compounds in human cervical HeLa cancer cell
line has been studied in UV-A light of 365 nm.
References
1. D. R. van Staveren, N. Metzler-Nolte, Chem. Rev. 2004, 104, 5931-5985.
2. G. Tabbì, C. Cassino, G. Cavigiolio, D. Colangelo, A. Ghiglia, I.Viano, D. Osella, J. Med. Chem.
2002, 45, 5786-5796.
3. F. Zapata, A. Caballero, A. Espinosa, A. Tárraga, P. Molina, J. Org. Chem. 2008, 73, 4034–4044.
4. N. M. Shavaleev, H. Adams, J. A. Weinstein, Inorg. Chim. Acta 2007, 360, 700–704.
92
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
P-35
Carbon Monoxide Release and Biological Properties of Manganese Tricarbonyl
Trispyrazolyl Complexes
Johanna Niesel,a Hendrik Pfeiffer,a and Ulrich Schatzschneider*a
a
Ruhr-Universität Bochum, Lehrstuhl für Anorganische Chemie I, Universitätsstrasse 150, D-44801
Bochum, Germany. E-mail: johanna.niesel@rub.de
Carbon monoxide is an important small molecule messenger in the human body.1 For its controlled
release to biological systems, transition metal carbonyl complexes can be utilized to exploit the
beneficial physiological effects of CO like vasodilatation and protection against oxidative stress. In
addition, cytotoxic activity of carbon monoxide against cancer cells and pathogenic microorganisms
has been established. In contrast to hydrolytic liberation of CO from metal carbonyl complexes,
photoactivated CO release will allow for a precise spatial and temporal control of its biological
activity.2 Recently, we have identified [Mn(CO)3(tpm)]+ with tpm = tris(1-pyrazolyl)methane as a
stable in aqueous solution and inactive against cancer cells in the dark. However, upon light activation
it efficiently kills HT29 human colon cancer cells.3,4 To study the influence of the ligand system on the
CO release and the biological properties, manganese trispyrazolylcomplexes with variations on the
pyrazol rings6 or the alpha carbon7 were synthesized and their CO release efficiency as well as
biological activity against human breast cancer cells MCF7 and colon cancer cells HT-29 was
investigated.
c(MbCO) in µM
30
20
10
0
0
50
100
t(min)
References
1. S.W. Ryter, J. Alam, A.M.K. Choi, Physiol. Rev. 2006, 583-650.
2. U. Schatzschneider, Eur. J. Inorg. Chem. 2010, 10, 1451-1467.
3. J. Niesel, A. Pinto, H. W. Peindy N'Dongo, K. Merz, I. Ott, R. Gust, U. Schatzschneider, Chem.
Commun. 2008, 1798-1800.
4. H. Pfeiffer, A. Rojas, J. Niesel, U. Schatzschneider, Dalton Trans. 2009, 4292-4298.
5. K. Meister, J. Niesel, U. Schatzschneider, N. Metzler-Nolte, D.A. Schmidt, M. Havenith, Angew.
Chem. 2010, 122, 3382-3384; Angew. Chem. Int. Ed. 2010, 49, 3310-3312.
6. D.L. Reger, R.D. Sommer, J. Organomet. Chem. 2000, 607, 120-128.
7. B.J. Liddle, J.R. Gardinier, J. Org. Chem. 2007, 72, 9794-9797.
93
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
P-36
Novel Polypyrrole Substituted Carbon Monoxide Releasing Molecules
(CO-RMs); New Delivery System for Carbon Monoxide
Niall B. McGuinness,a Carmel B. Breslin,a and A. Denise Rooneya
a
Environmental Technologies and Biomaterials Research Group, Department of Chemistry,
National University of Ireland, Maynooth, Co. Kildare, Ireland. Email: niall.b.mcguinness@nuim.ie
Research has shown that minute quantities of carbon monoxide (CO) molecules produced in the
human body are a fundamental component for life processes, but in larger doses the inherent toxic
nature of CO cannot be ignored. However, CO liberated from CO-RMs can be accurately controlled
and delivered at precise concentrations. Beneficial actions of CO include cardioprotection against
blood flow restriction, heart attack and cardiac graft rejection; prevention against the increase of
strength in muscle contraction of the heart; and suppression of the inflammatory response1. A problem
associated with several of the CO-RMs is the transition metal (T.M.) employed, which can be toxic
due to accumulation in the human body.
O
O
N
H
N
CO
OC
N
N
H
N
H
N
N
N
Mo
OC
N
H
N
CO
N
N
O
O
Tetracarbonyl (4,4'-bis-(N-propyl-3-pyrrole-carbamoyl)-2,2'-bipyridine)
molybdenum (0)
4,4'-Bis-(N -propyl-3-pyrrole-carbamoyl)-2,2'-bipyridine
1
Figure 1: Novel substituted pyrrole monomer and metal complex synthesised.
2
We have set out to bind T.M. carbonyl complexes to polypyrrole, a biocompatible conducting
polymer. The carbonyl complex is trapped in the polymer so that after CO is released into the tissue
the complex can then be removed. The monomer unit 1 has been synthesised and successfully
undergoes electrochemical polymerization. Mo(CO)4 has been complexed to this monomer at high
yield using a microwave-assisted method. Before investigating the electrochemical response of the
polymer formed from complex 2, studies were carried out on 2 in solution. Electrochemical studies
indicate that upon 1-electron oxidation, Mo(CO)4(bipy-pyr) undergoes CO subsitution in a
coordinating solvent (Figure 2). Direct evidence that the oxidation results in CO release was provided
by studies performed using an Optically Transparent Thin-Layer Electrochemical (OTTLE) cell with
IR detection. Our results indicate that this is a promising approach for the controlled release of CO
from a polymer.
0.0002
Black: redox couple of Mo(CO)4(bpy‐pyr)
in DCM
Grey: redox couple of Mo(CO)4(bpy‐pyr)
in DCM with 3 eq. of MeCN present
0.0001
*
2
I (Amps/cm )
*
1‐electron oxidation and reduction
of Mo(CO)4(bpy‐pyr)
0
-0.0001
0
0.25
*
0.50
0.75
Loss of reduction peak
caused by rapid CO
substitution due to
presence of MeCN
1.00
1.25
E (Volts)
Figure 2: Cyclic voltammograms of Mo(CO)4(bipy-pyr) in DCM and MeCN.
References
1. R. Foresti, M. G. Bani-Hani, R. Motterlini Intensive Care Med. 2008, 34, 649-658.
94
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
P-37
Cytotoxicity Studies on Rhenium(I) Tricarbonyl Complexes
Teck-Tian Wong, Li-Peng Wong, Peng-Foo Peter Lee and Yaw-Kai Yan*
Nanyang Technological University, National Institute of Education, Natural Sciences & Science
Education Department, 1 Nanyang Walk, Singapore 637616. E-mail: yawkai.yan@nie.edu.sg
Since the late 1980’s, there has been a steady growth of interest in ruthenium anti-cancer drugs as
reflected in the accelerating growth of publications in this area.1 In particular, a series of water soluble
and stable ruthenium(II) arene ethylenediamine complexes (1) was shown to exhibit promising anticancer activity in vitro and in vivo.2 Anti-cancer activity has also been observed in rhenium(I)
tricarbonyl complexes.3 Since both rhenium(I) and ruthenium(II) are d6 configuration metal ions, it
would be interesting to investigate the anti-cancer activity of rhenium(I) tricarbonyl complexes with
N,N- and P,P- chelating agents. The three CO ligands of the Re(I) complexes correspond to the arene
ligand of the Ru(II) complexes in that both donate six electrons. The chelating N,N- and P,P- ligands
of the Re(I) complexes correspond to the ethylenediamine ligand of the Ru(II) complexes and both
types of complexes have a single ligand exchange site occupied by a monoanionic ligand.
In this study, we are concerned with the synthesis and bio-physicochemical characterization of a series
of mononuclear rhenium(I) tricarbonyl complexes [Re(X)(CO)3L2] (2) [where X = Br, Cl, Cl2HCCO2;
L2 = ethylenediammine (en), N,N,N′,N′-tetramethylethylenediamine (tmen), 2,2′-bipyridine (bpy),
N,N′-dimethylethylenediamine
(dmen),
2,2′-bipyridine-4,4′-dicarboxylic
acid
(H2bpdc),
1,3-bis(diphenylphosphino)propane (dppp) and 1,1′-bis(diphenylphosphino)ferrocene (dppf)]. All the
complexes were characterized by IR and 1H NMR spectroscopy and elemental analysis. The rhenium
complexes and their respective ligands were screened using the human leukaemia (MOLT-4) cell line
via the MTT assay. The results will be presented in the poster.
R
+
OC
OC
Ru
Cl
N
CO
Re
X
L
N
1
L
2
References
1. A. Levina, A. Mitra, P. L. Lay, Metallomics 2009, 1, 458-470.
2. Y. K. Yan, M. Melchart, A. Habtemariam, P. J. Sadler, Chem. Commun. 2005, 4764-4776.
3. (a) J. Zhang, J. J. Vittal, W. Henderson, J. Wheaton, I. H. Hall, T. S. A. Hor, Y. K. Yan, J.
Organomet. Chem. 2002, 650, 123-132. (b) Y. K. Yan, S. E. Cho, K. A. Shaffer, J. E. Rowell, B. J.
Barnes, I. H. Hall, Pharmazie 2000, 55, 307-313. (c) W. Wang, Y. K. Yan, T. S. A. Hor, J. J. Vittal, J.
R. Wheaton, I. H. Hall, Polyhedron 2002, 21, 1991-1999.
95
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
P-38
Bioorthogonal Coupling Strategies in the Synthesis of CORM-peptide Conjugates
Hendrik Pfeiffer,a Johanna Niesel,b and Ulrich Schatzschneider*a
a
Ruhr-Universität Bochum, Department of Chemistry and Biochemistry,
Universitätsstrasse 150, 44801 Bochum, Germany, hendrik.pfeiffer@rub.de
In the human body carbon monoxide possesses versatile properties as a signalling mediator and
participates in important biological processes. Beside being a potent vasodilator, CO can exert anti1,2
inflammatory, anti-apoptotic, and anti-proliferative effects. Since it is a toxic gas and difficult to
handle, there is considerable interest in the development of CO releasing molecules (CORMs) as
"solid storage forms" for carbon monoxide. Therefore, transition metal carbonyl complexes are highly
3
interesting target structures. Compared to thermally induced liberation of CO, photoactivated CO
4
release will allow for a precise spatial and temporal control of its biological action. We have recently
synthesized several tungsten, molybdenum, and manganese complexes with bidentate as well as
tridentate nitrogen donor ligands as promising new photoCORMs, which are inert in the dark in
aqueous solution, but release CO upon irradiation.5
Carrier peptides are important vehicles to achieve accumulation of bioactive cargos in specific
biological target sites. Thus, we have explored the functionalization of the parent photoCORMs with
model peptides using bioorthogonal coupling strategies, such as oxime ligation, Sonogashira crosscoupling, or the alkyne-azide 1,3-dipolar cycloaddition (click reaction).6
References
1. S. W. Ryter, J. Alam, A. M. K. Choi, Physiol. Rev. 2006, 86, 583-650.
2. T. R. Johnson, B. E. Mann, J. E. Clark, R. Foresti, C. J. Green, R. Motterlini, Angew. Chem. Int. Ed.
2003, 42, 3722-3729.
3. J. Boczkowski, J. J. Poderoso, R. Motterlini, Trends Biochem. Sci 2006, 31, 614-621.
4. U. Schatzschneider, Eur. J. Inorg. Chem. 2010, 1451-1467.
5. J. Niesel, A. Pinto, H. W. Peindy N'Dongo, K. Merz, I. Ott, R. Gust, U. Schatzschneider, Chem.
Commun. 2008, 1798-1800.
6. H. Pfeiffer, A. Rojas, J. Niesel, U. Schatzschneider, Dalton Trans. 2009, 4292-4298.
96
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
P-39
Metallocarbonyl Complexes of Bromo- and Dibromomaleimide. Synthesis and
Reactions with Cysteine Derivatives
Bogna Rudolf,a* Marcin Palusiak,b and Emilia Fornalc
a
Department of Organic Chemistry, University of Łódź, Tamka 12, Łódź 91-403, Poland,
b
Department of Crystalography and Crystal Chemistry, University of Lodz, Tamka 12,
Łódź 91-403, Poland
c
Chemistry Department, Faculty of Mathematics and Life Sciencies, The John Paul II Catholic
University of Lublin, al. Krasnicka 102, 20-718 Lublin, E-mail:brudolf@chemia.uni.lodz.pl
The maleimide motif is widely used for the selective reactions with thiols and there are numerous N–
functionalized maleimide reagents applied for cysteine modification. Among them the (η5C5H5)M(CO)x(η1-N-maleimidato) (M = Fe, x = 2; M = W, Mo, x = 3) markers were reacted
with cysteine containing peptides and proteins. These metallocarbonyl complexes display
characteristic strong absorption bands in their IR spectra, C≡O, appearing in the 1950-2060
cm-1 spectral region, which is usually free of any absorption of biomolecules or biological
matrices.1,2
Recently it was reported that the bromomaleimide and its derivatives are of interest for
bioconjugation and reversible cysteine modification.3,4
O
OC
OC
O
Br
Fe
N
O
HS
OC
OC
cysteine derivatives
Fe
N
S
O
1
In this communication, synthesis of metallocarbonyl derivatives of bromo- and dibromomaleimide
(e.g. 1) along with reactions of these complexes with cysteine derivatives will be presented.
References
1. B. Rudolf, J. Zakrzewski, Tetrahedron Lett. 1994, 35, 9611-9612.
2. B. Rudolf, M. Palusiak, J. Zakrzewski, M. Salmain, G. Jaouen, Bioconjugate Chem. 2005, 16, 12181224.
3. L. M. Tedaldi, M. E. B. Smith, R. I. Nathani, J. R Baker, Chem. Com. 2009, 43, 6583-6585.
4. M. E. B. Smith, F. F. Schumacher, C. P. Ryan, L. M. Tedaldi, D. Papaioannou, G. Waksman,
S. Caddick, J. R. Baker J. Am. Chem. Soc. 2010, 132, 1960-1965.
97
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
P-40
Molybdenum Carbonyl Complexes as CO Releasing Molecules
Lukas Kromera and Carlos Romão*a,b
a
ITQB-UNL, Av. da República, Estação Agronómica Nacional, 2780-157 Oeiras, Portugal.
b
ALFAMA Lda., Taguspark, Núcleo Central 267, 2740-122 Porto Salvo, Portugal.
E-mail: kromer@itqb.unl.pt
Carbon Monoxide (CO) is an essential signalling molecule produced in the body. Endogenous
overproduction of CO in pathological situations strongly suggests medicinal applications for CO.
Rather than using CO gas; drug research is focused on the development of CO-releasing Molecules
(CO-RMs).1 Although there are a large number of CO-RMs known, few if any fulfil the essential
criteria for use as drugs, such as solubility in aqueous solutions of physiological pH, stability during
storage and controlled release of CO in vivo, and efficacy at non-toxic doses. Furthermore, targeting of
specific tissue is desirable. To obtain water-soluble organometallic complexes, they either have to be
charged or contain ligands that can be ionised in aqueous solutions through protonation or
deprotonation.
Charged complexes were synthesised with two types of ligands: 1,3-diketone and 2-hydroxyketone
ligands. Both types of ligand can be deprotonated and form anionic complexes with the general
structure (Et4N)[Mo(O-O)(CO)4].2 A second series of neutral complexes bearing functional groups
were synthesised with several mono- and bidentate amine ligands in a conventional microwave.3
OC
Mo
OC
OC
O
0, 1
O
CO
-
R
CO
OC
R
CO R
2
N
Mo
N
CO R2
CO‐Hb formation in blood
4.00
3.50
3.00
a)
2.50
CO
OC
Mo
OC
b)
O
C
. 2.00
q
e
c)
1.50
NHR
1.00
0.50
NHR
CO
0.00
0
20
40
60
80
time [min]
The synthesised complexes were fully characterised and investigated in terms of solubility,
stability in aqueous solution and the CO release rate was determined both in vitro by GC-TCD as in ex
vivo assays in sheep blood with an Oxymeter. The direct measurement of CO-Hb levels in sheep blood
gives you an immediate answer about CO release under biological conditions. The water soluble,
neutral amine complexes exhibited a ligand-dependant CO release rate decreasing from primary,
secondary to tertiary amine ligands with half life times between 15 and 60 minutes. In contrary, the
results from the non water soluble amine and the less stable anionic complexes showed the limitation
of the setup, in which the solubility and stability under physiological conditions is crucial. In
conclusion, complexes with tuneable CO release rates are accessible and led to further improvements
in terms of stability and solubility of CO-RM’s.
References
1. R. Motterlini, B. E. Mann, R. Foresti, Expert Opin. Invest. Drugs 2005, 14, 1305-1318. (b) S. W.
Ryter, L. E. Otterbein, Bioessays 2004, 26, 270-280. (c) R. Motterlini, J. E. Clark, R. Foresti, P.
Sarathchandra, B. E. Mann and C. J. Green, Circ. Res. 2002, 90, E17-E24.
2. G. Doyle, J. Organomet. Chem 1973, 61, 235-245.
3. M. Ardon, G. Hogarth, D.T.W. Oscroft, J. Organomet. Chem. 2004, 689, 2429-2435.
98
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
P-41
Constrained Peptides Constructed by Coordination
of Propargylcysteines with Tungsten
Thomas A. McTeague, Zephyr D. Dworsky, and Timothy P. Curran*
Department of Chemistry, Trinity College, 06106, Hartford, CT, USA.
E-mail: timothy.curran@trincoll.edu
In prior work we have demonstrated that alkynes can be appended to peptide carboxylic acids (via
acylation with propargylamine) and amines (via acylation with propargylchloroformate), that peptides
bearing two alkynes can be prepared, and that reaction of these dialkynylpeptides with W(CO)3(dmtc)2
yields a cyclic peptide that incorporates the tungsten atom (which is called a metallacyclicpeptide).1,2
We have sought to use the tungsten-alkyne coordination to constrain peptides to specific threedimensional conformations; in one case peptide turns were constrained by the tungsten-alkyne
coordination.2 In an effort to create helical peptides we have appended alkynes to the side chain
amines of lysines, and have constructed peptides having two of these alkynyllysines. Coordination of
these dialkynylpeptides to tungsten has produced metallacyclicpeptides. Investigations using NMR
spectroscopy has shown that these metallacyclicpeptides are too flexible to constrain the peptide to a
specific conformation. In particular, in these metallacycles we have found that the two alkyne groups
can rotate around the tungsten center, generating a number of conformational isomers in solution.
We have hypothesized that appending the alkyne group to the side chain amine of lysine locates the ligand too far from the peptide backbone for coordination to tungsten to constrain the peptide.
Accordingly, we have begun investigations to see whether locating the alkyne group closer to the
peptide backbone will make the complexes more rigid. Towards this end we have been investigating
the use of propargylcysteine as our alkynylamino acid. Attractive features of propargylcysteine are
that it can readily be prepared in multigram quantities from cysteine, and derivatives of
propargylcysteine are easy to work with in peptide synthesis.
This presentation will discuss the preparation of peptides possessing two propargylcysteines, the
coordination of both alkynes in these peptides to tungsten, and the conformational analysis of the
resulting metallacyclicpeptides. Particular emphasis will be on the study of compounds 1 and 2.
CONHR
S
N
O
H
N
O
H
N O
S
H
N
ButO
H
2
H
N
O
O
S
O
NH
H
N
W(dmtc)2
S
O
1
W(dmtc)2
References
1. T. P. Curran, R. S. H. Yoon, B. R. Volk, J. Organometallic Chem., 2004, 689, 4837-4847.
2. T. P. Curran, A. B. Lesser, R. S. H. Yoon, J. Organometallic Chem., 2007, 692, 1243-1254.
99
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
P-42
Characterisation of Zeise´s Salt - Analogues Regarding Cytotoxicity and Stability
Sandra Meieranza amdRonald Gust*a
a
Freie Universität Berlin, Institute of Pharmacy, Königin-Luise-Str. 2+4, 14195 Berlin, Germany.
Platinum complexes are widely used in antitumor therapy. DNA is their main target in cells forming a
covalent bond to the N7 position of guanine. The intolerable side effects and the acquired resistance
during the therapy encouraged the synthesis of new platinum compounds to afford drugs with
improved pharmacological properties and broaden antitumor activity.1 Therefore, we synthesized
Zeise´s Salts analogues and examined their cytotoxicity in comparison to cisplatin. The complexes
were prepared according to literature procedures.2 Zeise´s Salt is known as a water stable platinum
complex.
We tested the synthesized compounds on hormone dependent MCF-7 and hormone independent
MDA-MB-231 breast cancer cell lines. The cytotoxicity was very low. Therefore, we determine the
stability in aqueous solution using HPLC and LC-MS. Interestingly, the ester in our compounds is
rapidly cleaved resulting in inactive degradation products. Further investigations on the stability are of
interest to get stabile Zeise´s Salt analogue platinum complexes.
References
1. Wong, E.; Giandomenico, C. M. Chem. Rev. 1999, 99, 2451.
2. Chock, P. B.; Halpern, J.; Paulik, F. E. Inorg. Syn. 1973, 14, 90.
100
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
P-43
Bengin Reactions with Acetylferrocene for the Synthesis of some
Ferrocenylhydrazones of Expected Biological Activity
Mohamed A. Metwally*a
a
Chemistry Department, Faculty of Science, University of Mansoura, P.O. Box 23, Mansoura, Egypt.
Email: mamegs@mans.edu.eg
Waste-free environmentally benign solid-state reactions means 100% yield of one product without any
necessity for purifying workup by recrystallization, chromatography, etc. Continuing our earlier
studies on ferrocenes,1,2 the solid state reaction of acetylferrocene using the ball-milling technique
with several hydrazines and hydrazides resulted in the formation of the hydrazones 1 in quantitative
yields (95-98%). The products were screened for their antibacterial and antifungal activities and gave
promising results.
CH3
C
N.NH.R
Fe
1, a, R= -C6H5NO2-p,
b, R= -C6H3(NO2)2-2,4-,
c, R= -SO2C6H5,
d, R= -CSNH2,
e, R= -COCH2CN
References
1. M.A. Metwally, E.E.M. Kandel, F.A. Amer, J. Indian Chem. Soc. 1987, 64, 517-518.
2. M.A. Metwally, F.A. Amer, J. Indian Chem. Soc. 1988, 65, 51-53.
101
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
P-44
Ferrocenyl Flavonoids: A Novel Class of Cytotoxics
Jean-Philippe Monserrat,a Elizabeth A. Hillard,a and Gérard Jaouen*a
a
Organometallic Medicinal Chemistry Team, UMR 7223, Laboratoire Charles Friedel
11, rue Pierre et Marie Curie
75231 Paris Cedex 05
Occupying the second step of the mortality podium in the western countries, cancer has become one of
the most widely studied diseases in the world, and one of the most challenging targets for scientists. In
order to combat the common problem of drug resistance, we have decided to approach the problem via
the redox machinery of the cell. It is now accepted that elevated levels of cellular oxidative stress and
dependence on ROS-signaling for mitosis and apoptosis represent a specific vulnerability of cancer
cells that can be targeted by redox modulators.1
Ferrocene is an organometallic complex that possesses a stable and reversible redox couple, and
possesses many attractive qualities for use in medicinal chemistry. Ferrocene-tamoxifen derivatives, in
particular, are known to be highly toxic against cancer cells via a redox mechanism.2
O
N
OH
OH
HO
O
Fe
OH
OH
OH
O
quercetin
hydroxyferrocifen
Flavonoids are a large class of natural products, some of which are active against cancer and are
thought to act, at least partially, via a redox mechanism. For instance, quercetin, in the process of
scavenging free radicals, can be converted to four quinone forms (QQ), which can form adducts with
glutathione, thus disturbing the redox balance of the cell.3 Other polyphenols specifically act as
prooxidants in oxidizing environments.4 Because some cancer cells are under oxidative stress, these
properties could be useful in the design of selective cancer agents.5,6 By the introduction of ferrocene,
we hope to modulate the flavonoids’ redox properties and enhance their antiproliferative effects.
We have recently discovered a novel reaction which gives easy access to the first reported ferrocenyl
flavones. Preliminary results show that the antiproliferative effects of ferrocene flavones against the
highly aggressive B16 mouse melanoma cell line are considerably stronger than those of organic
flavones, with IC50 values in the low micromolar range. The synthesis and biological results of this
original class of molecules will be presented.
References
1. G. T. Wondrak, Antiox. Redox. Sign. 2009, 11, 3013-3069.
2. E. A. Hillard, A. Vessières, L. Thouin, G. Jaouen and C. Amatore, Angew. Chem. Int. Ed. 2006,
45, 285-290.
3. W. Boots, H. Li, R. P. F. Schins, R. Duffin, J. W. M. Heemskerk, A. Bast and G. R. M. M.
Haenen, Toxicol. App.Pharmacol. 2007, 222, 89-96.
4. Simić, D. Manojlović, D. Šegan and M. Todorović, Molecules, 2007, 12, 2327.
5. H. Pelicano, D. Carney and P. Huang, Drug Resist. Update 2004, 7, 97-110.
6. Hoffman, L. M. Spetner and M. Burke, J. Theor. Biol. 2001, 211, 403-407.
102
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
P-45
Octahedral Ruthenium Complexes as Phosphatidyl-inositol-3-kinase Inhibitors
Stefan Mollin,a Jie Qin,b Ronen Marmorsteinb and Eric Meggers*a
a
Philipps-Universität Marburg, Fachbereich Chemie, Hans-Meerwein-Straße, 35032, Marburg,
Germany. bThe Wistar Institute, 3601 Spruce Street, 19104, Philadelphia, PA, USA.
E-mail: stefan.mollin@chemie.uni-marburg.de
The design of bioactive compounds for applications in medicinal chemistry and chemical biology is
focused predominantly on organic molecules, whereas inorganic compounds are mainly known for
their reactivity (e.g. cisplatin) or imaging properties (e.g. gadolinum complexes in MRI).1 However, in
recent years, MEGGERS et al. developed a novel strategy, wherein inert ruthenium(II) complexes were
designed as protein kinase inhibitors.2 Here, the ability of metal complexes is used to organize organic
ligands in three-dimensional space to form structures with unique and defined shapes. Based on the
natural product staurosporine 1, a potent but unselective kinase inhibitor, MEGGERS et al. designed
half-sandwich complexes initially and achieved a number of potent and selective inhibitors.
Phosphatidyl-inositol-3-kinases (PI3Ks) are a family of lipid kinases which act as signal transducers.
They serve phosphatidylinositol-3,4,5-triphosphate (PIP3), an important second messenger which
recruits AKT/PKB. Disruption of the PI3K signaling pathway leads to uncontrolled cell proliferation,
survival, and cell growth. Thus, PI3K is a highly attractive target for the development of therapeutic
agents to treat cancer and other related diseases.
MARMORSTEIN and MEGGERS et al. found that a methylation of the pyridocarbazole-imide leads to a
selectivity switch between protein and lipid kinases. Whereas half-sandwich complexes with free
imides were found as nanomolar GSK-3 and Pim-1 inhibitors, complex 2 shows good selectivity for
PI3Ks.3 To further increase the potency and selectivity our focus has shifted now to octahedral
compounds 3 with even more defined and rigid shapes. Following this strategy more potent inhibitors
have been synthesized with up to tenfold selectivity between the different isoforms PI3Kα and PI3Kγ.
References
1. C. Orvig, M. J. Abrams, Chem. Rev. 1999, 99, 2201-2204.
2. (a) H. Bregman, P. J. Carroll, E. Meggers, J. Am. Soc. 2006, 128, 877-884. (b) E. Meggers, G. E.
Atilla-Gokcumen, H. Bregman, J. Maksimoska, S. P. Mulcahy, N. Pagano, D. S. Williams, Synlett
2007, 8, 1177-1189.
3. X. Peng, D. S. Williams, G. E. Atilla-Gokcumen, L. Milk, X. Min, K. S. M. Smalley, M. Herlyn, E.
Meggers, R. Marmorstein, ACS Chem. Biol. 2008, 3, 305-316.
103
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
P-46
New Topoisomerase II Poisons
Matthew P. Akerman,a Mark T. Muller,b and Orde Q. Munro*a
a University of KwaZulu-Natal, School of Chemistry, AuTEK Biomed, Private Bag X01, Scottsville,
Pietermaritzburg, South Africa. b University of Central Florida, College of Medicine, Biomolecular
Research Annex, 12722 Research Parkway, 32826-3227, Orlando, FL, USA.
E-mail: munroo@ukzn.ac.za
DNA topoisomerase II (topo II) is a well-established anticancer drug target. We have identified novel
metallo-drugs that act specifically on topo IIA. Topo II enzymes are essential for life and are primarily
responsible for decatenation of daughter chromatids during mitosis.1 To function as a decatenase, topo
II makes a transient double strand DNA break, providing an enzyme/DNA gate through which a distal
duplex strand may pass.1 The DNA cleavage intermediate is unique since a covalent DNA-topo II
complex exists during the trans-esterification at the site of the break. Compounds that react with this
transient intermediate, forming a ternary DNA-enzyme-drug complex, can arrest or poison the
cleavage/religation cycle, inducing permanent DNA breaks, thereby damaging the genome of the
target cell. Acute cytotoxicity results as the cell accumulates double strand DNA breaks. Drugs that
induce breaks are topo II poisons and are generally excellent anti-cancer agents.
We have synthesized and fully characterized a series of crystalline d8 coordination compounds with
tetradentate ligands. The compounds were screened by the National Cancer Institute (NCI, USA)
against their panel of 60 human cancer cell lines. The most active compound is chiral, has a mean IC50
of 14(2) M, and is more cytotoxic than cisplatin (mean IC50 = 27 M). Some cancer cell lines were
substantially more susceptible to the new compounds than to cisplatin (ca. 12–30% of the cell lines
tested, depending on the compound used). Statistical comparison of the ex vivo data for the most active
compounds with drugs having known modes of action in the NCI database indicated that the cellular
target is most likely topo II. This prediction was confirmed by in vitro DNA cleavage experiments
using purified topo I and II and supercoiled DNA substrate. The data indicate that the compounds act
as poisons at low concentrations (best current EC50 ∼ 1 M) and as catalytic inhibitors at higher
concentrations (typical EC50 ∼ 20–30 M). The compounds are specific for topo II and do not target
topo I, even at high concentrations. In vivo experiments are currently underway to assess whether the
compound can target topo II in a chromatin setting. Preliminary data demonstrate that topo I is not
being targeted in the cancer cell lines tested.
Some of the compounds hydrolyze in aqueous buffer to generate metal-hydroxo derivatives. All
hydrolysis-inert compounds bind calf thymus DNA (pH 7 phosphate buffer, 37 C) with association
constants ranging from 1.43(3) × 105 to 1.01(4) × 106 M–1. The compounds with a high affinity for calf
thymus DNA were all active cytotoxic agents in the NCI-60 screen. Reduction of the compounds by
cellular levels of glutathione (pH 7 phosphate buffer, 37 C) was followed by visible spectroscopy.
Loss of the metal-to-ligand charge transfer (MLCT) band and appearance of the –* band of the free
ligand confirmed reductive demetallation of the chelate in each case. The kinetics had second-order
rate constants ranging from 0.0463(2) to 0.301(7) M–1 s–1. Importantly, the most active compounds in
the NCI-60 screen had the slowest reduction kinetics. Several structure–activity relationships for this
new class of topoisomerase II poison have thus been delineated. A provisional patent has been filed
and toxicology screens on the most active compounds have been scheduled.
Acknowledgements: We thank AuTEK Biomed (Mintek and Harmony) for permission to publish selected data
and financial support, the Department of Science and Technology (SA-COST EU Reciprocal Agreement) for a
travel grant, and the Developmental Therapeutics Program (NCI, USA) cytotoxicity screens.
References
1. K. C. Dong, J. M. Berger, Nature 2007, 450, 1201-1205.
104
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
P-47
Organometallic Ruthenium and Osmium Complexes with Carbohydrate-Based
Ligands as Anticancer Agents
Alexey A. Nazarov,a * Muhammad Hanif,b Lucienne Juillerat-Jeanneret,a Christian G.
Hartinger,b Olivier Zava,a Michael A. Jakupec,b Bernhard K. Keppler,b Paul J. Dysona
a
Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne (EPFL),
CH-1015 Lausanne, Switzerland.
b
University of Vienna, Institute of Inorganic Chemistry, Waehringer Str. 42, A-1090, Vienna,
Austria.E-mail: alexey.nazarov@epfl.ch
Half-sandwich organometallic compounds have attracted increasing interest due to their potential as
anticancer drugs.1 Different approaches have been explored, including mono- and bifunctional
compounds such as RAPTA compounds, targeted approaches, kinase inhibitors, ruthenium-arene
clusters and polynuclear ruthenium arene compounds. Increase of glucose uptake in malignant cells
due to upregulation of glycolysis and glucose transporters in comparison to healthy cells is almost
universal for cancer cells. Attaching a carbohydrate moiety to a Ru or Os center provides new metalbased compounds that exploit the biochemical and metabolic functions used for sugars in living
organisms for transport and accumulation.2,3
This presentation will focus on synthesis of new sugar containing ruthenium(II) and osmium(II)–arene
complexes and their characterization in terms of stability and cytotoxicity. The structural modification
with regard to the arene ligand, the leaving group, and the nature the metal centers is discussed.
The authors are indebted to the EU for a Marie Curie Intra European Fellowship within the
7th European Community Framework Programme project 220890-SuRuCo (A.A.N.) and the
Higher Education Commission of Pakistan (M.H.).
References
1. C. G. Hartinger and P. J. Dyson, Chem. Soc. Rev., 2009, 38, 391-401.
2. C. G. Hartinger, A. A. Nazarov, S. M. Ashraf,; P. J. Dyson, B. K. Keppler, Curr. Med. Chem.,
2008, 15, 2574-2591.
3. I. Berger, M. Hanif, A. A. Nazarov, C. G. Hartinger, R. O. John, M. L. Kuznetsov, M. Groessl, F.
Schmitt, O. Zava, F. Biba, V. B. Arion, M. Galanski, M. A. Jakupec, L. Juillerat-Jeanneret, P. J.
Dyson, B. K. Keppler, Chem. Eur. J. 2008, 14, 9046 – 9057.
105
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
P-48
Cytotoxic Organoiridium(III) mono- and bis-intercalators with rigid bridging
ligands of different lengths
Ali M. Nazifa and William S. Sheldrick*a
a
Lehrstuhl für Analytische Chemie, Ruhr-Universität Bochum, D-44780 Bochum
We have recently reported significant in vitro activity for members of the organometallic halfsandwich series [(η5-C5Me5)IrCl(pp)]+ containing a single polypyridyl ligand (pp = dpq, dppz, dppn).
Their IC50 values towards human MCF-7 (breast carcinoma) and HT-29 cells (colon-carcinoma) lie in
the range 30.3 - 0.12M and correlate with the size of the polypyridyl ligand, i.e. the IC50 values
decrease significantly in the order dpq > dppz> dppn.
An attractive design strategy to enhance both the affinity and specificity of DNA interactions is to
combine an intercalator with other functionalities such as a second intercalator or a metal fragment
capable of coordinative binding to nucleobases. Bis-intercalators might be expected to exhibit a
greatly increased binding affinity for DNA, which could also lead to improved cytotoxicity owing to
both the increased number of DNA adducts formed and decreased effectiveness of DNA repair
proteins.
These considerations prompted us to investigate the suitability of rigid bridging ligands of different
lengths including pyrazine, 4,4'-bipyridine, trans-1,2-bis(4-pyridyl)ethylene and 1,2-bis(4pyridyl)ethyne for enabling bis-intercalation of the polypyridyl ligands belonging to the dinuclear
complexes [{(η5-C5Me5)Ir(pp)}2(B)](CF3SO3)4 (pp = dpq, dppz, dppn). The interaction of the
complexes with DNA was studied using UV/VIS spectroscopy, circular dichroism, viscosity titrations
and gel electrophoresis. The studies confirm dppz as representing an optimum surface area for
intercalation. In contrast, the dppn-containing complexes prefer surface binding with π-stacking.
Based on these results, our research has focused on dppz-containing complexes which exhibit high
cytotoxicities towards the human cell lines MCF-7 (breast cancer) and HT-29 (colon cancer), with
IC50 values of respectively 3.1 M and 3.7 M being observed for the cell lines for B =4,4´-bipyridyl.
Bis-intercalation of the 4,4´-bipyridyl complex was indicated by CD measurements and confirmed by
viscosity titration, where the degree of DNA lengthening was doubled in comparison to an analogous
monointercalator.1
Conclusive evidence for the bis-intercalative binding mode of [{(η5-C5Me5)Ir(dppz)}2(4,4´bpy)](CF3SO3)4 was also obtained from an NMR-NOESY study of its interaction with the
decanucleotide d(5´-CGCGTAGGCC-3´). The observed interruptions of intramolecular NOE cross
peaks between nucleobase H6/H8 protons and sugar H2´/H2´´ protons of the preceding nucleobase are
in accordance with a bis-intercalation mode sandwiching the G4/C17 and T5/A16 base pairs. A range
of intermolecular NOE cross peaks are also observed between the dppz complex and decanucleotide
protons. These include contacts between the H3 and H4 protons of one dppz ligand to T5-H2´ and
between the H3´ and H4´ protons of the other dppz ligand to C17-H2´. The presence of these and other
NOE cross peaks underlines the degree of detailed information that can be obtained from the NOESY
spectrum, and allows a satisfactory refinement of the NMR structure of the complex-DNA adduct.
References
1. M.A. Nazif, J.-A. Bangert, I. Ott, R. Gust, R. Stoll, W. S. Sheldrick, J. Inorg. Biochem. 2009, 103, 14051414.
106
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
P-49
Bioinspired Catalysts With Bifunctional P,N - Ligands in Alkyne – Hydration
Anna Louisa Noffkea and Peter C. Kunz*a
a
Department of Inorganic Chemistry I, Heinrich-Heine-University of Düsseldorf
Universitätsstr. 1, D-40225 Düsseldorf, Email: anna-louisa.noffke@uni-duesseldorf.de
Addition of water to terminal alkynes is a common path to carbonyl compounds. However, most
synthetic strategies suffer from rather intense conditions or low selectivity. In nature, the
tungstenoenzyme acetylene hydratase catalyzes the formation of ethanal from acetylene, for example
in pelobacter acetylenicus.1 For higher alkynes, the hydration-reaction can be equally accelerated
using transition-metal catalysts with bifuntional ligands.2 Systems similar to 1 (Fig. 1) perform with
high yields and splendit selectivity.2
Fig. 1 Preparation of a Ru(II)-vinylidene complex and P,N-Ligands used.
With ruthenium(II)-complexes of the general formula [(Cp)Ru(L)2Cl] (Cp = cyclopentadienyl) bearing
our water-soluble, hemilabile P,N-ligands3 (Fig. 1), catalytic activity in alkyne-hydration is observed
under certain conditions. The first mechanistic steps of this reaction involve formation of vinylidene
species which are subsequently aquated. In particular, the special role that is played by H-bonddonating and/or accepting ligand-functionalities within this catalytic process is explored in further
detail.
References
1. S. Antony and C. A. Bayse, Organometallics 2009, 28, 4938–4944. (b) M. A. Vincent, I. H. Hillier,
G. Periyasamy and N. A. Burton, Dalton Trans. 2010, 39, 3816–3822.
3. (a) D. B. Grotjahn, D.A. Lev; J. Am. Chem. Soc. 2004, 126, 12232. (b) D.B. Grotjahn, Dalton
Trans. 2008, 6497.
2. (a) P. C. Kunz, M. U. Kassack, A. Hamacher, B. Spingler, Dalton Trans. 2009, 7741-7747. (b) P. C.
Kunz, G. J. Reiß, W. Frank, W. Kläui, Eur. J. Inorg. Chem. 2003, 3945-3951.
107
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
P-50
A Tri-organometallic Derivative Containing a PNA Backbone: Synthesis and
Antibacterial Activity
Malay Patra,a Gilles Gasser,a# Dmytro Bobukhov,b Klaus Merz,a Alexander V. Shtemenkob
Julia E. Bandowc and Nils Metzler-Nolte*a
a
Lehrstuhl für Anorganische Chemie I, Fakultät für Chemie und Biochemie, Ruhr-Universität
Bochum, Gebäude NC 3 Nord, Universitätsstr. 150, 44801 Bochum, Germany; bDepartment of
Inorganic Chemistry, Ukrainian State Chemical Technological University, Gagarin Avenue 8,
Dnipropetrovs'k, 49005 Ukraine; cLehrstuhl für Biologie der Mikroorganismen, Fakultät für Biologie
und Biotechnologie, Ruhr-Universität Bochum, Universitätsstr. 150, 44801 Bochum, Germany. #new
address: Institute of Inorganic Chemistry, University of Zurich, Winterthurerstrasse 190, CH-8057
Zurich, Switzerland.
Novel synthetic routes for the incorporation of different organometallic entities into the same
biomolecule are highly demanded. With the strive of developing a reaction sequence for the controlled
and sequential insertion of distinct organometallics into a PNA oligomer, we have chosen, as a model
compound, namely, 2-(N-(2-(2-(9H-fluoren-9-yloxy)acetamido)ethyl)pent-4-ynamido)acetic acid
containing both a PNA backbone and an alkyne side-chain and three different organometallics,
azidomethyl ferrocene, β-cymantrenoyl-propionic acid and [{N, N-bis((pyridin-2-yl)methyl)prop-2yn-1-amine}Re(CO)3]PF6– were inserted using click chemistry, amide bond formation and
Sonogashira coupling as orthogonal derivatisation methods respectively. Moreover, we discovered, the
triorganometallic compound (1) has excellent antibacterial activity against a number of multidrug
resistant gram-positive bacterial strains.
References
1. M. Patra, G. Gasser, D. Bobukhov, K. Merz, A.V. Shtemenko, N. Metzler-Nolte, Dalton Trans.
2010, DOI: 10.1039/c003598j.
108
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
P-51
The Synthesis and Characterization of Aqueous and Organic Soluble, Acid
Selective Cytotoxic Ruthenium Anticancer Compounds
Paul J. Dyson,a Olivier Zava,a David J. Kavanagh,b and Andrew D. Phillips*b
a Ecole Polytechnique Fédérale de Lausanne (EPFL), Institut des Sciences et Ingénierie Chimiques,
CH-1015, Lausanne, Switzerland. b University College Dublin, School of Chemistry and Chemical
Biology, Belfield, Dublin 4 , Ireland.E-mail: andrew.phillips@ucd.ie
From the serendipitous discovery of cisplatin as an anticancer agent by Rosenberg in 1965,1 there has
been considerable interest in the field of metallopharmaceuticals. Currently only two further platinum
complexes have received worldwide application in cancer treatment, Oxaliplatin and Carboplatin.
Recently, organometallic ruthenium complexes have attracted greater attention as potential antitumour reagents2-4 and systems featuring oxidation states of +2 and +3 have entered clinical trials.5
These Ru compounds (i and ii) are relatively non-toxic in comparison to platinum compounds and the
mode of inducing apoptosis differs significantly from cisplatin. Therefore, Ru-based pharmaceuticals
offer valuable alternatives that may overcome Pt resistant tumours and alleviate problematic sideeffects observed with other chemotherapeutic drugs.
This project focuses on the synthesis of water soluble, selective and adaptable ruthenium(II)
complexes (iii) employing a mixed ligand set that convey a number of useful properties important for
metallo-pharmaceuticals. The oxygen-stable phosphine, PTA (1,3,5-triaza-7-phosphaadamantane)
confers water solubility, while the 5-coordinated anionic C5H5 group provides the necessary
lipophilicity for passive cell transport. Uniquely, the bidentate triazapentadienyl ligand allows for the
‘fine-tuning’ of hydrolysis behaviour by alternating the α-R groups and has proven more stable than
the related Ru complexes (ii). Moreover, the triazapentadienyl ligand in compound iii imparts
additional cytotoxicity as observed in previous work on similar 6-C6H6 Ru chloro β-diketiminates
(iv). Finally, we will present our latest research which discusses the further adaption of complexes of
type iv towards long term biological stability and increased cytotoxicity.
(i)
(ii)
(iii)
(iv)
References
1. B. Rosenberg, L. Van Camp, T. Krigas. Nature. 1965, 205, 698.
2. P. J. Dyson, A. D. Phillips. Organometallics. 2009, 28, 5061.
3. B K. Keppler, K. Jakupec. Organometallics. 2008, 27, 2405.
4. G. Sava, P. J. Dyson,. Int. J. Oncology. 2008, 33, 1281.
5. (a) C. G. Hartinger, B. K. Keppler, J. Inorg. Biochem. 2006, 100, 891. (b) H. M. Schellens, J. M.
Rademaker-Lakhai. Clin Cancer Res. 2004, 10, 3717.
6. A. D. Phillips, O. Zava, R. Scopelitti, A. A. Nazarov, P. J. Dyson. Organometallics. 2010, 29, 417.
109
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
P-52
Encapsulation of Pyrenyl-Containing Dendrimers in
Arene-Ruthenium Metalla-Prisms
A. Pitto-Barry,a N. Barry,a R. Deschenaux,a* and B. Therriena*
a
Université de Neuchâtel, Institut de chimie, 51 Ave de Bellevaux, 2000, Neuchâtel, Switzerland.
E-mail: bruno.therrien@unine.ch
Extravasation of macromolecules is considerably enhanced in tumor tissues. This phenomenon called
“enhanced permeability and retention” (EPR) effect is believed to play a major role in selective
delivery of nanomedicines.1 Nanomedicines lead up to 100 times greater intratumor drug delivery
efficacy to cancer cells as compared to healthy cells.2 Nanomedicines include antibodies and
polymeric drug but also large drug delivery vectors like micelles, nanoparticles and dendrimers.
Among new large drug carriers, we recently proposed to use metalla-prisms built from areneruthenium units.3 These water-soluble and cytotoxic metalla-assemblies offer many possibilities.
On the other hand, we have been working on dendritic system incorporating lipophilic functionalized
pyrenes. Encapsulation of the pyrenyl moiety in the hydrophobic cavity of the arene-ruthenium
metalla-prism, with the dendritic part hanging out of the cage, generates a potential target seeking
missile for cancer cells. The synthesis and characterization as well as the preliminary cytotoxicity
studies are presented.
References
1. Y. Matsumura, H. Maeda, Cancer Res. 1986, 46, 6387-6392.
2. H. Maeda, Adv Drug Deliv Rev. 2001, 46, 169-185.
3. B. Therrien, G. Süss-Fink, P. Govindaswamy, A. K. Renfrew, P. J. Dyson, Angew. Chem. Int. Ed.
2008, 47, 3773-3776.
110
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
P-53
Silicium dioxide nanoparticles as carriers
for bio-active organometal complexes
Gregor Dördelmanna and Ulrich Schatzschneidera*
a
Lehrstuhl für Anorganische Chemie I – Bioanorganische Chemie, Ruhr-Universität Bochum,
Universitätsstr. 150, D-44801 Bochum, Germany, E-Mail: gregor.doerdelmann@rub.de.
.
CO-releasing molecules (CORMs) find steadily increasing use as a stable storage form of carbon
monoxide for potential therapeutic applications. Several compounds reported, such as
[Mn(CO)3(tpm-L1)]PF6, show significant cytotoxicity after photoactivation, comparable to that of the
established anticancer agent 5-fluorouracil (5-FU).[1,2]
Most solid tumors possess unique pathophysiological characteristics that are not observed in normal
tissue, like leaky vasculature and impaired lymphatic drainage, leading to an enhanced permeability
and retention (EPR) of macromolecules in the malignant tissue.[3] Thus, we wanted to explore whether
silicium dioxide nanoparticles can be utilized as delivery agents for CORMs in solid tumors.
N N
N3
SiO2
CuSO4 5H2O
Na-ascorbate
O
+
N
N
N
CO
Mn CO
CO
tButOH, H2O
N
N
N
SiO2
N
N N
O
N
N
N
N
CO
Mn CO
CO
Silicium dioxide nanoparticles containing the azidopropyl group were prepared by emulsion
copolymerization of tetraethylorthosilicate and (3-azidopropyl)triethoxysilane.[4] This procedure
provides a reproducible synthesis of particles in the ~90 nm size regime as determined by transmission
electron microscopy (TEM) and dynamic light scattering (DLS). The presence of the azido groups and
the manganese CORM on the surface of the particles was analysed by spectroscopic methods like
UV/VIS, IR and NMR spectroscopy as well as energy dispersive X-ray spectroscopy (EDX).
Reference
1. J. Niesel, A. Pinto, H.W. Peindy N’Dongo, K. Merz, I. Ott, R. Gust, U. Schatzschneider, Chem.
Commun. 2008, 1798-1800.
2. H. Pfeiffer, A. Rojas, J. Niesel and U. Schatzschneider, Dalton Tran . 2009, 4292-4298.
3. I. Brigger, C. Dubernet, P. Couvreur, Adv. Drug Delivery Rev. 2002, 54, 631-651.
4. C. A. Bradley, B. D. Yuhas, M. J. McMurdo, T. D. Tilley, Chem. Matter. 2009, 21, 174-185.
111
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
P-54
Synthesis and Biological evaluation of [99mTc]-N-[4-nitro-3-trifluoromethylphenyl] Cyclopentadienyltricarbonyltechnetium Carboxamide, a Nonsteroidal
Antiandrogen Flutamide Derivative
Tensim Dallagi,a S. Top,b S. Masi,b G. Jaouen,b and M. Saidia
a
Unité d'utilisation Médicale et Agricole des Techniques Nucléaires Laboratoire des
Radiopharmaceutiques, Centre National des Sciences et Technologies Nucléaires,
Technopôle de Sidi Thabet, 2020 Sidi Thabet,Tunisie. E-mail : t.dallegi@laposte.net. b Ecole
Nationale Supérieure de Chimie de Paris, Laboratoire Charles Friedel, UMR 7223, 11, rue Pierre et
Marie Curie, F-75231 Paris Cedex 05, France. E-mail : siden-top@chimie-paristech.fr
Prostate cancer is one of the most frequently diagnosed cancers and is the second leading cause of
cancer death in American men, after lung cancer.1 In 2009, prostate cancer is predicted to kill 27,360
American men. A similar statistic holds for French men. It is important to note that when the cancer is
detected it has already had a long time to develop. Therefore, it is crucial to detect the cancer at its
earliest stages. Few compounds have been labelled with 99mTc for use as androgen receptor-based
prostatic imaging agents. 2,3 Rapid metabolic cleavage, low receptor binding affinity or inadequate
specific activity is a common feature of most of PET and SPECT radioimaging agents. We have
recently developed ferrocenyl derivatives of nonsteroidal antiandrogens and have found that
ferrocenyl nilutamide derivatives show a significant cytotoxicity on hormone-independent prostate
cancer cells PC-3.4
O2N
F 3C
O2N
O
N
H
Fe
O
F 3C
N
H
99mTc(CO)
NFFe
NF 99m Tc
NFRe
3
99mTc)
(M =
(M = Re)
In our efforts to develop a novel class of SPECT imaging agents based on nonsteroidal androgen
receptor (AR) antagonists, we have synthesized N-cyclopentadienyltricarbonyltechnetium-N-[4-nitro3-trifluoromethyl-phenyl] carboxamide (NF99mTc), an analog of the AR antagonist ligand flutamide.
NF99mTc was obtained in 82% yield from the reaction of N-[4-nitro-3-trifluoromethyl-phenyl]ferrocenecarboxamide (NFFe) with fac-[99mTc(H2O)3(CO)3]+ in DMF/water at pH 1 and at 150 °C for
1 h. We also prepared N-[4-nitro-3-trifluoromethyl-phenyl]-rheniumcyclopentadienyltricarbonylcarboxamide (NFRe) which is useful for the identification of the technetium compound. In vitro
assays demonstrated high stability of NF99mTc under physiological conditions, buffer and blood. The
tissue biodistribution in mature male Wistar rats showed a significant selective uptake by prostate but
this uptake was not blocked by an excess of testosterone acetate.
References
1. A. Jemal, R. Siegl, E. Ward, Y. Hao, J. Xu, M. J. Thun, CA Cancer J. Clin. 2009, 59, 225-249.
2. T. Das, S. Banerjee, G. Samuel, K. Bapat, S. Subramanian, M. R. A. Pillai, M. Venkatesh, Bioorg.
Med. Chem. Lett., 2006, 16, 5788-5792.
3 H. He, J. E. Morely, E. Silva-Lopez, B. Bottenus, M. Montajano, G. A. Fugate, B. Twamley, P. D.
Benny, Bioconjugate Chem. 2009, 20, 78-86.
4. O. Payen, S. Top, A. Vessières, E. Brulé, M.-A. Plamont, M. J. McGlinchey, H. Müller-Bunz, G.
Jaouen, J. Med. Chem. 2008, 51, 1791-1799.
112
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
P-55
Synthesis and
99m
Tc-Labeling of a PNA Oligomer Containing a New Ligand
Derivative of 2,2´-Dipicolylamine
Katrin Jäger,a Gilles Gasser,b Martin Zenker,a Ralf Bergmann,a Jörg Steinbach,a Holger Stephan,a
and Nils Metzler-Nolteb
a
Forschungszentrum Dresden-Rossendorf, Institute of Radiopharmacy, Bautzner Landstrasse 128,
01314 Dresden, Germany. b Ruhr-University Bochum, Faculty of Chemistry and Biochemistry,
Department of Inorganic Chemistry I, Universitätsstrasse 150, 44801 Bochum, Germany.
E-mail: k.jaeger@fzd.de
The search for chelating ligands which can be efficiently labeled with radiometals, and which also
contain a functional group allowing a facile conjugation to biomolecules is currently a hot topic in
radiopharmacy. The 2,2’-dipicolylamine (Dpa) has already been found to be a good candidate for
labeling with 186Re, 188Re and 99mTc1 while the Cu(I)-catalyzed [2+3] azide/alkyne cycloaddition, often
referred to as Click Chemistry,2 has been shown to be an effective coupling method. With this in mind,
we recently developed the facile synthesis of an azido derivative of Dpa (Dpa-N3, Figure 1).3
Furthermore, as a proof of principle of the possible functionalization of our ligand to a biomolecule,
Dpa-N3 was successfully coupled, on the solid phase, to a ethinyl-substituted Peptide Nucleic Acid
(PNA) oligomer employing the Click Chemistry methodology to give the expected Dpa-ethyl-triazolPNA. Both Dpa-N3 and Dpa-ethyl-triazol-PNA could be efficiently labeled with 99mTc using the
precursor [99mTc(H2O)3(CO)3]+ to afford [99mTc(CO)3(Dpa-ethyl-triazol-N3)]+ and [99mTc(CO)3(Dpaethyl-triazol-PNA], respectively. The radionuclide 99mTc was tightly bound by the Dpa-chelator
avoiding the formation of pertechnetate for at least 24h. Partitioning experiments in a 1-octanol/water
system confirmed that both [99mTc(CO)3(Dpa-N3)]+ and [99mTc(CO)3(Dpa-ethyl-triazol-PNA] are
rather hydrophilic. Biodistribution studies of [99mTc(CO)3(Dpa-ethyl-triazol-PNA] in Wistar rats
showed a fast blood clearance and only a modest accumulation in the kidneys. Similar results were
found when a mouse model (NMRI nu/nu) was used.
+
N
N
N3
(CO)3
99mTc
N
N
N
N3
N
Figure 1. Structures of Dpa-N3(left) and [99mTc(CO)3(Dpa-N3)]+ (right).
References
1. T. Storr, C. L. Fisher, Y.Mikata, S. Yano, M. J. Adam, C. Orvig, Dalton Trans., 2005, 654-655.
2. M. V. Gil, M. J. Arévalo, Ó. López Synthesis, 2007, 11, 1589-1620.
3. G. Gasser, K. Jäger, M. Zenker, R.Bergmann, J. Steinbach, H. Stephan, N. Metzler-Nolte, 2010,
submitted.
113
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
P-56
Novel MRI Contrast Agents based on a Silsesquioxane Core
Jörg Henig,a,b* É. Jakab-Tóth,c J. Engelmann,d S. Gottschalk,d H.A. Mayera
a
Universität Tübingen, Institut für Anorganische Chemie, Auf der Morgenstelle 18, 72076 Tübingen,
Germany. b Ruhr-Universität Bochum, Zentrum für Elektrochemie, Universitätsstraße 150, 44801
Bochum, Germany. c CNRS Orléans, Le Centre de Biophysique Moléculaire, 45071 Orléans, France.
d
Max-Planck-Institut für biologische Kybernetik, Hochfeld-Magnetresonanz-Zentrum, 72076
Tübingen, Germany. E-mail: joerg.henig@rub.de
Large macromolecular MRI contrast agents (CAs) bearing several paramagnetic gadolinium(III)
centres show usually significantly higher relaxivities than small size CAs and are particularly useful
for target specific imaging. However, the large size slows down the excretion rate of the CA, which is
a major limitation for clinical use. Furthermore, the Solomon-Bloembergen-Morgan theory predicts
that at the high magnetic fields of modern clinical and especially research MRI scanners, medium-size
CAs rather than very large systems are the most favored in order to achieve high relaxivities. Here we
present two novel medium-size CAs (Gadoxane G (GG) and Gadoxane B (GB), Figure 1), based on a
symmetric T8-silsesquioxane core. The use of the T8-silsesquioxane cube allows the grafting of eight
monohydrated lanthanide (Ln = Gd3+, Y3+) complexes in a confined space.
Both Gadoxanes can be synthesised with an intact silsesquioxane core. Diffusion 1H NMR
measurements showed rotational correlation times of about 3.35 ns for both compounds. Even though
both CAs have almost identical water exchange rates, due to the lower internal flexibility, the
longitudinal relaxivities of GB are significantly higher than those of GG over almost the whole range
of magnetic fields. Although both systems still possess a high internal flexibility, the strong effect of
the altered spacer on the relaxivity and the comparatively high relaxivity of both systems at proton
Larmor frequencies above 100 MHz points out the potential of moderate-size silsesquioxane-based
CAs. Furthermore, with hydrodynamic radii of about 1.44 nm both, GG and GB are still significantly
smaller than the small pores of the glomerular filtration system and hence should be excreted
relatively fast via the kidneys. A key feature is also the lability of the silsesquioxane cage under
physiological conditions (37°C, pH 7.4). No change in relaxivity is observed within the first three
hours, since the hydrolysis of the initial Si-O-Si moieties has no influence on rotational correlation
time. However, then the hydrolysis of the silsesquioxane core leads to smaller fragments and therefore
to a decrease in relaxivity. If needed, this degradation might allow the development of larger CAs,
whose fragments are then readily excreted via the kidneys.
8-
R
R
O
Si
O Si
O
O O Si R O
Si
R
O R Si O O Si R
O
O
Si O Si
R
R
O
O
N
O
Ln3+
N
N
O
R=
N
N
H
O
O
O
O
R=
O
O
O
O
N
O
Ln3+
N
N
N
H
O
O
Gadoxane B (GB)
Gadoxane G (GG)
Figure 1. Gadoxane G (GG) and Gadoxane B (GB)
114
N
O
O
O
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
P-57
New Hyperpolazied probes for 13C-MRI
S. Aime,a E. Cerutti,a S. Ellena,a R. Gobetto,a F. Reineri,a D. Santelia,a A. Viale
a
a
Department of Chemistry I.F.M., University of Torino, Via P. Giuria n° 7,
10125 Torino, Italy, E-mail: roberto.gobetto@unito.it
The extraordinary NMR signal enhancement obtained from Para-Hydrogen Induced Polarization
(PHIP) has been exploited in the investigation hydrogenation mechanisms and, more recently, in the
development of hyperpolarized contrast agents for MRI applications. In particular the high
signal/noise ratio that can be achieved on heteronuclei such as 13C or 15N allows to obtain molecules
that can be traced in vivo. In fact the complete absence of those signals in biological tissues leads to
images in which the background signal derives uniquely from instrumental noise. Furthermore, due to
long T1 values that can be reached on these nuclei, hyperpolarization can be maintained for enough
time to allow the acquirement of images in in vivo conditions.
In order to produce a 13C hyperpolarized contrast agent using this approach, an unsaturated substrate is
necessary (usually a triple bond containing molecule, that is efficiently para-hydrogenated in the
presence of a suitable catalyst), with an adjacent carbonyl group to which hyperpolarization is
transferred due to its coupling with parahydrogen protons. This group is also characterized by a long
T1 value (which limits the polarization loss due to relaxation).2 Then, in order to use heteronuclearPHIP for MRI application, longitudinal hyperpolarization must be obtained from spin order which
derives directly from parahydrogenation. This task can be achieved by means of both field cycling
procedure or an appropriate pulse sequence.
We present the synthesis and parahydrogenation experiments of a series of novel substrates with the
aim of obtaining an in-depth understanding of the potential of these species as 13C hyperpolarized
contrast agents. Particular attention is focused on bio-compatible and water soluble parahydrogenated
products. Problems concerning catalyst and organic solvent elimination have been also tackled.
References
1) K. Golman, O. Axelsson, H. Johannesson, S. Mansson, C. Olofsson, J.S. Petersson, Magn. Res.
Med. 2001, 46, 1.
2) F. Reineri, A. Viale, G. Giovenzana, D. Santelia, W. Dastrù, R. Gobetto, S. Aime, J. Am. Chem.
Soc. 2008, 130, 15047.
115
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
P-58
Affinity Binding for Controlled Orientation and Electrochemistry in Self
Assembled Monolayers of Reductases.
Nicolas Plumeré,a Ellen R. Campbell,b Bill H. Campbellb
a Ruhr Universität Bochum, Center for Electrochemical Science, Universitätsstrasse 150, 44780,
Bochum, Germany. b NECi, 334 Hecla Street, Lake Linden, USA. E-mail: nicolas.plumere@rub.de
Metal-chelating ligands have been designed in the field of immobilized metal ion affinity
chromatography1 (IMAC) for the purification of polyhistidine-tagged (His-tagged) proteins. Dense
monolayers of similar metal-chelating ligands on electrode surfaces have recently been applied for the
immobilization and controlled orientation of His-tagged proteins via affinity binding.2–4 In particular,
nitrilotriacetic (NTA) and imminodiacetic (IDA) acid terminated gold and carbon electrodes were used
for the immobilization of laccase,4 glucose oxidase,5 horseradisch peroxidase2 and hemoprotein.3 In
these cases, the attachment of the enzyme via His-tag yields fully active protein films in the presence
of electron mediators. In some cases, direct electron transfer was observed as well.5 Cu2+ and Ni2+
were used as the metal cations.
However, the use of affinity binding involving Ni2+ or Cu2+ is limited to applications that require redox
potentials less negative than the reduction potential of the metal cation complexes.2 Therefore, most
reductases cannot be used in such systems.
In order to overcome this limitation, we used Zn2+ as the metal cation for the coordination of a Histagged reductase. Nitrate reductase (NaR) as the enzyme and methyl viologen as the electron mediator
were chosen to test the affinity binding via Zn2+ cations on NTA modified glassy carbon electrodes.
The electrochemical investigations of the NaR monolayer on NTA-Zn2+ films demonstrate the activity
for the catalytic reduction of nitrate to nitrite in presence of methyl viologen. The catalytic current
density corresponds to the one expected for a fully active enzyme monolayer. Moreover, the reduction
of the Zn2+ is not observed at the potential necessary for the reduction of methyl viologen. Therefore,
affinity binding based on Zn2+ may be used for the immobilization of Nitrate reductases in their active
form.
References
1. G. S. Chaga J. Biochem. Biophys. Methods 2001, 49, 313-334.
2. R. Blankespoor, B. Limoges, B. Schöllhorn, J.-L. Syssa-Magalé, D. Yazidi Langmuir 2005, 21,
3362-3375.
3. V. Balland, S. Lecomte, B. Limoges Langmuir 2009, 25, 6532-6542.
4. V. Balland, C. Hureau, A. M. Cusano, Y. Liu, T. Tron, B. Limoges Chem. Eur. J. 2008, 14, 71867192.
5. S. Demin, E. A. H. Hall, Bioelectrochemistry 2009, 76, 19-27.
116
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
P-59
Synthesis, Characterization and Properties of the Cluster Rhenium(ІІІ)
Compound with β-Alanine Ligands
Mariia S. Randarevych,a Kateryna A. Zablotska,a Konstantin V. Domasevitch,b Alexander V.
Shtemenkoa
a
Department of Inorganic Chemistry, Ukrainian State Chemical Technological University, Gagarin
Ave. 8, Dnipropetrovs’k 49005, Ukraine. E-mail: shtemenko@ukr.net. b Department of Inorganic
Chemistry, Kiev University, Volodimirska Street 64, Kiev 01033, Ukraine. E-mail: dk@univ.kiev.ua.
The theoretical interest in binuclear complex compounds of dirhenium(ІІІ) is caused by the fact that
rhenium is one of the few elements that are able to form a multiplet metal-metal bond. From the
practical point of view, these compounds can be used in medical practice since they have
anticancerogenic, antihemolytic, and antiradical properties and lower toxicity in comparison with
other well-known compounds of transition metals.
One of the received cluster compounds of dirhenium(ІІІ) with γ-aminobutyric acid’s ligands has
already shown excellent antitumor properties.1 Owing to this, our purpose is to expand the range of
similar compounds by using other amino acids as ligands which possess own biological activity.
Therefore, the synthesis of new cluster aminocarboxylates of dirhenium(III) and the study of their
physicochemical and biological properties are of great interest for us. A synthetic procedure of
dirhenium(ІІІ) complex compound with β-alanine was developed. The properties of this compound are
investigated by spectral method. The compound cis-Re2Cl6{-AlaH}2 ·1.5H2O is shown to consist of
coordinating centre Re26 + with quadruple bond rhenium-rhenium. In equatorial positions there are
bridge groups containing β-alanine residues being in cys-position relative to Re-Re. The structure of
the given compound is presented on fig. 1.
Fig.1 cis-Re2Cl6{-AlaH}2 ·1.5H2O
The structure of this compound is confirmed by direct X-ray structure, thermal and spectral analyses.
We have also investigated the biological activity of the complex that revealed itself perspective as a
cytostatic and anticancer agent.
References
1. A. Shtemenko, P. Collery, N. Shtemenko, K. Domasevitch, E. Zabitskaya, A. Golichenko Dalton
Trans. 2009, 26, 5132 - 5136.
117
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
P-60
Exploring Histidines as Biomolecular Anchors to Re(CO)3+
Richard S. Herrick,a Christopher J. Ziegler,b Roger Rowlett, Americo Gambellaa
a College of the Holy Cross, Department of Chemistry, 1 College St., Worcester, MA 01610, USA.
b University of Akron, Department of Chemistry, KNCL 402, Akron, OH 444325, USA. c Department
of Chemistry, Colgate University, 13 Oak Drive, Hamilton, NY 13346 (USA).
E-mail: rherrick@holycross.edu
In recent years we have explored the potential of using amino acids and amino acid conjugates to bind
Re(CO)3+. We are currently exploring the use of histidine-containing peptide conjugates as models of
His-tags in order to test their ability to bind the Re(CO)3+. His-OMe, Ac-His-OH and His-His-OH
were each exposed to aqueous solution of Re(CO)3+. Reaction with His-OMe lead to ester cleavage
and formation of the previously observed Re(CO)3(3-N,N,O--His). Reactions with Ac-His-OH and
His-His-OH each led to novel compounds containing a carboxamido N-donor group. The
characterization, including X-ray crystallography, of each compound, and testing of each compounds
ability to withstand challenge experiments will be discussed.
We have also been interested in using proteins to bind Re(CO)3+. Little work has been carried out on
reactions between rhenium prodrug or drug model complexes and proteins. Such interactions can be
crucial to the biological processing of Tc/Re based imaging agents, since proteins, rather than
nucleotides or single amino acids, would be encountered in plasma. Alternatively, protein-Tc/Re
adducts could be novel targets for use as imaging or therapeutic agents. In order to probe this
chemistry, we are examining the interactions between Re(CO)3(H2O)3+ and the readily crystallizable
protein lysozyme. A crystal structure has been obtained of a lysozyme-Re(CO)3(H2O)2 adduct.
Experimental details, including the new crystal structure, will be discussed.
From these studies highlighting the binding of histidines in peptides and proteins to Re(CO)3(H2O)3+,
several conclusions can be drawn. These will be discussed along with future directions of this
research.
118
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
P-61
Fluorescent Rhenium(I)tricarbonyl Complexes Based on a Novel
Bisphenanthridinyl Chelate
Lukasz Raszeja,a and Nils Metzler-Nolte*a
a
Ruhr-University Bochum, Faculty of Chemistry and Biochemistry, Department of
Inorganic Chemistry I, Universitätsstr. 150, 44801 Bochum, Germany
E-mail: LukaszRaszeja@aol.com
Fluorescence microscopy is a powerful technique for the imaging of biological systems. Beside
making endogenous cell organelles visible by specific staining methods, it is also possible to monitor
the intracellular distribution of fluorescently labelled compounds such as peptides, oligonucleotides or
drugs in general. Right now most of the fluorescent dyes used for labelling are organic compounds
based on an aromatic heterocycle like in the case of fluorescein, acridine or cyanine. By now, the
number of applications of d6 metal complexes for cellular imaging experiments is modest. Published
systems use the typical luminescent Ir(III), Ru(II) and Re(I) metal complexes.1
We have developed a novel chelating ligand system based on phenanthridine. This ligand is
fluorescent itself, but by complexing a fac-Rhenium(I)tricarbonyl core the molecule exhibits an
enhanced absorption and a stronger and red shifted fluorescence. With a typical broad absorption
maximum between 310 nm and 380 nm the complex shows strong emission at 540 nm by excitation at
350 nm. The large Stokes shift is a big advantage in comparison to the typical organic dyes due to
prevent self-quenching processes. Beside the application in fluorescence microscopy our ligand could
act as a potential radio marker in the case of complexing the isostructural {99mTc(CO)3} core.
Several compounds based on the Bisphenanthridine moiety were synthesized (example in Fig. 1), fully
characterized and finally used for cellular imaging and uptake experiments (Fig. 2). The synthesis of
bioconjugates of peptides and PNA was also successful and cellular uptake studies show interesting
and promising results.
Br
O
O
N
N
I
Re
N
CO
CO
CO
Fig. 1 Structure of the fluorescent ReI complex 1.
Fig. 2 Fluorescence image of IMIM-PC2 cells after
incubation with 1 (5 µM, 24 h).
References
1. V. Fernández-Moreira, F. L. Thorp-Greenwood, M. P. Coogan, Chem. Commun. 2010, 46, 186-202.
119
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
P-62
Electrochemical Detection of Protein Kinases and Inhibitor Screening by Using
Ferrocene-ATP Bioconjugate
Sanela Martić, Mahmoud Labib and Heinz-Bernhard Kraatz*
The University of Western Ontario, Faculty of Science, Department of Chemistry, 1151 Richmond
Street, N6A 5B7, London, Canada.
E-mail: smartic@uwo.ca
Protein kinase plays a critical role in the cellular growth, signalling and function and its malfunction
has been linked to a number of diseases, such as cancer.1 For diagnostic and drug screening purposes
detecting, monitoring and quantifying kinase activity is critical. Recently, an electrochemical
biosensor was developed and was used in our laboratory for measuring casein kinase 2 (CK2) and
protein kinase C (PKC) activity on a Au surface by means of the electroactive adenosine-5’-[γferrocene] triphosphate conjugate (Fc-C6-ATP), as a co-substrate for the protein kinase.2 As an
extension of this work, we have investigated following kinases: sarcoma-related kinase (Src), cyclindependent kinase (CDK2) and extracellular signal–regulated kinase (Erk1), all of which are directly
involved in the cell cycle. The electrochemical detection of kinase activity and drug target screening
was performed in addition to the surface characterization of phosphorylated assays by MALDI-TOF
MS, XPS and TOF-SIMS techniques. A proof-of-concept study was performed using the newly
developed multiplex chip technology which allows for monitoring and quantifying multiple kinase
activities for the first time. The optimized electrochemical multiplex assay was also used for
identification of novel protein kinase inhibitors.
No electrochemical signal !
CDK2
O
Src
Fe
Erk1
N
H
6N
H
ATP
Electrochemical signal
after phosphorylation!
control
PO3Fc
References
1. (a) G. Manning, D. B. Whyte, R. Martinez, T. Hunter, S. Sudarsanam, Science, 2002, 298, 19121934. (b) J. S. Sebolt-Leopold, J. M. English, Nature, 2006, 441, 457-462.
2. (a) H. Song, K. Kerman, H. B. Kraatz, Chem. Commun. 2008, 502-504. (b) K. Kerman, H. Song, J.
D. Duncan, D. W. Litchfield, H. B. Kraatz, Anal. Chem. 2008, 80, 9395-9401.
120
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
P-63
Electrochemical Evaluation of the Interaction between Ru(II) mono-diimine
Complexes and Biomolecules
Mauro Ravera,a Ayesha Sharmin,b Edward Rosenberg,b Domenico Osella,a
a University of Piemonte Orientale “A. Avogadro”, Department of Environmental and Life Sciences,
Viale Michel 11, 15121, Alessandria, Italy. b Department of Chemistry and Bio-Chemistry, University
of Montana, Missoula, MT 59812, USA. E-mail: mauro.ravera@mfn.unipmn.it
Transition metal luminescent complexes containing one or more diimine ligands typically have
excited-state lifetimes ranging from about 100 ns to 10 s. Because the lifetimes of these
luminophores are long compared to fluorescent dyes that are used as biological probes, time-gated
detection can be used to suppress interfering auto-fluorescence from the biological sample. In
addition, highly polarized emission from some of these complexes has stimulated interest in using
them as biophysical probes for studying the dynamics of macromolecular assemblies and interactions
on membranes.
The series of complexes [XRu(CO)(L–L)(L’)2][PF6] (X = H, TFA, Cl; L–L = 2,2’-bipyridyl, 1,10phenanthroline, 5-amino-1,1’-phenanthroline and 4,4’-dicarboxylic-2,2’-bipyridyl; L’2 = 2PPh3,
Ph2PC2H4PPh2, Ph2PCH=CHPPh2) have been synthesized from the starting complex
K[Ru(CO)3(TFA)3] (TFA = CF3CO2). The purpose of the project was to synthesize a series of
complexes that exhibit a range of excited-state lifetimes and that have large Stokes shifts, high
quantum yields and high intrinsic polarizations associated with their metal-to-ligand charge-transfer
(MLCT) emissions. To a large degree these goals have been realized in that excited-state lifetimes in
1
the range of 100 ns to over 1 s are observed. The measured quantum yields and intrinsic anisotropies
are higher than for previously reported Ru(II) complexes. Interestingly, the neutral complex with one
phosphine ligand shows no MLCT emission. The compounds show multiple reduction potentials
which are chemically and electrochemically reversible in a few cases as examined by cyclic
voltammetry. The same technique has been use to evaluate the interaction between some of the
synthesized complexes and biomolecules (DNA and bovine serum albumin, BSA).
SWV of a solution of 1 with successive additions of BSA. Electrochemical conditions: 0.5 mM of
complex in 0.05 M phosphate buffer (pH 7.4) + 5% DMSO; glassy carbon electrode
References
1. A. Sharmin, R. C. Darlington, K. I. Hardcastle, M. Ravera, E. Rosenberg, J. B. A. Ross, J.
Organomet. Chem., 2009, 694, 988-1000.
121
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
P-64
Electrochemical Studies of Fc-PNA(•DNA) Surface Dynamics
Nina Hüsken,a Magdalena Gębala,b Wolfgang Schuhmannb and Nils Metzler-Nolte*a
a
Ruhr-Universität Bochum, Fakultät für Chemie und Biochemie, Lehrstuhl für Bioanorganische
Chemie, Universitätsstrasse 150, 44801 Bochum, Germany. b Ruhr-Universität Bochum, Fakultät für
Chemie und Biochemie, Analytische Chemie, Universitätsstrasse 150, 44801 Bochum, Germany. Email: nina.huesken@rub.de
The application of peptide nucleic acids (PNA) as receptor molecules in DNA biosensors promises an
enhanced specificity and selectivity for the analysis of DNA, due to the favourable hybridization
properties of PNA. N-terminal ferrocene (Fc) labelled and C-terminal gold surface confined PNA
oligomers present unique tools for electrochemical DNA biosensing, since structural and
conformational changes of the nucleic acid strand directly affect the Fc-electrode redox process.1
By means of fast scan cyclic voltammetry (FSCV), the kinetic of the Fc-electrode redox process was
studied at Fc-PNA(•DNA) modified gold electrodes. The gold surfaces were loosely packed (< 8%)
with Fc-PNA(•DNA) single or double strands, to exclude any lateral interactions between the probe
molecules and to facilitate with this an unrestricted thermal strand motion of the Fc tethered strands.
These studies primary revealed, that the large elasticity of the PNA single strand evokes a diffusion
like motion of the Fc head group (“Fc-on-rope”), whereas the Fc label attached to the rather rigid
PNA(•DNA) duplex exhibits a significantly less diffusional behaviour (“Fc-on-rod”). Based on the
FSCV studies, a clear correlation between the determined electron transfer (ET) rate constants k0 and
the inherent strand elasticity was developed. Thereby a large strand elasticity leads at high scan rates
to a ‘kinetic freeze’ of the tethered Fc head groups, to result in a large spectrum of Fc-electrode
distances and a large average Fc-electrode distance, being correlated to a rather low ET rate constant.
Vice versa, an increase in the strand rigidity leads to a smaller spectrum of possible Fc-electrode
distances and an average Fc-electrode distance, which is located closer to the gold surface due to an
attractive effect exerted by the electric field and hence correlates a larger ET rate constant.2
Concluding, the established correlation between the Fc-electrode ET rate constants, determined by
FSCV, and the inherent PNA(•DNA) strand elasticity renders the ET rate constants a new means to
study Fc-PNA(•DNA) surface dynamics. This correlation furthermore presents the basis for an
electrokinetic analysis of DNA with Fc-PNA biosensors.
References
1. N. Hüsken, M. Gębala, W. Schuhmann, N. Metzler-Nolte, ChemBioChem 2010, DOI:
10.1002/cbic.200900748
2. N. Hüsken, M. Gębala, W. Schuhmann, N. Metzler-Nolte, manuscript submitted.
122
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
P-65
Study of Heavy Metals Biosorption from Aqueous Solutions
by Using Biological Wastes
Mohammad Ali Zazouli,*a and Mayram Bagheria
a
Department of Environmental Health Engineering, Faculty of Health, Mazandaran University of
Medical Sciences, Sari, Iran, E-mail: Zazoli49@yahoo.com
Heavy metal pollution is posing significant threats to the environment and public health because of its
toxicity, non-biodegradability and bioaccumulation.1 The increasing environmental concern for these
contaminants, there has been serious interest in removal of heavy metals from contaminated
wastewater & water. A number of technologies such as precipitations, ion exchange, membrane
processes and adsorption on activated carbon, have been used over the years to remove toxic metals
from water but these techniques are often ineffective and/or very expensive in the reduction of heavy
metals from water at very low concentration.2 The search for alternative and innovate treatment
techniques has focused attention on the use of biological materials for heavy metal removal. The
objective of this study is to investigate of heavy metals (Cadmium, Chromium and lead) biosorption
from aqueous solutions by using orange mesocarp and rice husk.
The selected biomass were first cut into small size, washed with water to remove impurity and soluble
components and oven-dried at 100 oC for 24h until constant weight was reached. The washed and
dried materials were crushed and sieved using 1.00 mm mesh size sieve. Then pretreated separately
with soaking in NaOH(0.4N) and HNO3(0.4N) for 24h. After that washed with distilled water until it
had no color in the filtrate. Biosorption studies were carried out batch method. After the desired
contact time, the biosorbent was removed by filtration. The metal concentrations were measured by
using atomic absorption spectrophotometer. All experiments were conducted in duplicate. Finally,
Adsorption isotherms of metal on adsorbents were determined.
Results show that metal sorption initially increases with increasing in metal concentration in the
solution, and then becoming saturated after a certain concentration of metal. The maximum sorption
capacities with orange waste were for Cr and with rice husk was Pb. The results showed that the
percentage removal of metals as a function of equilibrium pH. The effect of pH on metals sorption was
very different for all metals and for two biosorbents. Biosorption was very fast for the first 30 min but
slowed markedly after 1 h. Biosorption continued to increase after which it became constant reaching
equilibrium. The adsorption data fit well with the Langmuir and Freundlich isotherm model for orange
waste and rice husk, respectively.
This study indicates that both biomass residues have the capacity to remove metal ions from aqueous
solution, and the amount of the heavy metal ions bound by cellulosic substrate depends on the metal
ion type, biosorbent type and dosage, pH and contact time. Thus, orange waste and rice husk could be
potentially used for the removal of heavy metals from aqueous solution as erials stand out as very
good and lowest biosorbents.
Keywords: Biosorption, Heavy metals, Orange wastes, Rice husk, Biological wastes
References
1. E.-S. Z. El-Ashtoukhy, N.K. Amin, O. Abdelwahab, Desalination. 2008, 223, 162-173.
2. A.B. Pérez-Marín, A. Ballester, F. González, M.L. Blázquez, J.A. Muñoz, J. Sáez, V. Meseguer
Zapata, Bioresour. Technol. 2008, 99, 8101-8106.
123
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
P-66
Synthetic Analogs for Evaluating Organometallic and Nickel(0) Involvement in
Acetyl Coenzyme A Synthase
Molly J. O’Hagan, Nathan A. Eckert, and Charles G. Riordan*a
a
University of Delaware, Department of Chemistry and Biochemistry, 19716, Newark, USA.
E-mail: riordan@udel.edu
Acetyl coenzyme A synthase (ACS) is a NiFeS protein found in archaea and anaerobic organisms that
can grow on CO2 as their sole carbon source.1 Some of these, including methane, acetate and sulfateproducing organisms are found in the intestinal tracts of higher mammals including humans. ACS
catalyzes the dis/assembly of a methylcorrinoid, CO and CoA to acetyl CoA. The mechanism of the
reaction undoubtedly involves bioorganometallic intermediates, although none have yet to be directly
identified. Using small molecule synthetic chemistry, we seek to establish chemical precedents for
relevant, elementary steps in ACS catalysis.2 Central among these is the transalkylation of
methylcorrinoid to a reduced site of the ACS cluster. One proposal for this site is a zero-valent nickel
ion.3 Studies detailed in this presentation establish the feasibility and mechanistic boundaries for alkyl
group transfer to nickel(0) and nickel(I) acceptors with emphasis on our recent results in deducing the
mechanism of a model in which SN2 transfer to nickel(0) is suggested.4
References
1. S.W. Ragsdale, E. Pierce, Biochim. Biophys. Acta 2008, 1784, 1873-1898.
2. (a) R. Krishnan, J.K. Voo, C.G. Riordan, L. Zakharov, A.L. Rheingold, J. Am. Chem. Soc. 2003,
125, 4422-4423; (b) R. Krishnan, C.G. Riordan, J. Am. Chem. Soc. 2004, 126, 4484-4485.
3. P.A. Lindahl, J. Biol. Inorg. Chem. 2004, 9, 516-524.
4. N.A. Eckert, W.G. Dougherty, G.P.A. Yap, C.G. Riordan, J. Am. Chem. Soc. 2007, 129, 92869287.
124
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
P-67
Synthesis of Mixed Gold(I)-Phosphine-Ferrocene-Phenylalanine
and Peptide Conjugates
Christine Doffek,a S. David Köster,a and Nils Metzler-Nolte*a
a
Ruhr-Universität Bochum, Lehrstuhl für Anorganische Chemie I, Universitätsstraße 150,
D-44801 Bochum, Germany. E-mail: christine.doffek@rub.de
The combination of gold(I)-phosphine and ferrocene derivatives enlarges the number of interesting
bioconjugates. The gold(I)-phosphine-ferrocene-phenylalanine conjugate 1 was prepared by Cu(I)catalyzed [3+2]-cycloaddition of azido-modified phenylalaninemethylester with the internal alkyne of
a gold(I)-phosphine-ferrocene-acetylide in good yields.1,2 The corresponding peptide conjugate was
synthesized using solid phase peptide synthesis (SPPS) in combination with Cu(I)-catalyzed [3+2]cycloaddition of the azido-modified peptide with the gold(I)-phosphine-ferrocene-acetylide, also
showing good yields. During the final cleavage the peptide conjugate decomposed. The gold(I)phosphine-ferrocene-phenylalanine conjugate 1 was comprehensively characterized by multinuclear
and multidimensional NMR spectroscopy, mass spectrometry and cyclic voltammetry (CV). The
electrochemical studies showed reversible processes of the redox couple Fc0/Fc+ (Fc = ferrocenyl) and
an irreversible reduction of Au+ to Au0.
O
Au
O
O
N
N N
Fe
1
References
1. D. A. Gray, L. Gao, T. S. Teets, J. B. Updegraff III, N. Deligonul, T. G. Gray, Organometallics
2009, 28, 6171-6182.
2. S. Back, R. A.. Gossage, H. Lang, G. van Koten, Eur. J. Inorg. Chem. 2000, 1457-1464.
125
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
P-68
Study of Interaction of Gold Drugs with Thiols
Using Various Analytical Techniques
Gohar T. Kazimia* and Mohammad S Iqbalb
a
Department of Chemistry, University of Sargodha, Sargodha 40100, Pakistan. E-mail:
gohartaqi@hotmail.com
b
Department of Chemistry, GC University, Lahore 54000, Pakistan. E-mail: saeediq50@hotmail.com
Since ancient times, gold has occupied a special place in medicine to cure diseases. Now a days gold
based drugs are being used in the treatment of an autoimmune inflammatory disease known as
rheumatoid arthritis (RA).1 SolganalTM (gold thioglucose), MyochrisineTM (gold sodium thiomalate)
and RidauraTM (auranofin, 2,3,4,6-tetraacetyl-β-1-D-thiogluco-pyranosato-S-(triethyl phosphine)gold(I), Et3PAuStagl) are used for the treatment of this disease but their mode of action is still
uncertain. Furthermore, several studies have demonstrated that several gold (I) and gold (III) salts also
exhibit anti-tumour activities.2-4 The pharmacokinetic and pharmacological properties of these drugs
mainly depend upon ligands present on them and various studies have shown that these ligands are
replaced in the body by some endogenous molecules.1
In this work some of the ligand exchange reactions of gold drugs with various thiols including
cysteine, glutathione, N-acetylcysteine and O-methylcysteine were studied in both solution and in
solid state. Various analytical techniques like ESI-MS, DESI-MS, pXRD and FT-IR used in this study
confirmed the ligand exchange mechanism. ESI-MS was successfully employed for characterization of
the ligand-exchange products. When cysteine reacts with auranofin in solution, the formation of
[Et3PAuSCy]– (m/z = 434), [taglSAuCyS]– (m/z = 680) and [Au(Stagl)2] – (m/z = 923) were observed
along with [Au(PEt3)2]+ (m/z =433) in the positive-ion spectrum. Similarly with O-methylcysteine the
formation of [TaglSSOMeCy]– (m/z = 497), [taglSAuSOMeCyS]– (m/z = 694), [Au(Stagl)2] – (m/z =
923) and [Et3PAuSOMeCy]+ (m/z =450) indicated the ligand exchange during reaction. DESI-MS,
pXRD and FT-IR were found to be helpful in characterization the products of the reactions performed
in the solid state.
This study provides very useful information in understanding the in vivo biochemistry of the gold
drugs used for rheumatoid arthritis.
References
1. C.F. Shaw, III, Chem. Rev. 1999, 99, 2589-2600.
2. E.R.T. Tiekink, P.D. Cookson, B.M. Linahan, L.K. Webster, Metal-Based Drugs 1994, 1,299.
3. L.K.Webster, S. Rainone, E. Horn, E.R.T. Tiekink, Metal-Based Drugs 1996, 3, 63.
4. D. Crump, G. Siasios, E.R.T. Tiekink, Metal-Based Drugs 1999, 6, 361.
126
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
P-69
Glutathione Reductase/Thioredoxin Reductase Systems as Molecular Target for
Antiproliferative Gold(I) Carbene Complexes
R. Rubbiania and I. Ott*a
a
Institute of Pharmaceutical Chemistry, Technische Universität Braunschweig, Beethovenstr. 55,
38106 Braunschweig, Germany, r.rubbiani@tu-bs.de
Human Thioredoxin-Reductase (TrxR) and Glutathione-Reductase (GR) are two NADPH-dependent
flavoenzymes belonging to the main responsibles of the antioxidant cellular network. They consist of a
FAD domain, a NADPH domain but they differ for the active site, which is characterized by a
cysteine-cysteine (Cyscys) bridge in the case of GR and by a cysteine-selenocysteine (Secys) bridge in
the case of TrxR. The main substrate of GR is glutathione (Glu), a tripeptide formed by γ-L-GlutamylL-cysteinylglycine that has the role to act directly against reactive oxygen species (ROS). The
substrate of TrxR is thioredoxin (Trx), a protein of 12 kDa with an active disulfide motif.1 With the
development of Auronafin, it has been demonstrated that certain metal complexes (especially gold
complexes) have a strong affinity for TrxR, based on the formation of a covalent bond.2 Because of the
overexpression of these enzymes in the tumoral cells, as well as their substrates, they become a
possible target for the developing of new active molecules. Based on a computational study, our
research focuses on gold(I) carbene complexes, a new stable class of compounds that show activity on
these enzymatic systems. We synthesized a series of di-substituted benzimidazole carbenes (see
figure) and evaluated their interactions with the mentioned substrates and enzymes. We also
investigated the proliferation inhibition in two tumoral cell lines. Our results indicate a selective
inhibition of TrxR in the nanomolar range, most probably due to the stronger affinity of gold(I) for
Secys compared to Cys. The proliferation studies showed a cytotoxic activity in the range of 7-16 µM.
References
1. S. Gromer et al., Med. Res. Rev. 2004, 24, 40-89.
2. I. Ott.,Coord. Chem. Rev. 2009, 52, 763-770.
127
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
P-70
Synthesis, Characterization and Antitumor Screening of some
Di- and Triorganotin(IV) Complexes of 2,9-Dimethyl-1,10-phenanthrolin
Mojdeh Safari,*a Mohammad Yousefi,a Maryam Bikhof,a Amir Amanzadeh,b
Mohammad Ali Shokrgozar,b and Fatemeh Tavakoliniaa
a
b
Azad University, Shahre-rey branch, Tehran, Iran
Pasteur Institute, Tehran, Iran. E-mail: msafari96@yahoo.com
Malignancy is the result from a multiple process by accumulation of mutations and other genetic
alteration.1 Searches for non-platin metal-based antitumor drugs have attracted considerate interest.
Diorganotin(IV) complexes are potential antitumor agents mainly active against P388 lymphocytic
leukemia and other tumors.2-4 Recent studies have shown very promising in vitro antitumor properties
of organotin compounds against a wide panel of tumor cell lines of human origin.5-11 In some cases,
organotin(IV) derivatives have also shown acceptable antiproliferative in vivo activity as new
chemotherapy agents.12-17 In this context ,we decided to study the cytotoxic activity of 2,9-Dimethyl1,10phenanthrolin tin(IV) derivatives, in order to observe the influence of the substituents attached to
the central Sn atom on the final anticancer activity of the organotin(IV) complexes. In the present
research the new complexes of organotin were obtained by reacting R2SnCl2 and Ŕ3SnCl (where R=
Methyl, Butyl, Benzyl and Ŕ= Phenyl) with 2,9-Dimethyl-1,10phenanthrolin. These complexes have
been characterized by FT-IR and 1H,13C,119Sn NMR and Mass spectroscopy. The cytotoxic activity of
the studied compounds has been investigated against K562 cell line and the IC50 values have been
determined.
References
1. P. Blume-Jensen, T. Hunter, Nature, 2001, 411, 355–357.
2. A.J. Crowe: Antitumor activity of tin compounds in Metal Compounds in Cancer Therapy; S.P.
Fricker, Ed., Chapman & Hall: London, GB, 1994, pp. 147–179.
3. A.J. Crowe, P.J. Smith, C.J. Cardin, H.E. Parge, F.E. Smith, Cancer Lett., 1984, 24, 45–48.
4. (a) A.K. Saxena, F. Huber, Coord. Chem. Rev., 1989, 95, 109–123. (b) M. Gielen (Ed.), Tin-Based
Anti-Tumor Drugs, Springer-Verlag, Berlin, 1990.
5. M. Gielen (Ed.), Tin-Based Anti-Tumor Drugs, Springer-Verlag, Berlin, 1990.
6. M. Gielen, Coord. Chem. Rev., 1996, 151, 41-51.
7. P. Yang, M. Guo, Coord. Chem. Rev., 1999, 189, 185–186.
8. M. Gielen, M. Biesemans, D. De Vos, R. Willem, J. Inorg. Biochem., 2000, 79, 139-145.
9. M. Gielen, Appl. Organomet. Chem., 2002, 16, 481-494.
10. S.K. Hadjikakou, N. Hadjiliadis, Coord. Chem. Rev., 2009, 253, 235-249.
11. in Tin Chemistry: Fundamentals,Frontiers, and Applications; M. Gielen, A.G. Davies, K. Pannell,
E. Tiekink, Ed.: John Wiley and Sons, Wiltshire, 2008.
12. L. Nagy, A. Szorcsik, K. Kovacs, Pharm. Hungarica, 2000, 70, 53-71.
13. M. Nath, S. Pokharia, R. Yadav, Coord. Chem. Rev., 2001, 215, 99-149.
14. M. Gielen, in: NATO ASI Ser. 2, vol. 26, 1997, p. 445.
15. D. De Vos, R. Willem, M. Gielen, K.E. Van Wingerden, K. Nooter, Met. Based Drugs, 1998, 5,
179-188.
16. C. Pettinari, Main Group Met. Chem., 1999, 22, 661-692.
17. S.P. Fricker, Ed., Metal Compounds in Cancer Therapy, Chapman & Hall, London, UK, 1994, pp.
147–179.
128
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
P-71
Synthesis of Chromium-Containing Diterpene Analogs
for the Modulation of NOD Proteins
Aroonchai Saiaia, Janna Veldera, Harald Bieligb, Tomas A. Kuferb, Hans-Günther Schmalz*a
a
Institute for Organic Chemistry, University of Cologne, Greinstr.4, 50939, Cologne, Germany.
Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, JosephStelzmann-Str.9, Geb.37, 50931, Cologne, Germany. E-mail: asaiai@smail.uni-koeln.de
b
Polymorphisms in NOD1 and NOD2 are linked to chronic inflammatory barrier diseases such as
asthma, Blau syndrome, early onset sarcodoisis and Crohn’s disease.1 Many synthetic compounds in
our group are structurally related pseudoterosins which exhibit pronounced analgesic and antiinflammatory properties were screened. In continuative research, we found that AKS-01 can inhibit
NOD2-mediated NF-KB activation.
H
N
H
OMe
Cr(CO)3
AKS-01
To investigate the structure-activity relationships, Cr(CO)3-complexed compounds which structurally
related to AKS-01were synthesized.2,3
1
R
O
R2
H
OMe
OMe
Cr(CO)3
OMe
Cr(CO)3
1
2
3
4
5
6
7
8
R1 = H
R1 = F
R1 = Me
R1 = OMe
R1 = CF3
R1 = H
R1 = H
R1 = H
R2 = H
R2 = H
R2 = H
R2 = H
R2 =H
R2 = F
R2 = Me
R2 = CF3
Synthesis and biological evaluation will be presented in details.
References
1.(a) P. Hysi, M. Kabesch, M. F. Moffatt, M. Schedel, D. Carr, N. Klopp, A.W. Musk, A. James, G.
Nunez, N. Inohara and W.O. Cookson, Hum mol genet. 2005, 14, 935-941; (b) P. Rosenstiel, A. Till
and S. Schreiber, Microbes and infection. 2007, 9, 648-657.
2. H.-G. Schmalz, S. Siegel and J.W. Bats, Angew. Chem. Int. Ed. 1995, 34, 2383-2385.
3. O. Hoffmann and H.-G. Schmalz, Synlett. 1998, 12, 1426-1428.
129
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
P-72
Analyzing Drug Action on Mitochondrial Targets using Functional Assays with
Isolated Biological Active Mitochondria
Suzan Can,a Ana Kitanovic,a Igor Kitanovic,a Annegret Hille,b Ronald Gust,b Melanie Oleszak,c
Yvonne Geldmacher,c William S. Sheldrick,c Andreas Meyer,d Riccardo Rubbiani,d Ingo Ottd and
Stefan Wölfl*a
a
Institute of Pharmacy and Molecular Biotechnology, University Heidelberg, Im Neuenheimer Feld
364, 69120 Heidelberg, Germany. b Institute of Pharmacy, Department of Pharmaceutical Chemistry,
Free university of Berlin, Germany. c Faculty of Chemistry and Biochemistry, Department of
Analytical Chemistry, University Bochum. d Institute of Pharmaceutical Chemistry, Technische
Universität Braunschweig, Germany. email: wolfl@uni-hd.de
Mitochondria play crucial roles in living cells. They are not only the source of energy via oxidative
phosphorylation and ATP synthesis, but are also an important regulators of cellular survival and in the
control of programmed cell death. Mitochondrial damage and inhibition of the electron transfer in the
respiratory chain can trigger the production of reactive oxygen species (ROS) and the release of
cytochrome c. The latter initiates mitochondrial induction of apoptosis. Previous studies in intact cells
showed that several bioorganometallic compounds significantly induced ROS formation and triggered
cell death inducing pro-apoptotic pathways.
To further elucidate their specific activity we wanted to investigate if mitochondria and mitochondrial
activity are direct targets of some of these compounds. With the central role of mitochondria in the
regulation of cell death such compounds could play an important role for anti-cancer therapy to trigger
cell death in proliferating cancer cells.
We isolated mitochondria from mouse liver and established a series of tests that show mitochondrial
functionality. With these functional assays for several complexes of the respiratory chain and by
measuring oxygen consumption we analysed the capability of various substances to influence
respiration and selectively inhibit respiratory chain components in isolated mitochondria. Results
revealed that some salophene iron complexes (AG Gust) and rhodium (III) polypyridyl complexes
(AG Sheldrick) directly inhibit mitochondrial respiration. Furthermore it could be shown that
treatment with several bioorganometallic substances lead to a release of cytochrome c and to changes
of mitochondrial membrane potential which indicates a strong influence on the integrity of the
mitochondrial membrane.
This work is supported by the DFG as part of the Forschergruppe FOR630.
130
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
P-73
Asborin Meets Titanium
Matthias Scholza and Evamarie Hey-Hawkins*a
a Universität Leipzig, Institute of Inorganic Chemistry, Johannisallee 29, D-04103 Leipzig, Germany,
E-mail: mscholz@chemie.uni-leipzig.de
Asborin, the carbaborane analogue of aspirin®, is one of the few examples in which carbaboranes are
used as phenyl-mimetic pharmacophores. Asborin was synthesised in a high-yield procedure starting
from ortho-carbaborane. The compound proved to inhibit both cyclooxygenase (COX) isozymes, the
target enzymes of aspirin.1 The COX inhibition potential, however, was lower compared to aspirin and
the general pharmacological profile was also different to that of aspirin. Integration of the cluster in
place of the phenyl ring turned aspirin into a more toxic compound, which triggers apoptosis
pathways. Asborin was cytotoxic toward several cancer cell lines and exhibited the lowest potency
toward healthy fibroblasts. This behaviour made the carbaborane compound interesting for anticancer
drug development. As the IC50 values obtained from the cytotoxicity assays were higher than those of
commercial chemotherapeutic agents, the compound requires further fine-tuning of its cytotoxic
profile.
A promising approach to increase the antitumour activity of asborin is combination with another
cytotoxic moiety. Therefore, we decided to modify asborin with titanium complexes, as some
derivatives were found to be active toward several tumour cells. The most prominent anticancer
titanium derivatives are the organometallic compound titanocene dichloride and the bioinorganic
complex budotitane.2 The carboxyl group and carbaborane moiety of asborin allow it to form both
bioinorganic and organometallic titanium compounds. Coordination of asborin as carboxylate could
displace the chloride ions in titanocene dichloride. Alternatively, instead of a cyclopentadienyl ring the
nido carbaborane cluster can act as ligand for titanium. Thus, carbaboranes can easily be deboronated
to give anionic nido clusters, which feature an open pentagonal plane. These anions can then form
different metallocene analogues.
References
1. M. Scholz, K. Bensdorf, R. Gust, E. Hey-Hawkins, ChemMedChem. 2009, 4, 746-748.
2. J. C. Dabrowiak: Titanium compounds for treating cancer in Metals in Medicine; 1. Ed.; Wiley:
New York, USA, 2009; pp. 167-177.
131
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
P-74
Coordination Behavior and Spectroscopic Studies of Biologically Active
Organotin(IV) Complexes of 2-(N-naphthylamido)benzoic Acid
Khadija Shahida
a
Riphah Institute of Pharmaceutical, Sciences 7th Avenue, G-7/4, Riphah International
University, Islamabad-45320 Pakistan
New organotin(IV)complexes of 2-(N-naphthylamido)benzoic acid were synthesized in
stoichiometric ratio in anhydrous toluene under the reflux yield the organotin(IV) carboxylates with
general formula R4-nSnLn(R= Me, n-Bu, Ph, n-Oct, Bz and n= 2, 3). All the complexes have been
characterized by various spectroscopic methods (IR, 1H, 13C, 119Sn NMR) and mass spectrometry.1
Cytotoxicity of the synthesized compounds was checked against Brine-shrimp larvae.
In vitro activities against some Gram-positive and Gram-negative bacteria and fungi were also
determined.2 Antimicrobial activities show that species with tetrahedral geometry in solution are
more toxic.3
Scheme: Synthesis of Di/Tri organotin Complexes.
References
1. (a) K. Shahid, S. Ali, S. Shahzadi, J. Coord. Chem. 2009, 62(17), 2919–2926. (b) K. Shahid, S.
Shahzadi, J. Serb Chem. Soc. 2009, 74(2), 141-154.
2. A. Rahman, M.I. Choudhary, W.J. Thomsen, Bioassay Techniques for Drug Development;
Hardward Academic Press, Amsterdam 2001.
132
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
P-75
Raman Microscopic Cell Uptake Studies of
Bioactive Organometal Peptide Conjugates
Thomas Sowika, Eugen Edengeiserb, Martina Havenith-Newen,b and Ulrich Schatzschneidera*
a
Lehrstuhl für Anorganische Chemie I – Bioanorganische Chemie, Ruhr-Universität Bochum,
Universitätsstr. 150, D-44801 Bochum, Germany, E-Mail: thomas.sowik@rub.de.
b
Lehrstuhl für Physikalische Chemie II, Ruhr-Universität Bochum, Universitätsstr. 150, D-44801
Bochum, Germany.
A major problem is the lack of molecular markers which do not influence the intracellular distribution
and biological activity and show signals where constitutions of the cell normal do not. Raman
microscopy, however, is a potent technique for cell imaging and drug uptake studies.1 The C-D
stretching vibration of deuterated compounds appears in a spectroscopic window between 2100 and
2350 cm-1 where bio (macro) molecules do not show vibrational signals. Thus, it is possible to
investigate the cell uptake and metabolism of these compounds.2 Peptide bioconjugates with
cyclopentadienylrhenium- or cyclopentadienylmangenese tricarbonyl are known for their biological
activity depending on the peptide sequence.3 Their analogues with deuterated metal complexes are
promising candidates for Raman microscopy (Fig. 1). An example is sC18 with the sequence
GLRKRLRKFRNKIKEK-NH2 which delivers metal complex bioconjugates to cancer cells.
1907
1942
2020
2352
1650
D
D
3119
D
Re
OC
D
COOH
CO
CO
Rayleigh signal
0
1000
2000
3000
4000
Wavenumber cm-1
Figure 1: Raman spectrum (left) of deuterated cyclopentadienylrhenium(I) tricarbonyl carbocylic acid (right). The C-D
stretching vibrations appear at 2352 cm-1.
Within this work we have prepared deuterated cyclopentadienyl carboxylic acid, which was reacted
with dirhenium decacarbonyl to deuterated cyclopentadienylrhenium(I) tricarbonyl carboxylic acid.
Subsequently, bioconjugates were prepared and their biodistribution and cell-uptake was studied using
Raman spectroscopy and microscopy.
Reference
1. C. Matthäus, T. Chernenkoa, L. Quinteroc, L. Milanb, A. Kaleb, M. Amijib, V. Torchilinb, M.
Diema, Proc. SPIE 2008, 6991.
2. H.-J. v. Manen, A. Lenferink, C. Otto, Anal. Chem. 2008, 80, 9576–9582.
3. K. Meister, J. Niesel, U. Schatzschneider, N. Metzler-Nolte, D. A. Schmidt, M. Havenith, Angew.
Chem. 2010, accepted for publication.
133
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
P-76
Synthesise of New Butyl Tin(IV) Compounds and Investigation About Their
Toxicity and Anti-inflammatory Studies
Fatemeh Tavakolinia,a Mohammad Yousefi,a Saeed Amanpour,b Samad Mohammadnejad,b
and Mojdeh Safari*b
a
b
Azad University, Shahre-rey Branch, Tehran, Iran
Experimental Lab, Cancer Research center, Tehran university of medicinal sciences, Tahran, Iran.
E-mail: ftavakolinia@yahoo.com
Chemistry of organotin(IV) complexes has developed considerably during the last 30 years,
highlighting the synthesis of a number of complexes with interesting properties.1-3 One of the most
important bioinorganic chemistry research areas as regards organotin compound is the investigation
of their cytotoxic/antitumor activities. In addition many organotin(IV) compounds have been tested for
their in vitro activity against a large variety of tumor lines and have been found to be as effective or
better than traditional heavy metal anticancer drugs such as Cis-platin.4,5 In general, toxicity of
organotin(IV) compounds seems to increase with the chain length of the organic alkyl group, which
are often more active than aryl ones, and follow the order R3Sn> R2Sn> RSn.6 In this research three
new organotin(IV) complexes of the general formula R3SnŔ and R2SnŔ2 (where R=Ph, Bu, and Ŕ=1Butane, 2-Butane, Ph) have been synthesized by the Grignard reaction of triphenyltin chloride with 1iodo butane and 2-chloro butane in 1:1 molar ratio and the reaction of dibutyltin dichloride with chloro
benzene in 1:2 molar ratio. The resulted complexes are Ph3Sn1-Bu (1), Ph3Sn2-Bu (2), Ph2SnBu2 (3).
The sample of synthesise of one of the complexes comes below. These new derivatives have been
characterized by FT-TR, 1H, 13C, 119Sn NMR and Mass spectroscopy. The toxicity study and antiinflammatory effect are going to carry out and the LD50 value is going to determine.
ICH2CH2CH2CH3 + Mg  IMgCH2CH2CH2CH3
IMgCH2CH2CH2CH3 + Ph3SnCl  Ph3SnCH2CH2CH2CH3 (1) + MgClI
References
1. M.J.Clarke, F. Zhu, D. R.Frasca, Chem. Rev. 1999, 99, 2511.
2. J.Beckmann, K. Jurkschat, Coord. Chem. Rev. 2001, 215, 267.
3. L.Pellerito, L.Nagy, Chem. Rev. 2002, 224, 111.
4. M. Gielen, App. Organomet. Chem.2002, 16, 481.
5. M. Gielen, Coord. Chem. Rev. 1996, 26, 1.
6. D. Dc Vos, R.Willem, M. Gielen, K. E. Van Wingerden, K. K. Nooter, Net. Based drugs 1998, 5.
134
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
P-77
Water Enables Direct Palladium-Catalyzed C-allylation of Cyclic 1,3-Diones with
Allylic Alcohols without Activators
Shyh-Chyun Yang*a and Yi-Jen Shuea
a
Kaohsiung Medical University, School of Pharmacy, 100 Shih-Chuan 1st Road, 807, Kaohsiung,
Taiwan. E-mail: scyang@kmu.edu.tw
The palladium-catalyzed allylation is a powerful tool for C–C, C–N, and C–O bond formation, which
has been widely applied to organic chemistry. We have recently disclosed a new catalytic system for
palladium/carboxylic acid–catalyzed allylation with allylic alcohols in water as a suspension medium.1
Organic reactions in water have recently attracted much attention, because water is a safe and
economical substitute for conventional organic solvent. Herein, we report that palladium-catalyzed
ally-OH bond cleavage in the absence of activating agents. Allylation of cyclic 1,3-diones worked well
with aromatic allylic alcohols in water and gave generally good to high yields. This is a simple and
efficient route for C–C bond formation.
R
O
O
R
R
R
OH
O
O
+
O
O
Pd /P-ligand, H2O
References
1. (a) S.-C. Yang, Y.-C. Hsu, K.-H. Gan. Tetrahedron 2006, 62, 3949-3958. (b) K.-H. Gan, C.-J.
Jhong, S.-C. Yang, Tetrahedron 2008, 64, 1204-1212.
135
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
P-78
In Vitro Interactions of Rhenium(III) Compounds with Phospholipids and
Nucleic Bases Derivatives
a
Dina Y. Yegorova, bNataliia I. Shtemenko, aAlexander V. Shtemenko
a
Department of Inorganic Chemistry, Ukrainian State Chemical Technological University,
Gagarin Ave. 8, Dnipropetrovs’k 49005, Ukraine. E-mail: shtemenko@ukr.net, bDepartment
of Biophysics and Biochemistry, Dnipropetrovs’k National University, 72 Gagarin avenue,
Dnipropetrovs’k 49010, Ukraine
In our previous investigations it was shown that rhenium(III) complexes had antitumor, antihemolytic
and red blood cells stabilizing properties. 1 The important component of the integral biological activity
of any substance is its ability to cross the cell membrane and to react with nuclear bases. Investigations
of the interaction between rhenium(III) cluster complexes and phospholipids as one of the main
components of a cell membrane and nuclear bases is of great importance as may help to understand
the mechanism of their action and to find further synthetic directions.
In this work the experiments were accomplished with cluster rhenium(III) compounds with common
formulas:
[Bu4N]2×[Re2Cl8],
cis-[Re2(CH3COO)2Cl4]×2H2O,
trans-Re2(C2H5COO)2Cl4
,
Re2(RCOO)3Cl3, Re2(RCOO)4Cl2, where R - CH3, C2H5, i-C3H7, C10H15; with phospholipids:
phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine and nuclear bases derivatives: 9methyladenin and 9-methylguanin. The electronic absorbtion spectra of mixtures of the substances
were studied.
According to the obtained spectra the strongest interaction was found with phosphatidylholine among
other main phospholipids of cells membrane. It was shown that the mechanism of interaction
depended on the structural type of cluster rhenium(III) complexes. In the case of tetra-μ-carboxylates
bridged equatorial carboxylic groups were replaced by phosphate groups of phosphatidylholine with
following formation of monodentate derivatives. During interaction of phosphatidylholine with cistetrachlorodi-μ-carboxylates of dirhenium(III) replacement of terminal chlorides by
phosphatidylholine ligands with formation of monodentate derivatives with the change of the
previous structural type was shown. The same interactions were shown to be realized during formation
of nanoliposomes of cluster rhenium(III) compounds and phosphatidylholine.
Hydrolytic process of the complex rhenium(III) compounds was shown to take place in water
solutions, that’s why nanoliposomal forms of rhenium(III) complex compounds were obtained from
phosphatidylholine to prolong their therapeutic effect. It was shown that the coordination of phosphate
groups of phosphatidylholine to the cluster centre (unit) of Re26+ provided prevention of hydrolytic
process and increased the stability of these compounds.
Bidentate coordination of the 9 MeA to equatorial position of the cluster Re26+ centre through N1/N6
atoms of the nucleic base heterocidic ring was shown. Another type of coordination was shown for
Guanine derivative: 9MeG coordinated by monodentate mode to axial position of the Re26+ centre only
through N1 atom of the heterocidic ring. The mechanism of interaction between nucleic bases and
rhenium(III) compounds was different in comparison with the same for platinides that explained the
effectiveness of the Rhenium – Platinum antitumor system in the earlier experiments in vivo.
References
1. (a) N. Shtemenko, P. Collery, A. Shtemenko, Anticancer Res. 2007, 27, 2487-2492. (b) A.
Shtemenko, P. Collery, N. Shtemenko, K. Domasevitch, E. Zabitskaya, A. Golichenko, Dalton Trans.
2009, 5132-5136.
136
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
P-79
Tris(pyrazolyl)borates as Versatile Ligands in the Synthesis of Bioorganometallic
Compounds
Johannes Zagermann,a Matthew C. Kuchta,a Klaus Merz,a Nils Metzler-Noltea*
a
Fakultät für Chemie und Biochemie, Ruhr-Universität Bochum, Universitätsstraße 150,
44801 Bochum, Germany, Johannes.Zagermann@rub.de
While cyclopentadienyl (Cp) containing compounds such as ferrocene have found various applications
in bioorganometallic chemistry, little work is found concerning analogue compounds containing Cp
surrogates. As such, we have been interested in exploiting the rich coordination chemistry of
tris(pyrazolyl)borate (Tp) ligands for the synthesis of bioconjugates with possible applications in
biomedical, electrochemical or spectroscopical studies.
We describe the synthesis and characterization of mixed ligand (Cp/Tp) and (Tp/Tp') ruthenium
sandwich compounds,1 both incorporating a “third-generation” p-BrC6H4Tp (Tp') ligand,2 and their
application in the formation of peptide bioconjugates. More recently, we utilized iodocarbonyltungsten
complexes containing a regular Tp* ligand to label peptides via η2-coordinated alkyne ligands
including the unusual amino acid propargylglycine.3
References
1. (a) J. Zagermann, M. C. Kuchta, K. Merz, N. Metzler-Nolte, J. Organomet. Chem. 2009, 694, 862867.
(b) J. Zagermann, M. C. Kuchta, K. Merz, N. Metzler-Nolte, manuscript in preparation.
2. J. Zagermann, M. C. Kuchta, K. Merz, N. Metzler-Nolte, Eur. J. Inorg. Chem. 2009, 5407-5412.
3. J. Zagermann, K. Merz, N. Metzler-Nolte, Organometallics 2009, 28, 5090-5095.
137
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
P-80
Synthesis of Some Metal Dye-complexes as Antimicrobial Agents
Ibrahim F. Zeid*a and Husein A. Agwaa
a
Department of Chemistry, Faculty of Science, Monoufia University Shibin El-Koam, Egypt
E-mail: ifzeid@hotmail.co.uk
An enormous number of 4-arylazo-2-pyrazolin-5-ones has been reported in the literature as dyes of
commercial value. The reaction of 4-arylazo-l-phenyl-3 -(methyl or phenyl)-2-pyrazolin-5-ones with
copper and cobalt salts resulted in the formation of some new metal dye complexes.1,2 The importance
of the newly synthesized complexes as antimicrobial agents has been discussed.
Ph
N=NAr
R
N=NAr
R
M
N
O
N
N
Ph
O
N
N
N
R
O
ArN=N
Ph
1
2
References
1. F. A. Amer, A. H. Harhash, M. A. Metwally, Z .Natuforsch. 1977, 32b, 943.
2. A. A. Fadda, M. A. Metwally. A.M. Khalil, Indian J. Text. 1983, 8, 82.
3. M. A. Metwally, A. A. Fadda, H. M. Hassan, E. Afsah, Org. Prep. Proc. Int. 1985, 17, 198.
4. I. F. Zeid, M.T. Omar, A. A. Makhlouf, M. M. Kamel, N. M. Khalifa, Egypt. J. Pharm. Sci. 1996,
37, 251.
138
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
P-81
Apoptosis induction and cytotoxicity by metalbased drugs:
lights and shadows of DNA
Gianni Savaa,b and Alberta Bergamob
a
University of Trieste, Department of Life Sciences, via L. Giorgieri 7, 34127, Trieste, Italy. bCallerio
Foundation Onlus, via A. Fleming 22-31, 34127, Trieste, Italy. E-mail: gsava@units.it
Cisplatin is a well known DNA-damaging agent and the current thinking is that DNA platination
(DNA-adduct formation) is an essential first step in the cytotoxic activity of the drug. Information
about the chemistry of the platinum compounds and correlations of their structures with anticancer
activity have provided guidance for the design of novel anticancer drug candidates based on the
proposed mechanisms of action.1 The question is: DNA-adduct formation guided synthesis of metalbased anticancer drugs is a real concept or a misleading interpretation? The mechanism(s) whereby the
DNA adducts kill cells is not fully understood. One potentially important way by which cisplatinDNA adducts may kill cells is by induction of programmed cell death or apoptosis (Figure 1).2,3
From:
to:
Figure 1. types of DNA adduct formation of platinum drugs: (a) interstrand cross-link, (b) 1,2intrastrand cross-link, (c) 1,3-intrastrand crosslink, (d) protein-DNA cross-link (adapted from Lit. 2)
However, these concepts are not sufficient to account for the particular effectiveness of the most
important platinum drugs in cancer therapy where cisplatin and carboplatin (two drugs with a rather
different chemistry) are active on the same tumours, oxaliplatin is active on colorectal tumours and
satraplatin (the emerging oral platinum drug) is active on prostate cancer. None of these tumours were
selected a priori as the targets for these drugs. Then, how focusing on the ligands that allow DNA
binding or to get insensitivity to acquired resistance, may help researchers to understand what to take
into consideration to design the expected more potent, more selective and less toxic new metal-based
antitumour drugs? Apoptosis and cell death is not simply related to DNA binding properties as shown
by the many biological and targeted drugs emerged in the last years which killed cells by apoptoptic
mechanisms following interactions with protein components of important cellular pathways. Given
that cisplatin and also many platinum drugs have a poor capacity to enter the nucleus compartment (in
the case of cisplatin almost 99% of the cellular drug is in the cytoplasm) the focus should be directed
on what are the final destinations of all these platinum molecules in this protein-rich compartment. As
an example, interesting data are emerging on HSP90 block by cisplatin, a phenomenon that could
account for many apoptotic cytotoxicities observed. This work was done in the framework of COST
D39 – WG3.
References
1. K.S. Lovejoy, S.J. Lippard, Dalton Trans. 2009, 48, 10651-10659.
2. A. Eastman: The mechanism of action of cisplatin: From adducts to apoptosis in: Cisplatin.
Chemistry and Biochemistry of a Leading Anticancer Drug; B. Lippert, Ed.; Wiley-VCH: Basel,
Switzerland, 1999, pp. 111–134.
3. R.C. Todd, S.J. Lippard, Metallomics 2010, 4, 280-291.
139
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
P-82
Selective Recognition of Actinides by Protein-Based Reagents
Salih Özçubukçu,aSeraphine V. Wegner,a Kalyaneswar Mandal,b Stephen B. H. Kent,b
Mark P. Jensen,c and Chuan He*a
a
The University of Chicago, Department of Chemistry, 60637, Chicago, IL, USA. b The University of
Chicago, Department of Chemistry, Department of Biochemistry and Molecular Biology, Institute for
Biophysical Dynamics, 60637, Chicago, IL, USA. c Argonne National Laboratory, Chemical Sciences
and Engineering Division, 60439, IL, USA,.
e-mail: chuanhe@uchicago.edu
It is generally accepted that trivalent actinides prefer softer chelating atoms such as sulfur rather than
oxygen; hence selective separation of trivalent actinides from trivalent lanthanides can be obtained by
soft-donor ligands.
Barbara Imperiali and her coworkers have developed a series of peptides, called lanthanide binding tag
(LBT) which selectively binds lanthanide ions with high affinities1. This pre-organized ligand template
provides an ideal system to study these long standing questions regarding separate trivalent actinides
from trivalent lanthanides. Pre-organization of the ligands by the peptide scaffold provides high
binding affinity. We can redesign these small peptides with nitrogen- and sulfur- based ligands to
provide selectivity. We plan to systematically screen ligand types and geometries to achieve selective
binding of actinides over lanthanides (Figure 1).
References
1. M. Nitz, M. Sherawat, K. J. Franz, E. Peisach, K. N. Allen, B. Imperiali, Angew. Chem. Int. Ed.
2004, 43, 3682-3685.
140
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
P-83
Iridium Complex with Antiangiogenic Properties
a
b
b
b
a
Alexander Wilbuer, D. H. Vlecken, D. J. Schmitz, C. P. Bagowski, and Erik Meggers*
a
Philipps Universität Marburg, Fachbereich Chemie, Hans-Meerwein Str., 35032 Marburg,
Germany. bLeiden University, Institute of Biology, Wassenaarseweg 64,
2333 AL Leiden, The Netherlands. Wilbuer@chemie.uni-marburg.de
Substitutionally inert metal complexes are promising emerging scaffolds for targeting enzyme active
sites.1 Our group has demonstrated over the last five years that inert ruthenium(II) complexes can
serve as highly selective nanomolar and even picomolar inhibitors of protein kinases.2 Octahedral
metal coordination geometries in particular offer new gateways to design rigid, globular molecules
with defined shapes that can fill protein pockets such as enzyme active sites in a unique fashion.3
Although most of our previous efforts were focused on ruthenium(II) complexes, we envisioned that
octahedral iridium(III) complexes might be interesting scaffolds for two reasons: First, coordinative
bonds with Ir(III) tend to be very inert4 and therefore Ir(III) complexes should be able to serve as
stable scaffolds for the design of enzyme inhibitors.5 Second, octahedral Ir(III) complexes can be
accessed from square planar Ir(I) complexes by stereospecific oxidative addition reactions.6 Here we
present the discovery of an octahedral iridium(III) complex, synthesized through oxidative addition as
the key synthetic step. The organometallic compound functions as a low nanomolar and highly
selective inhibitor of the protein kinase Flt4, also known as VEGFR-3 (vascular endothelial growth
factor receptor 3). Flt4 is involved in angiogenesis and lymphangiogenesis and we were able to
demonstrate that this iridium complex can indeed interfere with the development of blood vessels in
vivo in two different zebrafish angiogenesis models.
References
1.
2.
3.
4.
5.
6.
E. Meggers, Curr. Opin. Chem. Biol. 2007, 11, 287-292.
E. Meggers, G. E. Atilla-Gokcumen, H. Bregman, Synlett 2007, 8, 1177-1189.
J. Maksimoska, L. Feng, K. Harms, J. Am. Chem. Soc. 2008, 130, 15764-15765.
J. Burgess, Inorg. React. Mechanism 1972, 2, 140-195.
T.-H. Kwon, J. Kwon, J.-I. Hong, J. Am. Chem. Soc. 2008, 130, 3726-3727.
J. U. Mondal, D. M. Blake, Coord. Chem. Rev. 1982, 47, 205-238.
141
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
P-84
New Oxorhenium(V) Complex with Aminothiazole Ligand, and Radiochemical
Behavior of its Oxotechnetium(V) Complex Analog
Norah S. Al-Hokbany,a* R.M. Mahfouz,a and I.J. Al-Jammazb
a
King Saud University, Department of Chemistry, College of Science, P.O.Box 2455, Riyadh, 11451
Kingdom of Saudi Arabia. b Cyclotron and Radiopharmaceuticals Department, King Faisal Specialist
Hospital and Research Center. P.O. Box 3354, Riyadh 11211, Kingdom of Saudi Arabia.
Tel:+966 1 4772245; Fax: +966 1 4772245. e-mail: nhokbany@ksu.edu.sa
A [ReO(amino)2OH] complex was successfully synthesized by ligand exchange method of
oxorhenuim gluconate with aminothiazole ligand. Geometry optimization of complex has been carried
out using DFT at the B3LYP/LANL2DZ functional in singlet state. B3LYP predicted infrared
spectrum of geometrical optimized structure using the same level of the theory and the same basis set
showed good agreement with experimentally observed values. The complex has been characterized
using elemental analysis and different spectroscopic techniques (IR, UV-Vis, NMR and MS).
At the technetium tracer level, the 99mTcO-complex has been synthesized by two methods (99mTcgluconate as precursor; direct reduction). The radiochemical purity of the complex was over 95% as
measured by thin layer chromatography. In vitro studies showed that the complex possessed good
stability under physiological conditions. Its partition coefficient indicated that it was a hydrophilic
complex. The electrophoresis results showed the complex was neutral. Normal biodistribution of 99m
Tc complex, exhibit high lung, liver and spleen uptake (27%, 11%, and 12%, respectively). Blood and
lung clearance was quite fast (% injection dose in blood and lungs 0.36% and 0.18%, respectively at 1
hr post-injection), while liver activity remained high for a longer period (% injection dose 12% at 1 hr
post-injection). The radioactivity from the novel technetium complex was excreted mainly through the
hepatobiliary system (35% at 1 h post-injection) and partially kidney.
99m
TcO4-
pH=9 NaBH4
r.t
45min
99m
ReO4Na-gluconate
Na-gluconate
SnCl2. 2H2O
SnCl2. 2H2O
TcO(gluc)2-
N
+
NH2
S
ReO(gluconate)2-
O
NH
N
S
M
S
OH
HN
N
were M = Re,99mTc
References
1. P. Bouziotis, D. Papagiannopoulou, I. Pirmettis, M. Pelecanou, C.P. Raptopoulou, C.I.
Stassinopoulou, A. Terzis, M. Friebe, H. Spies, M. Papadopoulos, E. Chiotellis, Inorg. Chim. Acta
2001, 320, 174-177.
2. H. Zhang, M. Dai, C. Qi, X. Guo, Appl. Radiat. Isot. 2004, 60, 643-651.
3. B. Dhara, P. Chattopadhyay, Appl. Radiat. Isot. 2005, 62, 729-735.
4. K. Schwochau, Technetium Chemistry and Radiopharmaceutical Applications, Wiley-VCH,
Weinheim, 2000.
142
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
Participants
143
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
Sergey Abramkin
Universität Wien, Austria
sergey.abramkin@univie.ac.at
Oladipo Ademola
Lautech, Nigeria
suspyo@yahoo.com
Ebenezer Aidoo
University of South Africa, South Africa
lincollnn@yahoo.com
Prof. Dr. Roger Alberto
Univerität Zürich, Switzerland
ariel@aci.uzh.ch
Hamed Alborzinia
Universität Heidelberg, Germany
hamed.alborzinia@uni-heidelberg.de
Dr. Noura Al-Hokbany
King Saud University, Saudi Arabia
nhokbany@ksu.edu.sa
Dr. Wee Han Ang
National University of Singapore, Singapore
chmawh@nus.edu.sg
Anusch Arezki
ENSCP, France
anusch-arezki@chimie-paristech.fr
Dr. Braja Gopal Bag
Vidyasagar University, India
bgopalbag@yahoo.co.in
Nicolas Barry
University of Neuchatel, Switzerland
nicolas.barry@unine.ch
Prof. Dr. Wolfgang Beck
Ludwig-Maximilians-University München, Germany
wbe@cup.uni-muenchen.de
Samaneh Beheshti
University of Western Ontario, Canada
sbehesh@uwo.ca
Dr. Alberta Bergamo
Callerio Foundation, Italy
a.bergamo@callerio.org
144
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
Ruth Bieda
Ruhr-Universität Bochum, Germany
ruth.bieda@rub.de
Sebastian Blanck
Universität Marburg, Germany
sebastian.blanck@chemie.uni-marburg.de
Dmytro Bobukhov
Ukrainian State Chemical Technology University, Ukraine
dbobukhov@googlemail.com
Dr. Diane Bouvet-Muller
ICMPE Paris 12, France
muller@u-pec.fr
Adam Boynton
Trinity College, USA
timothy.curran@trincoll.edu
Nadine Brückmann
Universität Düsseldorf, Germany
brueckmn@uni-duesseldorf.de
Prof. Dr. Peter Buglyo
University of Debrecen, Hungary
buglyo@delfin.unideb.hu
Daniel Can
Universität Zürich, Switzerland
daniel.can@aci.uzh.ch
Suzan Can
Universität Heidelberg, Germany
suz.c@gmx.de
Dr. Angela Casini
EPFL, Switzerland
angela.casini@epfl.ch
Prinessa Chellan
University of Cape Town, South Africa
prinessa.chellan@uct.ac.za
Dr. Joao Correia
ITN, Portugal
jgalamba@itn.pt
Prof. Dr. Timothy Curran
Trinity College, USA
timothy.curran@trincoll.edu
145
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
Tensim Dallagi
ENSCP, France
t.dallegi@laposte.net
Prof. Dr. Marcetta Darensbourg
Texas A&M University, USA
marcetta@mail.chem.tamu.edu
Prof. Dr. Roman Dembinski
Oakland University, USA
dembinsk@oakland.edu
Jan Dittrich
Ruhr-Universität Bochum, Germany
jan.dittrich@rub.de
Prof. Dr. Holger Dobbek
Humboldt-Universität zu Berlin, Germany
holger.dobbek@biologie.hu-berlin.de
Christine Doffek
Ruhr-Universität Bochum, Germany
christine.doffek@rub.de
Gregor Dördelmann
Ruhr-Universität Bochum, Germany
gregor.doerdelmann@rub.de
Anica Dose
University of Kent, Great Britain
ad308@kent.ac.uk
Prof. Dr. Paul Dyson
EPFL, Switzerland
paul.dyson@epfl.ch
Dr. Johannes Eble
Universität Frankfurt, Germany
eble@med.uni-frankfurt.de
Prof. Dr. Richard Fish
Lawrence Berkeley National Laboratory, USA
rhf@lbl.gov
Ying Fu
University of Warwick, Great Britain
fuyingpku@gmail.com
Dr. Christian Gaiddon
University of Strasbourg, France
gaiddon@unistra.fr
146
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
Dr. Gilles Gasser
Univerität Zürich, Switzerland
gilles.gasser@aci.uzh.ch
Luca Gaviglio
University of Piemonte Orientale, Italy
luca.gaviglio@mfn.unipmn.it
Yvonne Geldmacher
Ruhr-Universität Bochum, Germany
yvonne.geldmacher@rub.de
Prof. Dr. Roberto Gobetto
University of Torino, Italy
roberto.gobetto@unito.it
Meral Gormen
ENSCP, France
meral-gormen@chimie-paristech.fr
Annika Groß
Ruhr-Universität Bochum, Germany
annika.gross@rub.de
Prof. Dr. Ronald Gust
Freie Universität Berlin, Germany
rgust@zedat.fu-berlin.de
Frauke Hackenberg
Ruhr-Universität Bochum, Germany
frauke.hackenberg@rub.de
Didier Hamels
ENSCP, France
didier.hamels@hotmail.fr
PD Dr. Christian Hartinger
Universität Wien, Austria
christian.hartinger@univie.ac.at
Masoumeh Hazratilivari
Iran
zazoli49@yahoo.com
Dr. Jörg Henig
Ruhr-Universität Bochum, Germany
joerg.henig@rub.de
Prof. Dr. Richard Herrick
College of the Holy Cross, USA
rherrick@holycross.edu
147
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
Prof. Dr. Toshikazu Hirao
Osaka University, Japan
hirao@chem.eng.osaka-u.ac.jp
Dr. Elizabeth Hillard
ENSCP, France
elizabethhillary@yahoo.com
Pavlo Holenya
Universität Heidelberg, Germany
Wanning Hu
Ruhr-Universität Bochum, Germany
wanning.hu@rub.de
Dr. Jamie Humphrey
Royal Society of Chemistry, Great Britain
humphreyj@rsc.org
Nina Hüsken
Ruhr-Universität Bochum, Germany
nina.huesken@rub.de
Maxim Izumsky
Ukrainian State Chemical Technology University, Ukraine
maksimizumsky@gmail.com
Kartin Jäger
Forschungszentrum Rossendorf, Germany
k.jaeger@fzd.de
Rajkumar Jana
Universität Stuttgart, Germany
jana@iac.uni-stuttgart.de
Prof. Dr. Gerard Jaouen
ENSCP, France
gerard-jaouen@chimie-paristech.fr
Prof. Dr. Andres Jäschke
Universität Heidelberg, Germany
jaeschke@uni-hd.de
Dr. Violeta Jevtovic
University of Novi Sad, Serbia
violeta.jevtovic@dh.uns.ac.rs
Prof. Dr. Jorge Jios
Universidad Nacional de La Plata
Argentina
jijios@quimica.unip.edu.ar
148
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
Prof. Dr. Kenneth Kam-Wing Lo
City University of Hong Kong, Hong Kong
bhkenlo@cityu.edu.hk
Christine Kasper
Ruhr-Universität Bochum, Germany
christine.kasper@rub.de
Syed Gohar Taqi Kazimi
University of Sargodha, Pakistan
gohartaqi@hotmail.com
Dr. Srecko Kirin
Institut Ruđer Bošković, Croatia
srecko.kirin@irb.hr
Dr. Igor Kitanovic
Universität Heidelberg, Germany
igor.kitanovic@urz.uni-heidelberg.de
Malte Kokoschka
Ruhr-Universität Bochum, Germany
malte.kokoschka@rub.de
Dr. Konrad Kowalski
University of Lodz, Poland
kondor15@wp.pl
Prof. Dr. Heinz-Bernhard Kraatz
University of Western Ontario, Canada
hkraatz@uwo.ca
Dr. Erik Kriel
Mintek , South Africa
erikk@mintek.co.za
Dr. Lukas Kromer
ITQB-UNL, Portugal
kromer@itqb.unl.pt
Dr. Peter Kunz
Universität Düsseldorf, Germany
peter.kunz@uni-duesseldorf.de
See Mun Lee
University of Malaya, Malaysia
annieleesm@gmail.com
Prof. Dr. Emanuela Licandro
University of Milano, Italy
emanuela.licandro@unimi.it
149
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
Zhe Liu
University of Warwick, Great Britain
z.liu.2@warwick.ac.uk
Olessya Loiko
Karaganda State University, Kazakhstan
olessya0905@gmail.com
Dr. Jason Lynam
University of York, Great Britain
jml12@york.ac.uk
Prof. Dr. Stefano Maiorana
University of Milano, Italy
stefano.maiorana@unimi.it
Basudev Maity
Indian Institute of Science Bangalore, India
ipcbasudev@gmail.com
Sergey Malinkin
Kiev National Taras Shevchenko University, Ukraine
malinachem@mail.ru
Dr. Sanela Martic
University of Western Ontario, Canada
smartic@uwo.ca
Niall McGuinness
National University of Ireland, Irland
nmguinness@hotmail.com
Thomas McTeague
Trinity College, USA
Prof. Dr. EricMeggers
Universität Marburg, Germany
meggers@chemie.uni-marburg.de
Sandra Mieranz
Freie Universität Berlin
Germany
Prof. Dr. Morten Meldal
Carlsberg Laboratory, Denmark
mpm@crc.dk
Prof. Dr. Mohamed Metwally
University of Mansoura, Egypt
mamegs@mans.edu.eg
150
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
Prof. Dr. Nils Metzler-Nolte
Ruhr-Universität Bochum, Germany
nils.metzler-nolte@rub.de
Andreas Meyer
TU Braunschweig, Germany
andreas.meyer@tu-bs.de
Stefan Mollin
Universität Marburg, Germany
stefan-mollin@web.de
Jean-Philippe Monserrat
ENSCP, France
jean-philippe-monserrat@chimie-paristech.fr
Prof. Dr. Toshiyuki Moriuchi
Osaka University, Japan
moriuchi@chem.eng.osaka-u.ac.jp
Prof. Dr. Orde Munro
University of KwaZulu-Natal, South Africa
munroo@ukzn.ac.za
Ali Nazif
Ruhr-Universität Bochum, Germany
alinazif@hotmail.com
Dr. Alexey Nazarov
EPFL, Switzerland
alexey.nazarov@epfl.ch
Johanna Niesel
Ruhr-Universität Bochum, Germany
johanna.niesel@rub.de
Dr. Stephan Niland
Universität Frankfurt, Germany
niland@med.uni-frankfurt.de
Anna-Luisa Noffke
Universität Düsseldorf, Germany
anna-louisa.noffke@uni-duesseldorf.de
Luciano Oehninger
TU Braunschweig, Germany
oehninger@gmail.com
Dr. Melanie Oleszak
Ruhr-Universität Bochum, Germany
m.oleszak@gmx.de
151
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
Obiora Augustine Orakwue
Hyqid Nigeria Ltd., Nigeria
hyqidenergy@gmail.com
Prof. Dr. Chris Orvig
University of British Columbia, Canada
orvig@chem.ubc.ca
Prof. Dr. Domenico Osella
University of Alessandria, Italy
domenico.osella@mfn.unipmn.it
Prof. Dr. Ingo Ott
TU Braunschweig, Germany
ingo.ott@tu-bs.de
Dr. Salih Özçubukçu
University of Chicago, USA
salih@uchicago.edu
Prof. Dr. Mallayan Palaniandavar
Bharathidasan University, India
palanim51@yahoo.com
Malay Patra
Ruhr-Universität Bochum, Germany
malay.piu@gmail.com
Dr. Andrew Phillips
University College Dublin, Ireland
andrew.phillips@ucd.ie
Hendrik Pfeiffer
Ruhr-Universität Bochum, Germany
hendrik.pfeiffer@rub.de
Anais Pitto-Barry
Universität Neuchatel, Switzerland
anais.pitto-barry@unine.ch
Dr. Nicolas Plumere
Ruhr-Universität Bochum, Germany
nicolas.plumere@rub.de
Maria Proetto
Freie Universität Berlin, Germany
Lukasz Raszeja
Ruhr-Universität Bochum, Gmany
lukaszraszeja@aol.com
152
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
Mariia Randarevych
Ukrainian State Chemical Technology University, Ukraine
m_randarevich@mail.ru
Prof. Dr. Mauro Ravera
Universtiy of Piemonte Orientale, Italy
mauro.ravera@mfn.unipmn.it
Prof. Dr. Charles Riordan
University of Delaware, USA
riordan@udel.edu
Steffen Romanski
Universität zu Köln, Germany
romansks@uni-koeln.de
Prof. Dr. Edward Rosenberg
University of Montana Missoula, USA
edward.rosenberg@mso.umt.edu
Riccardo Rubbiani
TU Braunschweig, Germany
r.rubbiani@tu-bs.fr
Dr. Bogna Rudolf
University of Lodz, Poland
brudolf@chemia.uni.lodz.pl
Mojdeh Safari
Azad University, Iran
msafari96@yahoo.com
Hamid Samouei
Shiraz University, Iran
samouei@gmai.com
Prof. Dr. Gianni Sava
Callerio Foundation, Italy
g.sava@callerio.org
Aroonchai Saiai
Universität zu Köln, Germany
asaiai@smail.uni-koeln.de
Dr. Ulrich Schatzschneider
Ruhr-Universität Bochum, Germany
ulrich.schatzschneider@rub.de
Prof. Dr. Hans-Günther Schmalz
Universität zu Köln, Germany
schmalz@uni-koeln.de
153
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
Matthias Scholz
Universität Leipzig, Germany
mscholz@chemie.uni-leipzig.de
Julia Schur
TU Braunschweig, Germany
j.schur@tu-bs.de
Dr. Brigitte Schwederski
Uni Stuttgart, Germany
schwederski@iac.uni-stuttgart.de
Dr. Khadija Shahid
Riphah International University, Pakistan
khadijajee@yahoo.com
Marjan Shahmir
Amirkabir University, Iran
marjanshahmir@yahoo.com
Prof. Dr. William Sheldrick
Ruhr-Universität Bochum, Germany
william.sheldrick@ruhr-uni-bochum.de
Prof. Dr. Alexander Shtemenko
Ukrainian State Chemical Technology University, Ukraine
shtemenko@ukr.net
Prof. Dr. Nataliia Shtemenko
Ukrainian State Chemical Technology University, Ukraine
n.shtemenko@i.ua
Dr. Gregory Smith
University of Cape Town, South Africa
gregory.smith@uct.ac.za
Thomas Sowik
Ruhr-Universität Bochum, Germany
thomas.sowik@rub.de
Katrin Splith
Universität Leipzig, Germany
splith@uni-leipzig.de
Robert Ssekanyonyi
Kiriibwa AIDS Caring Center, Uganda
rebeccanawanji@yahoo.com
Marilena Stefanopoulou
Ruhr-Universität Bochum, Germany
stef_point@hotmail.com
154
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
Dr. Pratima Srivastava
ENSCP, France
pratima-srivastava@chimie-paristech.fr
Dr. Svetlana Strashnova
People's Friendship University of Russia, Russia
sstrashnova@mail.ru
Prof. Dr. Georg Süss-Fink
Universität Neuchatel, Switzerland
georg.suess-fink@unine.ch
Prof. Dr. Matthias Tacke
University College Dublin, Ireland
matthias.tacke@ucd.ie
Fatemeh Tavakolinia
Azad University, Iran
ftavakolinia@yahoo.com
Dr. Siden Top
ENSCP, France
siden-top@chimie-paristech.fr
Prof. Dr. John Valliant
McMaster University, Canada
valliant@mcmaster.ca
Prof. Dr. Gerard van Koten
Utrecht University, The Netherlands
g.vankoten@uu.nl
Dr. Anne Vessieres
ENSCP, France
a-vessieres@chimie-paristech.fr
Prof. Dr. Yoshihito Watanabe
Nagoya University, Japan
yoshi@nucc.cc.nagoya-u.ac.jp
Prof. Dr. Wolfgang Weigand
Universität Jena, Germany
wolfgang.weigand@uni-jena.de
Alexander Wilbuer
Universität Marburg, Germany
wilbuer@chemie.uni-marburg.de
Dr. Dirk Wolters
Ruhr-Universität Bochum, Germany
dirk.wolters@rub.de
155
ISBOMC `10
5.7 – 9.7. 2010 Ruhr-Universität Bochum
Prof. Dr. Stefan Wölfl
Universität Heidelberg, Germany
wolfl@uni-hd.de
Dr. Teck Tian Wong
Nanyang Techological University, Singapore
nhswtt@nus.edu.sg
Dr. Yaw-Kai Yan
Nanyang Techological University, Singapore
yawkai.yan@nie.edu.sg
Prof. Dr. Shyh-Chyun Yang
Kaohsiung Medical University, Taiwan
scyang@kmu.edu.tw
Dina Yegorova
Ukrainian State Chemical Technology University, Ukraine
dino4ka_ego@ukr.net
Kateryna Zablotska
Ukrainian State Chemical Technology University, Ukraine
pragma8@i.ua
Johannes Zagermann
Ruhr-Universität Bochum, Germany
johannes.zagermann@rub.de
Dr. Mohammad Ali Zazouli
Iran
zazoli49@yahoo.com
Prof. Dr. Ibrahim Zeid
Monoufia University, Egypt
ifzeid@hotmail.co.uk
Macolm Zimbron
Universität Basel, Switzerland
malcolm.zimbron@unibas.ch
Dr. Fabio Zobi
Univerität Zürich, Switzerland
fzobi@aci.uzh.ch
156