Metal-Based Drugs: Novel Targets
Bulk elements
Trace elements
Possibly essential
Metallopharmaceuticals
AntiDepressive
Insulin
Mimetic
H
He
Li
Be
B
C
N
O
F
Ne
Na
Mg
Al
Si
P
S
Cl
Ar
K
Ca Sc
Ti
V
Cr
Mn
Fe Co
Ni
Se Br
Kr
Rb
Sr Y
Zr
Nb Mo
Tc
Ru Rh
Pd Ag Cd In
Sn
Sb Te
Cs Ba Ln
Hf
Ta
Re
Os
Pt
Pb
Bi
Fr
Th
Pa U
Ra Ac
W
Diagnostic Agents: X-ray, MRI
Ir
Cu Zn Ga Ge As
Au Hg Tl
Po At
Antiulcer
Anticancer
Antiinfective
Radiopharmaceuticals
I
Antiarthritic
Xe
Rn
Metal-Based Drugs: New targets
Current ARC funded projects

Kinetics and mechanism of binding of platinum
anticancer drugs to DNA

Development of metal-based antimitochondrial
antitumour agents
DNA Interactions of platinum anticancer drugs
University of Western Australia
Prof Sue Berners-Price
Dr Junyong (June) Zhang
Don Thomas
Joe Moniodis
Virginia Commonwealth University, USA
Prof Nick Farrell
(Network International Advisory panel USA)
Funding
ARC Discovery (2002-4), ARC Linkage Int (2002-4)
NIH, NSF, Am Cancer Soc.
Facilities
UWA NMR Facility (600, 500 MHz Spectrometers)
H3N
Cl
Cl
Pt
H3N
H3N
NH3
Pt
Pt
Cl
H3N
Cisplatin
NH2(CH2)nH2N
NH3
1,1/t,t; n=6 (BBR3005)
ID50 (L1210) = 2.4 mM
TWI%(LX-1) = 38@4.0 mg/kg
NH3
Cl
ID50 (L1210) = 3.03 mM
TWI%(LX-1) = 72@3.0 mg/kg
H3N
Pt
H3N
Cl
2+
NH2(CH2)nH2N
Pt
NH2(CH2)nH2N
NH3
Pt
NH3
H3N
1,0,1/t,t,t; (n = 6,6) (BBR3464)
ID50 (L1210) = 0.0094 mM
TWI%(LX-1) = 73@0.3 mg/kg
Cl
4+
1H
NMR : 14-mer DNA duplex
+ 1.6 mM
Cl
15N-
NH3
H3N
Pt
H3N
NH2(CH2)6H2N
Pt
NH2(CH2)6 H2N
(4 h 25 oC)
4+
Pt
NH3
H3N
T-CH3
Cl
aromatic
(G H8)
Pt-NH2
imino
14
NH3
12
10
8
d/ppm
6
Pt-NH3
4
2
0
[1H, 15N] NMR : 14-mer DNA duplex
+ 1.6 mM 15N-
Cl
NH3
H3N
Pt
H3N
NH2(CH2)6H2N
Pt
NH2(CH2)6 H2N
NH3
(4 h 25 oC)
Pt
NH3
H3N
Cl
Pt-NH3
Pt-NH2
End
Groups
4+
(H2O)
Linker
-48
-64
d 15N
-46
-62
-44
End
Groups
Linker
-60
5.4
5.2
5.0
4.8
4.6
d
1H
4.6
4.4
4.2
4.0
1,4- and 1,6-GG Interstrand Crosslink Formation
Cl
T
A
G
Pt T
A
Pt
C
T
G
C
T
Pt
Cl
A
A
k2
Pt
kH
Cl
k -H
k1
Cl
Pt
+
Pt
OH2
A
G
T
A
C
T
T
C
A
G
Pt T
A
C
T
k3
A
T
G
A
Pt
A
G Pt
T
A
C
T
OH2
T
C
A
T
Pt G
A
Cox et al J. Am. Chem. Soc. 123, 1316-1326 (2001)
Hegmans et al. J. Am. Chem. Soc. (2004) in press.
T
C
A
T
G
A
Kinetics of formation of 1,6- and 1,4- Interstrand Crosslinks
H3N
Y
Pt
NH2
NH3
H2N
H3N
Pt
NH3
NH2
H3N
Y/Y
H2N
Pt
Y
4+
NH3
5'-d(T-A-T-G-T-A-T-A-C-A-T-A)
5'-d(A-T-A-T-G-T-A-C-A-T-A-T)
3'-d(A-T-A-C-A-T-A-T-G-T-A-T)
3'-d(T-A-T-A-C-A-T-G-T-A-T-A)
(1,6-GG)
(1,4-GG)
2.00
2.00
1.60
G/G
Cl/Cl
Cl/Cl
1.50
[Pt2]
1.20
(m
M)
0.80
G/G
1.00
G/Cl
0.50
G/Cl
0.40
0.00
0.00
0
10
20
30
Time (h)
40
50
0
10
20
30
Time (h)
40
50
Formation of a 1,4- GG Interstrand Crosslink
Guanine N7
Metal-Based Drugs: New targets
Current ARC funded projects

Kinetics and mechanism of binding of platinum anticancer drugs
to DNA

Development of metal-based antimitochondrial antitumour
agents
[Au(dppe)2]Cl: Antitumour Activity

Active against a spectrum of mouse
tumour models (4 i.p. tumours; 3
s.c. tumours)

Active in a cisplatin-resistant
subline of P388 leukaemia

Acts synergistically with cisplatin
against moderately advanced P388
leukaemia
Berners-Price at. al. (1986) Cancer Research 46, 5486
Metal complexes of bidentate pyridyl phosphines
+
R1
Ar
Ar
Ar
Ar
R1-R4
M
Ar
Ar
P
Ar
R4
R2
P
P
P
P
R3
P
N
Ar
M = Au(I), Ag(I), Cu(I)
2-pyridyl
or
N
3-pyridyl
or
N
4-pyridyl
Cytotoxic potency against human ovarian
tumours vs partition coefficient
o/
CH 1/ -cisR
/
41 M/ -cisR X SKOV-3
1000
R
P
R
100
IC 50
(mM)
P
R´
+
R´
M
10
R
P
R
P
R´
R´
[Au(dppe)2]+
1
0.1
0.0
0.01
0.1
1
10
Partition coefficient
100
Antitumour activity vs log kw
Colon 38 mouse tumour model
[Au(dppe)2]Cl
(R = Ph)
100
log Kw
5.4
R = 4-pyridyl
100
log Kw
2.2
R = 2-pyridyl
100
Relative
Tumour
Volume
10
10
10
1
1
1
0
5
10 15 20
0
log Kw
2.9
5 10 15 20
0 5 10 15 20
Time (days)
McKeage et al. Cancer Chemother. Pharmacol. 2000, 46, 343
Mitochondrial Control of Apoptosis
Cytoplasm
inhibits apoptosis, binds
ICE proteins and
suppresses release of
cytochrome c and AIF
+
Apoptosis
-
ICE
CED-4
accumulate
within
mitochondria
Bcl2
Antitumou
r
Lipophilic
Cations
?
+
-
cytochrome
c
AIF
Mitochondria
released from
mitochondria by
apoptotic stimuli
Mitochondrial Permeability Transition Pore
Complex
Voltage Dependent
Anion Channel
Hexokinase
å
Benzodiazepin receptor
Bax,
Bak
Intermembrane
space
Bcl-2
Creatine Kinase
Adenine Nucleotide
Translocase
Cyclophilin-D
Matrix
Mitochondrial Permeability Transition Pore
Complex
Inducers: Ca2+, ROS
å
Inducers:BH3
peptides
Inducers: PBR ligands
Bax,
Bak
Bcl-2
Intermembrane
space
Inducers: Ca2+, ROS, NO
thiol oxidation
Inhibitor: thiol reduction
Inhibitor:Cyclosporin A
Matrix
Targeting mitochondrial cell death pathways
in chemotherapy
More than 20 cytotoxic drugs are now known to induce cell death by
permeabilizing mitochondrial membranes
(demonstrated in a cell-free system)
e.g.
_
Etoposide, Paclitaxel,
_
PBR ligands (PK11195)
_
ANT ligands : Ionidamine, Arsenite, CD437
See Debatin, Poncet, Kroemer, Oncogene, 2002 21 8786-8803
Antimitochondrial activity of Auranofin

At submicromolar concentrations
Auranofin induces mitochondrial
H OAc
permeability transition (requires Ca2+,
H O
AcO
AcO
cyclosporin-A sensitive)
S Au PEt 3
H
H
OAc
H

Attributed to inhibition of mitochondrial
thioredoxin reductase

Au(I) binds to active site selenocysteine
Rigobello, Bindoli et al. Br. J. Pharmacol. (2002) 136 1162
Absorbance
Antimitochondrial activity
2+
IV
1.5
2
III
II
N
Au
N
N
Au
I
1.0
N
N
N N
N
N
N
Au
N
N
Au
N
N
N
N
0.5
0
5
I
10
mg Au/mg protein
Time (min)
II
2+
5
N
I
III
4
N
N
2+
N
N
N
N
N
Au
N
N
Au
N
N
Au
Au
3
N
N
II
N
N
N
N
N
2
IV
1
0
III
0
5
10
15
IV
N
University of Western Australia
Prof Sue Berners-Price
Prof David Day
A/Prof Murray Baker
A/Prof George Yeoh
Dr Peter Barnard
James Hickey
Funding
ARC Discovery (Berners-Price, Baker 2004-6)
Gold Phosphine and Carbene Complexes as Potential
Antimitochondrial Agents: Design,Synthesis and Biological
Chemistry
Collaborators
A/Prof Mark McKeage, Bruce Baguley (Auckland)
Prof Peter Sadler (Edinburgh)
(Network International Advisory panel (EU))