Abstract
The work carried in the research tenure has been compiled in the form of a thesis
entitled “Synthesis and Biological Evaluation of New Hybrids of Pyrrolo[2,1c][1,4]benzodiazepines
and
Combinatorial
Synthesis
of
Chalcone-Triazole
Derivatives”. The main aim of this work has been to design and synthesize biologically
active molecules like pyrrolobenzodiazepines, which are known for their DNA-binding
ability and potent anticancer activity. Furthermore, the biologically active chalcone1,2,3-triazole library has been designed and synthesized by developing solid-phase
combinatorial methods. The thesis has been divided into four chapters.
 CHAPTER I: This chapter gives the general introduction about cancer chemotherapy,
covalent
interactions
of
drug-DNA,
particularly
of
pyrrolo[2,1-c]
[1,4]benzodiazepine (PBD) antitumour antibiotics, combinatorial chemistry and
including the objectives of the present work.
 CHAPTER II: This chapter describes the synthesis of a series of phenanthrylphenolPBD conjugates connected through simple alkane spacers as well as triazole
containing alkane spacers and these conjugates have been evaluated for their
biological activity.
 CHAPTER III: This chapter deals with the synthesis of new PBD hybrids by linking
dithiocarbamates and piperazine moieties at the C8-position of the PBD scaffold
with varying alkane spacers. The present chapter is mostly focused on the DNAbinding affinity and anticancer activity of the newly synthesized PBD hybrids. This
study has been directed towards the improvement of the DNA sequence specificity
and antitumour activity by these new molecules.
 CHAPTER IV: In this chapter, a new solid-phase synthetic strategy has been
developed to synthesize nitrogen-containing heterocyclic compounds based on
hydroxy chalcones and 1,2,3-triazoles. It is the first time a solid-phase synthesis of
chalcone-triazole conjugates has been demonstrated.
CHAPTER-I
INTRODUCTION

This chapter describes the general introduction about pyrrolobenzodiazepines and
combinatorial chemistry..
PYRROLO[2,1-c][1,4]BENZODIAZEPINES

Cancer is a diseases characterized by uncontrolled growth or spread of abnormal
cells. It involves the conversion of any normal cell to a cancerous cell showing tandem
replication and cell division at much faster rate in comparison to the normal cells and
thus provides a potential target area for the development of chemotherapeutic agents. It
is now clear that chemotherapy’s most effective role in solid tumours is as an adjuvant
to initial therapy by surgical or radiotherapeutic procedures. Chemotherapy becomes
critical to effective treatment because only systemic therapy can attack micrometastases.
These agents can be categorized into functional subgroups like alkylating agents,
antimetabolites, antibiotics, and antimitotics. The pyrrolo[2,1-c][1,4]benzodiazepines
belonging to the class of DNA-interactive antitumour antibiotics have the potential as
regulators of gene expression with possible therapeutic application in the treatment of
genetic disorders including cancer. The first PBD antitumour antibiotic anthramycin has
been described by Leimgruber et. al., in 1963, and since then a number of compounds
have been developed on the PBD ring system leading to some efficient DNA binding
ligands.
H3C 8
OH H
OCH3
9 N 11
H
10
11a
7
6
2
N
5
4
N
HO
H
1
O
Anthramycin
N
H
O
N
N
H3CO
CONH2
3
O
Tomaymycin
O
N
N
OCH3 H3CO
O
SJG-136
H
O
Figure 1
PBD’s are a family of potent naturally occurring low molecular weight antitumour
antibiotics originally isolated from various Streptomyces species. Their common
interaction with DNA has been extensively investigated and it is considered unique
since they bind within the minor groove of DNA forming a covalent aminal bond
between the C11-position of the central B-ring and the N2 amino group of guanine base.
A number of naturally occurring and synthetic compounds based on PBD ring system,
such as anthramycin, tomaymycin, DC-81 and its dimers (presently, one of the dimer
SJG-136 is under clinical evaluation), have shown varying degrees of DNA binding
affinity and anticancer activity.
O
carbinolomine
H2N
OH H OH
H
10 N
11
N
DNA
N
N
N
HN
OH H
10 N
H
DNA
N
NH
11
NH2
N
O
O
N
HN
NH2
N
O
O
Anthramycin
O
Figure 2

COMBINATORIAL CHEMISTRY
Combinatorial chemistry is a new methodology developed by researchers in the
pharmaceutical industry to reduce the time and costs associated with producing
effective and competitive new drugs. By accelerating the process of chemical synthesis,
this method is having a profound effect on all branches of chemistry, especially in drug
discovery. Through the rapidly evolving technology of combinatorial chemistry, it is
now possible to produce libraries of small molecules for screening new bioactivities.
This powerful technology has begun to help pharmaceutical companies to find new
drug candidates quickly, save significant money in preclinical development costs and
ultimately change their fundamental approach to drug discovery.
Combinatorial chemistry has been used to synthesize large number of chemical
compounds by combining sets of building blocks. Each newly synthesized compound’s
composition is slightly different from the previous one. In this way the bench chemists
can single handedly prepare many hundreds or thousands of compounds in the time
usually taken to prepare only a few by routine methodologies. Over the last few years,
the combinatorial chemistry has emerged as an exciting new paradigm for the drug
discovery. In a very short time the topic has become the focus of considerable scientific
interest and research efforts.
CHAPTER-II
In search for new potential anticancer drugs, we designed and synthesized
combilexins, in which DNA intercalator is linked to a minor groove binding component.
A new type of DNA intercalator comprising of phenanthrylphenol fragment has been
tethered by ether linkage to the PBD ring system and these have been evaluated for
their biological activity. An attempt, based on the in vitro cytotoxic activity exhibited in
these compounds made to rationalize their mechanism of action through cell cycle
analysis and DNA interaction studies. Cell cycle phase distribution and apoptosis is
measured using flow cytometry and DNA ladder assay. The DNA binding
characteristics of these conjugates have been evaluated by thermal denaturation studies
and ethidium bromide displacement assay. A molecular modeling study has been
carried out for a set of compounds 18a-c, and calculated their binding score. The data
obtained suggest that the spacer length is crucial for optimal interaction. One of the
representative compounds 18a of this series has been tested against a panel of 57 human
cancer cell lines. Further, compounds 18a and 18c induce marked influence on the cell
cycle phase distributions with significant G1 arrest in MOLT-4 cells, followed by the
induction of apoptosis along with DNA minor groove binding.
 SYNTHESIS
OF PHENANTHRYLPHENOL LINKED PYRROLOBENZODIAZEPINE
(PP-PBD)
CONJUGATES
Synthesis of phenanthrylphenol-pyrrolobenzodiazepine conjugates (18a-c) has
been carried out by employing the commercially available vanillin (1) as the starting
material. Oxidation of vanillin to form the corresponding carboxylic acid followed by
acid-catalyzed esterification with methanol provided methyl benzoate in quantitative
yield. This is followed by benzylation and nitration by employing the literature method
provides 4-benzyloxy-5-methoxy-2-nitrobenzoic acid (6). This has been further coupled
to L-proline methyl ester to afford the intermediate 7, which upon reduction with
DIBAL-H produces the corresponding aldehyde 8. The aldehyde group of this
compound has been protected with EtSH/TMSCl to give 9, which upon debenzylation
provides the key intermediate 10 (Scheme 1).
HO
HO
HO
(i)
(ii)
H
MeO
1
OH
MeO
3
O
2
O
OMe
MeO
O
(iii)
NO2
BnO
(v)
OH
MeO
6
NO2
BnO
OMe
MeO
5
O
(iv)
BnO
OMe
MeO
4
O
O
(vi)
NO2
BnO
COOMe
N
MeO
7
NO2
BnO
(vii)
N
MeO
8
O
CHO
O
(viii)
HO
MeO
NO2 CH(SEt)2
BnO
(ix)
N
MeO
NO2
CH(SEt)2
N
9 O
10 O
Scheme 1. Reagents and conditions: (i) NH2SO3H, NaClO2, H2O, rt, 2 h, 90%; (ii) H2SO4, MeOH,
reflux, 4 h, 85%; (iii) benzylbromide, K2CO3, acetone, reflux, 24 h, 92%; (iv) SnCl4, fuming
HNO3, CH2Cl2, 5 min, -25 oc, 78%; (v) 2N LiOH, MeOH, H2O, THF (1:1:3), rt, 12 h, 83%; (vi)
SOCl2, C6H6, L-proline methylester hydrochloride, THF- H2O, 1-2 h, rt, 85%; (vii) DIBAL-H,
CH2Cl2, 1-1.30 h, -78 oC, 65%; (viii) EtSH, TMSCl, CH2Cl2, 8-12 h, rt, 72%; (ix) BF3.OEt2, EtSH,
CHCl3, rt, 8 h, 75%.
The phenanthrylphenol precursors required for the preparation of the desired
PBD-conjugates have been prepared as shown in Scheme 2. The first synthetic step has
been accomplished from commercially available 9-bromophenanthrene that employs a
Suzuki-Miyaura
coupling
to
afford
the
corresponding
compound
12.
Then
demethylation of 12 has been carried out by its treatment with boron tribromide (BBr 3)
at –78 ºC to give phenanthrylphenol (13). This upon subsequent treatment with
propargylbromide affords the required intermediate 14.
OMe
OMe
(ii)
(i)
O
OH
(iii)
B(OH)2
11
12
13
14
Scheme 2. Reagents and conditions: (i) 4-methoxy phenylboronic acid, Pd(PPh3)4, K3PO4 (aq),
1,4-dioxane, 80 oC, 16 h, 70%; (ii) BBr3, CH2Cl2, -78 °C, 3 h, 80%; (iii) propargyl bromide,
K2CO3, DMF, rt, 24 h, 80%.
PBD subunit precursors required for the preparation of these conjugates have been
synthesized by employing the procedure reported in the literature. Accordingly, (2S)-N[4-(bromoalkoxy)-5-methoxy-2-nitrobenzoyl]pyrrolidine-2-carboxaldehyde
diethylthioacetal (15a-c) has been prepared and linked to phenanthrylphenol precursor
13 by etherification in the presence of K2CO3 and DMF to provide intermediate 16a-c.
This nitro thioacetal 16a-c has been reduced to the amino thioacetal 17a-c with
SnCl2.2H2O in refluxing MeOH and then cyclized by treatment with HgCl2 and CaCO3
in MeCN-H2O (4:1) to afford the desired conjugates 18a-c (Scheme 3).
Br
()
O
n
O
NO2 CH(SEt)2
(i)
NO2 CH(SEt)2
O
n
N
MeO
N
MeO
()
O
O
16a-c n = 3-5
15a-c n = 3-5
(ii)
O
O
()
n
N
N
MeO
O
18a; n = 3
18b; n = 4
18c; n = 5
H
O ()O
n
(iii)
NH2 CH(SEt)2
N
MeO
O
17a-c n = 3-5
Scheme 3. Reagents and conditions: (i) 13, K2CO3, dry acetone, reflux, 24 h, 90%; (ii) SnCl2.2H2O, MeOH,
reflux, 4 h, 80-82%; (iii) HgCl2, CaCO3, CH3CN-H2O (4:1), rt, 12 h, 58-60%.
Later, the terminal C≡C bond of propargylated phenanthrylphenol (14) has been
ligated to the azide residue of the debenzylated nitrothioacetal (19a-c) using the copper
(I)-catalyzed 1,3-dipolar cycloaddition to afford the click products 20a-c (Scheme 4).
The reaction has been performed in t-BuOH/H2O (1:1) in the presence of sodium
ascorbate and copper sulfate with a little excess of azide at room temperature leading to
the product. Finally, these nitro-thioacetal intermediates have been reduced followed by
deprotective-cyclization to yield the other desired PBD-triazole-phenanthrylphenol
conjugates (22a-c).
Br
()
O
n
MeO
NO2 CH(SEt)
2
N3
(i)
N
()
NO2 CH(SEt)
2
O
n
N
MeO
O
15a-c n = 3-5
O
19a-c n = 3-5
(ii)
N N
N
O
O
n
NO2
MeO
N
()
CH(SEt)2
O
(iii)
20a-c n = 3-5
N N
N
O
O
n
NH2
MeO
N
()
O
21a-c n = 3-5
(iv)
O
CH(SEt)2
N N
N
()
O
n
N
H
N
MeO
O
22a; n = 3
22b; n = 4
22c; n = 5
Scheme 4. Reagents and conditions: (i) NaN3, dry DMF, 80 oC, 6 h, 85-90%;
(ii) 15, CuSO4.5H2O (5 mol%), sodium ascorbate (1 mol%), t-BuOH-H2O (1:1), 10
min, 85-90%; (iii) SnCl2.2H2O, MeOH, reflux, 4 h, 78-82%; (iv) HgCl2, CaCO3,
CH3CN-H2O (4:1), rt, 12 h, 58-62%.
The restriction endonuclease inhibition results show that hybrid agents (18a-c)
inhibit BamHI digestion. Our finding suggested that hybrid agents bind to DNA more
efficiently than DC-81. In addition, molecular modeling study has been carried out for a
set of PP-PBDs (18a-c) in order to rank them through their complementarity to the
CGCGATCGCG, according to their interaction energies with B-DNA. The optimal
number of methylene linkers calculated from the GOLD docking and the experimental
numbers are in reasonably good agreement.
Some of the studied compounds have shown prominent growth inhibitory effect.
According to the in vitro screening data, compound 18a has significant cytotoxicity
against all the cancer cell lines with GI50 values ranging from 0.04 to 1.76 µM and has
shown more potency against leukemia and renal cancer cell lines with average GI 50
values of 0.19 and 0.57 µM respectively. Besides, it induced strong sub G1/G0 arrest of
the cell cycle followed by apoptosis, which is in accordance with the DNA intercalative
binding mode determined by the restriction endonuclease digestion assay. On the basis
of the cytotoxicity results of PP-PBDs, triazole-containing PP-PBD derivatives also be
supposed to considered as promising lead compounds for further biological
investigation.
CHAPTER-III
In an effort to establish new candidates with improved anticancer activity,
pyrrolobenzodiazepine derivatives bearing dithiocarbamate side chains synthesized
and their DNA interaction has been evaluated by thermal denaturation studies. The
cytotoxic studies of the hybrid agents on human cancer cell lines indicate most of the
hybrids induced higher cytotoxicity.

SYNTHESIS OF C8-LINKED PYRROLO[2,1-C][1,4]BENZODIAZEPINE HYBRIDS
WITH 3-CYANO-3,3-DIPHENYLPROPYL 1-PIPERAZINE CARBODITHIOATE
The precursors in the present study is the 3-cyano-3,3-diphenylpropyl hexahydro-
1-pyrazinecarbodithioate of formula 3 and (2S)-N-[4-(n-bromoalkyl)oxy-5-methoxy-2nitro-benzoyl]pyrrolidine-2-carboxaldehyde diethyl thioacetal of formula 4 have been
prepared by literature methods. The precursor 3 has been prepared by treatment of the
substrate 3-cyano-3,3-diphenyl propylbromide (1) with equimolar amount of N-Boc
piperazine in the presence of carbon disulfide and anhydrous potassium phosphate in
dry acetone at room temperature, leads to the formation of compound 2, followed by
the Boc-group deprotection with TFA provides the required compound 3 (Scheme 1).
Br + CS
2
+
HN
N Boc
CN
1
S
CN
N
(i)
N Boc
(ii)
S
N
NH
CN
S
3
2
S
Scheme 1. Reagents and conditions: (i) K3PO4, acetone, rt, 2 h; (ii) dry-CH2Cl2, TFA, 0 oC rt, 6 h
Synthesis
of
3-cyano-3,3-diphenylpropylhexahydro-1-pyrazinecarbodithioate-
pyrrolo[2,1-c][1,4]benzodiazepine conjugates (7a-c) has been carried out by employing
(2S)-N-[4-(bromoalkoxy)-5-methoxy-2-nitrobenzoyl]pyrrolidine-2-carboxaldehyde
diethyl thioacetal (4a-c) as the starting material. The nitro thioacetal intermediate (4a-c)
has been coupled to 3-cyano-3,3-diphenylpropyl hexahydro-1-pyrazinecarbodithioate
(3)
to
give
C8-linked
3-cyano-3,3-diphenylpropylhexahydro-1-
pyrazinecarbodithioatenitrothioacetal (5a-c). The nitro group of this 5a-c has been
reduced employing SnCl2.2H2O affords the corresponding aminothioacetal 6a-c.
Deprotection of the thioacetal group of 6a-c with HgCl2 and CaCO3 affords the desired
PBD hybrids 7a-c (Scheme 2).
Br
()O
n
NO2
MeO
N
S
CN
CH(SEt)2
(i)
S
N
N
O
4a-c n = 3-5
()
NO2 CH(SEt)
2
O
n
N
MeO
5a-c
O
(ii)
S
CN
S
N
N
()
NH2 CH(SEt)
2
O
n
N
MeO
6a-c
(iii)
O
S
CN
S
N
N
N
O
( )n
H
N
MeO
7a-c
O
Scheme 2. Reagents and conditions: (i) compound 3, K3PO4, dry-acetone, rt, 2 h; (ii) SnCl2. 2H2O,
CH3OH, reflux, 2 h; (iii) HgCl2, CaCO3, CH3CN-H2O, (4:1).
The synthesis of 3-cyano-3,3-diphenylpropyl 1-piperazine carbodithioate–PBD
hybrids shows that dithiocabamate fraction can be efficiently integrated in other PBD
hybrids as well. This method should be easily extended to the synthesis of various C8substituted PBD derivatives of biological interest.

SYNTHESIS OF PBD-NAPTHALIMIDE HYBRIDS LINKED
DITHIOCARBAMATE PIPERAZINE SIDE ARMED ALKANE SPACERS
THROUGH
The cancer chemopreventive structure of dithiocarbamate moiety has been
integrated in the midst of napthalimide-pieprazine-PBD analogues and found their in
vitro antitumour activity. The synthesis of these new PBD hybrids has been carried out
by employing piperazine linked naphthalimide 10. This has been obtained by alkylation
of naphthalimide with 1,3-dibromopropane followed by coupling with N-Boc
piperazine and deprotection of Boc with trifluoroacetic acid (Scheme 3).
O
O
(i)
NH
+
Br
Br
N
Br
O
O
8
(ii)
O
O
N
N
NH
(iii)
O
N
N
N
Boc
O
10
9
Scheme 3. Reagents and conditions: (i) dibromoalkane, K2CO3, dry-acetone, reflux, 24 h; (ii) 1-Boc-piperazine,
K2CO3, dry-acetonitrile, reflux, 24 h, (iii) dry-CH2Cl2, TFA, 0 oC rt, 4 h;
The nitro thioacetal 4a-c has been coupled with 2-(3-piperazinopropyl)-2,3dihydro-1H-benzo[de]isoquinoline-1,3-dione (10) and carbondisulfide to give 11a-c. This
compound has been reduced by SnCl2.2H2O to afford the corresponding amino
thioacetal 12a-c. Deprotection of the thioacetal group of 12a-c with HgCl2 and CaCO3
affords the desired PBD-naphthalimide hybrids linked through dithiocarbamate
piperazine side armed alkane spacers (13a-c) as shown in Scheme 4.
O
10 + CS2 + 4a-c
(i)
S
N
()
3
N
N
S
O
N
S
()
3
N
N
S
O
O
O
NH2 CH(SEt)
2
O
()
n
MeO
N
12a-c O
(iii)
N
N
O
11a-c n = 3-5
(ii)
O
NO2 CH(SEt)
2
O
()
n
MeO
S
()
N
3
N
S
N
O
()
n
MeO
H
N
O
13 a-c
Scheme 4. Reagents and conditions: (i) K3PO4, acetone, rt, 2 h; (ii) SnCl2. 2H2O,
CH3OH, reflux, 2-4 h; (iii) HgCl2, CaCO3, CH3CN-H2O, (4:1), rt, 12 h .
 SYNTHESIS OF PBD-N-METHYLPIPERAZINE HYBRIDS WITH DITHIOCARBAMTE SIDE
CHAINS
The in vitro results of the napthalimide-piperazine-PBD dithiocarbamate
derivatives are encouraging. Further, the common feature dithiocarbamate fragment
has been incorporated into the C8-alkylamino substituted PBD’s. This investigation has
highlighted the effect of dithiocarbamate moiety with PBD derivatives; it appeared of
interest to investigate whether such derivatives may lead to effective antitumour agents.
The nitrothioacetal intermediates 14a,b have been synthesized by reacting 4b,c
with N-methylpiperazine in the presence of carbondisulfide and anhydrous potassium
phosphate in dry acetone. These upon reduction with tin chloride provides 15a,b.
Deprotection of the thioacetal by using HgCl2/CaCO3 results in the formation of the
desired imine compounds 16a,b (Scheme 5).
S
Me
(i)
NH + CS2 + 4b,c
N
Me N
N
()
S
O
NO2
MeO
N
n
CH(SEt)2
O
(ii)
S
Me N
N
14a,b n = 2,3
S
S
()
n O
N
H
(iii)
Me N
N
MeO
O
16a,b
N
S
()
n O
NH2
MeO
N
CH(SEt)2
O
15a,b
Scheme 5. Reagents and conditions: (i) K3PO4, acetone, rt; (ii) SnCl2. 2H2O, CH3OH, reflux, 2 h; (iii) HgCl2,
CaCO3, CH3CN-H2O, (4:1).
Then in vitro anticancer activity studies for the compounds 7a,b has been carried
out at the National Cancer Institute (NSC No. 744469, 744470 respectively). Both
compounds exhibit an interesting profile of activity and selectivity for various cell lines.
Out of these compounds 7a showed a distinctive potential pattern of sensitivity against
some individual cell lines. Compounds 7a exhibited a super sensitivity profile towards
about 33 different cancer cell lines with GI50 values lying in the submicromolar
concentration range (GI50 values <0.99 μM ).
Compounds 13a-c and 16a,b have been evaluated for their in vitro cytotoxicity in
selected human cancer cell lines like MCF7 (breast), A2780 (ovarian), Colo205 (colon),
PC3 (prostate), SiHa (cervix), A-549 and Hop62 (lung) and KB (Leukemia) by
employing the sulforhodamine B (SRB) assay. The results show that all the new
compounds are significantly cytotoxic, with the molar concentration of the drug that
inhibits 50% net cell growth inhibition (GI50) ranging from 0.1 to 2.1 μM.
From the thermal denaturation data, some interesting results can be interpreted.
All compounds have shown higher ΔTm with respect to naturally occurring DC-81 this
may be attributed to the presence of noncovalent interactions of C8-substituted
derivatives. The compounds 7a and 13b,c elevated the helix melting temperature of CTDNA by 4.0, 5.0, and 4.6 respectively, after incubation at 37 °C for 18 h. Therefore, the
enhancement of DNA binding ability of these hybrids can be correlated to other
interactions produced by the 3-cyano-3,3-diphenyl moiety, naphthalimide component
in addition to covalent linkage of the imine component. In case of N-methylpiperazinePBD derivatives with dithiocarbamates, compound 16b has been found to be an
efficient stabilizing agent of double stranded CT-DNA. This compound elevates the
helix melting temperature of CT-DNA by 10.9 °C.
CHAPTER-IV
Design and solid-phase combinatorial synthesis of chalcone-1,2,3-triazoles library
has been developed by using 1,3-dipolar cycloaddition (‘click reaction’) with polymersupported chalcone-azides and various terminal alkyne-arylpiperazines.
 SOLID-PHASE SYNTHESIS OF CHALCONE-TRIAZOLES LIBRARY
The synthetic strategy has been started with substituted 2-hydroxyacetophenone
(1), coupled to Merrifield resin with NaH to give resin-bound substituted 2hydroxyacetophenone (2). Followed by substituted benzaldehydes and NaOMe have
been added to the resin 2 (preswelled in an equal volume of THF) affords the required
resin-bound enone 3-8 as shown in Scheme 1.
R1
OH
CH3
X
1
X = H, Cl
O
O
(i)
(ii)
CH3
X
O
2
O
R2
X
O
X = H; R1 = OH, R2 =H; 3
X = Cl; R1 = OH, R2 =H; 4
X = H; R1 = OH, R2 = OMe; 5
X = Cl; R1 = OH, R2 = OMe; 6
X = H; R1 = OMe, R2 =OH; 7
X = Cl; R1 = OMe, R2 =OH; 8
Scheme 1. Reagents and conditions: (i) Merrifield resin, NaH, DMF, 50-60 °C, 48 h; (ii) substituted
hydroxybenzaldehydes, NaOMe/THF/MeOH, rt, 4 days.
Later, the polymer-bound chalcones 3-8 and anhydrous K2CO3 upon stirring with
dibromoalkanes in N,N-dimethylformamide at 50 °C gives the polymer-bound
chalcone-halides (9-14) (Scheme 2). The polymer-bound chalcone-azides (15-20) have
been synthesized by using excess of sodium azide and polymer-bound chalcone-halides
(9-14) at 60-70 °C for 12 h. Azide acts as a 1,3-dipole in cycloaddition reaction with
alkynes. Huisgen’s 1,3-dipolar cycloaddition between the obtained azido-compounds
15-20 and varied terminal alkynes in the presence of CuSO4 and sodiumascorbate in
DMF provided the polymer-bound chalcone-1,2,3-triazoles (22-117). Finally, the resins
have been cleaved with TFA/CH2Cl2 (1:1) affords the chalcones-1,2,3-triazole library
118-213.
OH
O
O
(i)
R1
O
Br
( )n
O
R1
O
(ii)
R1
X
X
X
N
( )n 3
O
O
O
38
X = H, Cl ; R1 = H, OMe
914ac; n = 35
1520ac
(iii)
N N
N
O
()
n
OH
N N
N
O
()
n
R2
O
(iv)
R1
R2
R1
X
X
O
O
118213a-c
22117
X = H, Cl ; R1 = H, OMe
R2 = building blocks
R2 = 21ap
Scheme 2. Reagents and conditions: (i) dibromoalkanes, K2CO3/DMF 50 °C, 24 h; (ii) NaN3/DMF 70 °C, 12 h;
(iii) building blocks (36) CuSO4.5H2O/DMF sodium ascorbate, 3-12 h; (iv) TFA/CH2Cl2 (1:3) rt, 2-8 h.
Cl
Cl
O
OH
Me
O
21a
N
N
Cl
21b
21c
21d
21e
Cl
F
N
F
N
N
N
N
N
21g
21f
Cl
21h
MeO
N
OMe
N
N
N
N
N
21k
21j
21i
O
N
N
OMe
N
O2N
O
21l
N
N
N
N
21m
21n
O
O
N
S
O
N
N
O
N
21p
21o
Building blocks
S
Me
Finally, at this stage of the work, 96 derivatives of the projected 384 derivatives
composing the library has been obtained. Once the library is completed, it will be
submitted to in vitro cytotoxicity assay. The prepared compounds have been screened as
antitubulinic agents, allowing us to identify three new compounds with high potency.
These compounds will now be tested in various human cancer cell lines. The long-term
objective of these studies is to develop highly potent tubulin inhibitors used for
anticancer drugs.