An efficient synthesis and biological study of novel indolyl-1,3,4-oxadiazoles as potent anticancer agents

Article abstract of DOI:10.1016/j.bmcl.2009.03.172

A facile, convenient and high yielding synthesis of a series of novel 5-(3′-indolyl)-2-(substituted)-1,3,4-oxadiazoles from readily available starting materials has been described. The key step of this protocol is oxidative cyclization of N-acylhydrazones

Full text of DOI:10.1016/j.bmcl.2009.03.172

Bioorganic & Medicinal Chemistry Letters 19 (2009) 4492–4494
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
An efficient synthesis and biological study of novel indolyl-1,3,4-oxadiazoles
as potent anticancer agents
a
b
b,
Dalip Kumar a, , Swapna Sundaree , Emmanuel O. Johnson , Kavita Shah
*
*
a Chemistry Group, Birla Institute of Technology and Science, Pilani 333 031, India
b Department of Chemistry and Purdue Cancer Center, Purdue University, 560 Oval Drive, West Lafayette, IN 47907, USA
a r t i c l e i n f o
a b s t r a c t
A facile, convenient and high yielding synthesis of a series of novel 5-(30-indolyl)-2-(substituted)-1,3,4-
oxadiazoles from readily available starting materials has been described. The key step of this protocol
is oxidative cyclization of N-acylhydrazones 1 using [bis(trifluoroacetoxy)iodo]benzene under solvent-
free condition. The 5-(30-indolyl)-2-(substituted)-1,3,4-oxadiazoles were screened for their in vitro anti-
cancer activity against various human cancer cell lines. Compounds 3c, 3d and 3j exhibited potent cyto-
Article history:
Received 13 January 2009
Revised 17 March 2009
Accepted 26 March 2009
Available online 13 June 2009
toxicity (IC50 ꢀ1
l
M) and selectivity against human cancer cell lines.
Keywords:
1,3,4-Oxadiazole
Solvent-free
Ó 2009 Elsevier Ltd. All rights reserved.
Hypervalent iodine
Anticancer agent
Selective cytotoxicity
1,3,4-Oxadiazoles are an important class of heterocyclic com-
pounds with a wide range of biological activities such as antiviral,1
antimicrobial,2 antineoplastic,3 fungicidal,4 inhibition of tyrosi-
nase5 and cathepsin K.6 The five-membered 1,3,4-oxadiazole het-
erocycles are also useful intermediates in organic synthesis7 and
widely employed as electrontransporting and hole-blocking mate-
rials.8 Further, 1,3,4-oxadiazole heterocycles are very good bioisos-
teres of amides and esters, which can contribute substantially in
increasing pharmacological activity by participating in hydrogen
bonding interactions with the receptors.9 The strategy of using bio-
isosterism in developing new therapeutically active analogs has
attained a noteworthy growth in the pharmaceutical industry.
There are many reported synthetic approaches to 1,3,4-oxadiaz-
ole heterocycles. One such approach involves the cyclodehydration
of 1,2-diacyl or 1,2-diaroylhydrazines with a variety of anhydrous
reagents such as thionyl chloride,10 phosphorous pentoxide,11
phosphorous oxychloride,12 triflic anhydride,13 triphenylphos-
phine,14 polyphosphoric acid,15 and sulfuric acid.16 An alternative
route for synthesis of 1,3,4-oxadiazoles is by cyclization of isoni-
cotinic acid hydrazide with either acid chlorides, aromatic acids
or aromatic aldehydes followed by dehydration in the presence
of dehydrating reagents like sulfuric acid, phosphorous oxychlo-
ride, etc.17 However, most of these procedures involve the use of
toxic and lachrymatory reagents, difficult handling procedures,
and ultimately moderate yield of product.
Cancer treatment has been a major endeavor of research and
development in academia and pharmaceutical industry for the last
many years as it is one of the leading causes of death.18 Many of the
available anticancer agents exhibit undesirable side effects such as
reduced bioavailability, toxicity and drug-resistance.19–23 There-
fore, the search for novel and selective anticancer agents is
urgently required due to problems associated with currently avail-
able anticancer drugs.
The naturally occurring 5-(30-indolyl) oxazoles are known to
display diverse biological activities.24 Labradorin 1 and Labradorin
2 were found to be cytotoxic against NCI–H 460 (lung-NSC) human
cancer cell line with GI50 values of 9.8
l
g/mL and 9.6 lg/mL,
respectively.24
N
O
N
O
N
N
H
H
Labradorin 1
Labradorin 2
In view of interesting biological activities exhibited by naturally
occurring 5-(30-indolyl) oxazoles and our efforts to search for novel
and selective antitumor agents, we report herein [bis(trifluoroacet-
oxy)iodo]benzene (BTI) mediated synthesis and antitumor activities
of analogues 5-(30-indolyl)-2-(substituted)-1,3,4-oxadiazoles (3)
* Corresponding authors. Tel.: +91 1596 245073 279; fax: +91 1596 244183
(D.K.); tel.: +1 765 496 9470 (K.S.).
E-mail addresses: dalipk@bits-pilani.ac.in (D. Kumar), shah23@purdue.edu (K.
Shah).
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.03.172

D. Kumar et al. / Bioorg. Med. Chem. Lett. 19 (2009) 4492–4494
4493
ide to furnish 5-(30-indolyl)-2-phenyl-1,3,4-oxadiazole 3a (Scheme 1).
Encouraged by the successful synthesis of 3a, the protocol was
extended for the preparation of analogues 5-(30-indolyl)-2-(substi-
tuted)-1,3,4-oxadiazole 3b–m. All the synthesized compounds
(3a–m) were characterized by 1H NMR and MS data.
N
N
H
N
N
H
N
R
N
R
R
O
O
(ii)
(i)
O
N
N
H
N
SO2Ph
SO2Ph
3
1
2
In order to study the structure–activity relationship (SAR), syn-
thesized indolyl-1,3,4-oxadiazoles 3a–m were screened in vitro for
their anticancer potential against human cancer cell lines from
prostate (PC3, DU145 and LnCaP), breast (MCF7 and MD-
MDA231), and pancreas (PaCa2). The cell viability results of
3a–m are summarized in Table 1. With few exceptions, most of
the compounds decreased cell viability significantly as established
by colorimetric MTT mitochondrial assay with IC50 values ranging
3a: R = C6H5
3b: R = CH2C6H5
3c: R = 4-pyridyl
3d: R = 3-pyridyl
3e: R = 4-CH3OC6H4
3f: R = 4-ClC6H4
3g: R = 3,4-di-CH3OC6H3
3h: R = 2,3,4-tri-CH3OC6H2
3i:R= 4-BnO-3-CH3OC6H3
from 1 lM to 1 mM concentration. The SAR study reveals that sub-
stitution at the C-2 position of the 1,3,4-oxadiazole ring plays an
(iii)
3j: NH = NCH3; R = 4-BnO-3-CH3OC6H3,
3k: R = 4-HO-3-CH3OC6H3
3l: R =CH3
important role. The compound 3a with C-2 phenyl group exhibited
moderate activity against MCF7 (388.4 lM) and poor activity
against other cell lines. Interestingly, replacement of the phenyl
ring with a benzyl group (3b) exhibited better inhibitory activity
3m: R = CF3
against MCF7 (39.2
cer cell line (934.3
tivity was observed against PC3 (4.1
(1.6 M) for the analogue 3c with a 4-pyridyl group indicating that
it is a good replacement for the phenyl group. This result is intrigu-
ing since 3c was cytotoxic in most of the cell lines at 1–10 M con-
l
l
M) with 24-fold selectivity versus PaCa2 can-
M). A significant increase in activity and selec-
M), MCF7 (1 M) and PaCa2
Scheme 1. Reagents and conditions: (i) PhI(OCOCF3)2,grinding, rt, 65–81%; (ii)
NaOH, EtOH–H2O, reflux, 3 h, 80–92%; (iii) CH3I, KOH, DMSO, stirring, rt, 80%.
l
l
l
under solvent-free conditions. Reactions under solvent-free condi-
tions have continuously attracted the attention of researchers both
from academia and industry. This is due to the fact that organic
reactions under solvent-free conditions have an improved selectiv-
ity and efficiency, ease of manipulation, pure product formation,
avoids the use of toxic or volatile solvents.25 This expeditious
synthesis of 3 involves reacting 1-benzenesulfonyl-indole-3-alde-
hyde26 with various substituted hydrazides in the presence of acetic
acid under refluxing condition affording the corresponding indolyl-
3-aldehyde N-acylhydrazones 1 in excellent yields. Our initial trials
for the cyclization of indolyl-3-aldehyde N-acylhydrazones 1 using
iodobenzenediacetate were unsatisfactory due to the poor yield of
product and prolonged reaction time. However, a neat grinding of
l
centration, but showed no effect in MDA-MB-231 cells even at
1 mM concentration. However, when the position of nitrogen atom
was shifted to C-30 in the C-2 pyridyl ring (3d), it was specific
against PaCa2 cell line (0.9 lM). Subsequently, the SAR of the phe-
nyl ring was investigated by introducing various groups. Substitu-
tion at the para position of C-2 phenyl ring with a methoxy group
resulted in compound 3e with a loss in cytotoxic activity against all
the cell lines. Compound 3f with a p-chloro substituent displayed
relatively better activity against PC3 (41.6
lM) and MCF7
(48.2 M) cell lines. Introduction of 3,4-dimethoxyphenyl or
l
3,4,5-trimethoxyphenyl group at the C-2 position of 1,3,4-oxadiaz-
ole ring gives compound 3g or 3h with weak activity against
different cancer cell lines. The compound 3i with bulkier 4-benzyl-
oxy-3-methoxyphenyl moiety at the C-2 position showed very
poor activity. However, N-methylation of the indole nitrogen was
found to be beneficial for the activity as in the case of compound
indolyl-3-aldehyde N-acylhydrazone
1
(1.0 mmol) with BTI
(1.2 mmol) for 10 min at room temperature resulted in rapid forma-
tion of indolyl-1,3,4-oxadiazoles 2 in good yield without any
by-product (Scheme 1).26 Removal of the benzenesulfonamide
group of 2 was achieved by refluxing with aqueous sodium hydrox-
Table 1
In vitro cytotoxicity data of 5-(30-indolyl)-2-(substituted)-1,3,4-oxadiazoles 3
N
N
R
O
N
H
a
Compound
R
Cytotoxicity IC50 (lM)
PC3
DU145
LnCaP
MDA-MB-231
MCF7
PaCa2
3a
3b
3c
3d
3e
3f
C6H5
CH2C6H5
4-Pyridyl
3-Pyridyl
4-CH3OC6H4
4-ClC6H4
3,4-(CH3O)2C6H3
3,4,5-(CH3O)3C6H2
4-BnO-3-CH3OC6H3
4-BnO-3-CH3OC6H3
4-HO-3-CH3OC6H3
CH3
>103
>103
4.1
>103
>103
20.4
170
>103
>103
10.0
69.4
>103
582.6
>103
>103
>103
>103
>103
>103
>103
>103
>103
>103
>103
>103
>103
>103
>103
>103
>103
>103
>103
>103
388.4
39.2
1.0
>103
934.3
1.6
710.8
>103
41.6
>103
>103
>103
>103
>103
>103
>103
5.4
0.9
>103
192
>103
48.2
556.7
121.2
>103
35.2
>103
198.3
>103
>103
6459
>103
>103
>103
1.4
3g
3h
3i
>103
>103
>103
>103
>103
>103
>103
3jb
3k
3l
>103
145
3m
CF3
>103
a
Data obtained for each compound was done in triplicates and IC50 values given in micromolar concentrations were obtained using a dose response curve by nonlinear
regression using a curve fitting program, GraphPad Prism 5.0.
b
NH@NCH3.

4494
D. Kumar et al. / Bioorg. Med. Chem. Lett. 19 (2009) 4492–4494
References and notes
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the replacement of the aromatic group with an aliphatic substitu-
ent. The compound 3l with C-2 methyl group was moderately cyto-
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Acknowledgments
26. Synthesis of indolyl-1,3,4-oxadiazoles 3a–k: The indole-3-carboxaldehyde N-
acylhydrazone 1 (1 mmol) and BTI (1.2 mmol) were ground in a mortar and
pestle at room temperature for 10 min. During the admixing, reaction was
initiated and turned dark brown rapidly. The completion of reaction was
confirmed by TLC (7:3 hexane/ethylacetate). The reaction mixture was taken
into water and extracted with ethylacetate (2 ꢁ 5 mL). Organic phase was
dried over anhydrous sodium sulfate, and the solvent was distilled off under
reduced pressure. The residue was percolated through a bed of silica gel using
ethyl acetate/hexane (1/9, v/v) as eluent to afford the pure product 3a–k in
good yield. Compound 3a: 1H NMR (400 MHz, DMSO-d6): dH 11.22 (s, 1H, NH),
8.29 (dd, 1H, J = 6.08, 3.12 Hz), 8.17–8.13 (m, 2H), 8.02 (d, 1H, J = 2.92 Hz),
7.57–7.50 (m, 4H), 7.30 (dd, 2H, J = 6.10, 3.18 Hz). Calcd m/z for C16H11N3O:
261.0902, found: 262.1002 (M+H)+.
The authors acknowledge financial support from the University
Grants Commission, New Delhi (Project F. No. 32-216/2006). S.S. is
thankful to the Council of Scientific and Industrial Research, New
Delhi for Research Fellowship.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2009.03.172.