A Facile Synthesis of Novel Bis-(indolyl)-1,3,4-oxadiazoles as Potent Cytotoxic Agents

Full text of DOI:10.1002/cmdc.201200363

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DOI: 10.1002/cmdc.201200363
A Facile Synthesis of Novel Bis-(indolyl)-1,3,4-oxadiazoles as Potent
Cytotoxic Agents
Dalip Kumar,*[a] V. Arun,[a] N. Maruthi Kumar,[a] Glen Acosta,[b] Brett Noel,[b] and Kavita Shah*[b]
Natural products that are selectively toxic towards cancer cells
have attracted significant interest among medicinal chemists
due to their specificity.[1] In particular, indole-based alkaloids
play a versatile role in imparting cytotoxicity to many naturally
occurring anticancer agents.[2] Figure 1 shows examples of bis-
(indole)-derived natural products. Recently, bis(indole)alkaloids
isolated from marine organisms have emerged as a new class
of indole-based antitumor agents.[3] Nortopsentins (1) isolated
from the marine sponge Spongosorites ruetzleri exhibit moder-
ate in vitro cytotoxicity against P388 cells (IC50 =4.5–20.7 mm),
while their N-methylated derivatives exhibit improved activity
against the same cell line (IC50 =0.8–2.1 mm).[4] Similarly, topsen-
tins (2) inhibit the proliferation of cultured human and murine
tumor cells at micromolar concentrations (IC50 =4–40 mm). Ex-
perimental studies, such as fluorescence spectroscopy and
competitive binding experiments, have demonstrated that top-
sentins (2) bind specifically to the minor groove of DNA.[5] Of
the dragmacidins, dragmacidin B (3) possesses a broad range
of biological properties, and
dragmacidin D (structure not
shown) exhibits inhibitory activi-
ty towards protein phosphatase
(PP1) and neural nitric oxide syn-
thase (bNOS).[6] Asterriquinone
(4), a member of a family of nat-
urally occurring bis(indolyl) dihy-
droxyquinones isolated from As-
pergillus terreus, was identified as
a potent Src homology 2 (SH2)
inhibitor.[7]
Bis(indole) alkaloids with linear
spacers, such as coscinamides
(5) were extracted from the
marine sponge Coscinoderma
sp., exhibit efficacy in an XTT-
based anti-HIV assay carried out
by the US National Cancer
Institute.[8a] Subsequently, Gupta
et al. reported 8,9-dihydrocoscin-
amide B (structure not shown)
and its analogues as potent anti-
leishmanial agents.[8b] Rhopala-
din B was shown to inhibit
cyclin-dependent kinases (IC50
Figure 1. Representative structures of naturally occuring bis(indole)alkaloids. Bis(indole)-derived compounds have
been isolated from a variety of natural sources, including marine sponges and fungi.
=7.4–12.5 mm) and Rhopaladin C
exhited antibacterial activity
against Sarcina lutea and
Corynebacterium
(MIC=16 mm).[8c]
xerosis
[a] Prof. D. Kumar,+ V. Arun, N. Maruthi Kumar
Department of Chemistry
Due to the biological significance of nortopsentins, several
bis(indoles) with a variety of heterocyclic ring spacers, such as
thiazole 7, isoxazole 8a (X=O), pyrazole 8b (X=NH), thio-
phene 9a (X=S), and furan 9b (X=O), have been studied as
nortopsentin analogues.[9] Ahn et al. reported a series of top-
sentin analogues of type 10 as inhibitors of tubulin assembly
with promising in vitro and in vivo activities against multidrug-
resistant prostate cancer cells.[10] The same group has also re-
ported anticancer activity for several other bis(indoles). The
limitations associated with the isolation of natural bis(indoles)
Birla Institute of Technology and Science
Pilani-333031, Rajasthan (India)
E-mail: dalipk@bits-pilani.ac.in
[b] G. Acosta, B. Noel, Prof. K. Shah+
Department of Chemistry
Purdue Cancer Center, Purdue University
560 Oval Drive, West Lafayette, IN 47907 (USA)
E-mail: shah23@purdue.edu
[+] These authors contributed equally to this work.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/cmdc.201200363.
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Scheme 1. Rational approach to the design of bis(indolyl)-1,3,4-oxadiazoles (12).
in large quantities and the huge demand for material have
prompted the development of synthetic protocols for the
preparation of bis(indoles). More recently, nortopsentins, top-
sentins and dragmacidin B were synthesized using an inter-
mediate oxotryptamine.[11] In our recent reports, we have syn-
thesized a novel series of bis(indolyl)-1,2,4-thiadiazoles (11)
through the oxidative dimerization of indole thiocarboxamides
and bis(indolyl)hydrazide-hydrazones from the reaction of
indole carbohydrazides and indolecarboxaldehydes. These thia-
diazoles proved to be potent and selective anticancer
agents.[12]
There are many synthetic procedures available to construct
1,3,4-oxadiazole ring systems. For example, oxidative cycliza-
tion of acylhydrazones using a variety of oxidative agents,
such as ceric ammonium nitrate (CAN),[25] potassium perman-
ganate,[26] bromine,[27] lead tetracetate,[28] chloramine T,[29] and
Dess–Martin periodinane.[30] Another alternative approach in-
volves the initial reaction of arylhydrazides with acid chloride,
followed by cyclodehydration using any number of dehydrat-
ing agents, such as thionyl chloride,[31] phosphorus oxychlor-
ide,[32] sulphuric acid,[33] triflic anhydride,[34] and polyphosphoric
acid.[35] Very recently, Guin et al. reported the synthesis of 1,3,4-
oxadiazoles through an imine CꢀH functionalization of N-aryli-
denearoylhydrazide using catalytic amounts of Cu(OTf)2.[36]
However, most of these procedures involve the use of corro-
sive solvents, toxic and lachrymatory reagents and afford prod-
ucts in only moderate yields.
Oxadiazoles possess a number of chemical and biological
properties. More importantly, 1,3,4-oxadiazoles exhibit a wide
range of biological applications, such as antiviral,[13] antimicro-
bial,[14] fungicidal,[15] and anticonvulsant activities, as well as in-
hibition of tyrosinase[16] and HDACs.[17] Besides their biological
applications, 1,3,4-oxadiazoles are also used as electron-con-
ducting and light-emitting devices (LEDs).[18] The 1,3,4-oxadia-
zole scaffold is present in many anticancer agents and provides
tunable cytotoxic properties. Some 1,3,4-oxadiazole-containing
compounds have been identified as tubulin binding agents
and DNA intercalators.[19] Recently, Bostrom et al. highlighted
the roles of this scaffold in various drug discovery pro-
grammes.[20] We have also recently reported that the 1,3,4-oxa-
diazole ring plays a key role in imparting and enhancing the
cytotoxicity of indolyl-1,3,4-oxadiazoles.[21]
Recently, organic transformations using hypervalent iodine
reagents have gained wide popularity among synthetic chem-
ists due to their practical advantages, such as enhanced reac-
tion rates, high yields, improved selectivity and relatively
benign experimental conditions. Previously, we used hyperva-
lent iodine reagents in the synthesis of several bioactive mole-
cules, including as indolyl-1,3,4-oxadiazoles, 5-(3’-indolyl)oxa-
zoles, 4-(3’-indolyl)oxazoles, diarylthiazoles and diarylimida-
zoles.[21,22,37] More recently, we reported the iodobenzene diac-
etate-mediated short synthesis of bis(indolyl)-1,2,4-thiadiazoles
and identified them as potent and selective anticancer
agents.[12b] In the context of our ongoing programme to devel-
op new protocols for the construction of bioactive molecules,
herein we report the iodobenzene diacetate-mediated synthe-
sis of novel bis(indolyl)-1,3,4-oxadiazoles 12.
Bis(indolyl)-1,3,4-oxadiazoles 12 were synthesized as de-
scribed in Scheme 2. Indole-3-carboxaldehydes 14 were pre-
pared from corresponding indoles 13 using a Vilsmeier–Haack
formylation reaction followed by N-alkylation. Indole-3-carbo-
hydrazides 16 were synthesized in three steps:[12a] first, indoles
15 were converted into the corresponding indole-3-carboxylic
acids, which were then esterified and treated with hydrazine
hydrate to get desired indole-3-carbohydrazides 16. Condensa-
tion of indole-3-carboxaldehydes 14 with indole-3-carbohydra-
Our efforts to identify indole-based anticancer agents result-
ed in various indolylazoles, such as 4-(3’-indolyl)oxazoles,[22]
5-(3’-indolyl)-1,3,4-thiadiazoles[23] and indolyl-1,2,4-triazoles.[24]
Further systematic structural exploration of bis(indoles) led us
to discover bis(indolyl)-1,2,4-thiadiazoles and bis(indolyl)-
hydrazide-hydrazones, and allowed us to thoroughly under-
stand the role of the linker for further exploration.[12] Owing to
the biological potential of 1,3,4-oxadiazoles and bis-
(indolyl)heterocycles, we designed a series of novel bis-
(indolyl)-1,3,4-oxadiazoles by incorporating a 1,3,4-oxadiazole
unit as a linker between the indole rings (Scheme 1). Herein,
we describe the synthesis and subsequent evaluation of these
derivatives against a panel of human cancer cell lines.
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iodobenzene and acetic acid would afford the desired product
12.
Synthesized bis(indolyl)-1,3,4-oxadiazoles 12a–m were stud-
ied for their cytotoxic activity (IC50) against six human cancer
cell lines: pancreas (AsPC1), prostate (DU145 and PC3), cervical
(HeLa), breast (MDA-MB-231) and ovarian (OVCAR). Most of the
compounds exhibited potent anticancer activities, with IC50
values in the micromolar to nanomolar range (Table 1). The in-
fluence of the various substituents on the indole ring on the
cytotoxic effects were studied.
The structure–activity relationship study revealed that sub-
stituents at the C-5 position of the indole ring impart potent
activity and selectivity. Compound 12a showed good cytotox-
icity against multiple cancer cell lines, with IC50 values of less
than 1 mm, with the highest activity observed against breast
(MDA-MB-231, IC50 =0.09 mm) and ovarian (OVCAR, IC50 =
0.10 mm) cancer cells. Substituents at the C-5 position of the
indole ring play a significant role in improving the cytotoxicity
of bis(indolyl)-oxadiazoles 12. For example, compound 12b
with a bromo group at this position was the most active agent
in the series, with good cytotoxicity against all cell lines tested
(IC50 <0.3 mm) and potent cytotoxicity against prostate and cer-
vical cancer cells (IC50 =20 nm). In contrast, compound 12c
with a methoxy group at the C-5 position showed selective cy-
totoxicity against pancreas cancer cells (AsPC1, IC50 =60 nm).
Introduction of fluorine at the C-6 position of the indole
ring, resulted in a derivative (12d) with improvement selective
cytotoxicity against PC3 cancer cells when compared with 12a.
Incorporation of fluorine at the C-6 position of the indole
moiety bound to the C-5 of oxadiazole of compounds 12b–d
gave rise to derivatives 12e–g. Compounds 12e and 12 f
showed slightly decreased cytotoxic activities when compared
Scheme 2. Reagents and conditions: a) 1. POCl3, DMF; 2. R3X, NaH, DMF,
08C!RT, 4 h, 82%; b) 1. (CF3CO)2O, DMF, 08C, 3 h, 90% and NaOH, 1008C,
12 h, 88%; 2. EtOH, H+, 808C, 10 h, 80%; 3. R5X, NaH, DMF, 308C, 3 h, 96%;
4. NH2NH2·H2O, EtOH, 908C,12 h, 70%; c) EtOH, AcOH, 658C, 3 h, 91%;
d) iodobenzene diacetate, CH3CN, 258C, 30 min, 90%.
zides 16 in presence of a catalytic amount of acetic
acid in ethanol gave intermediate bis(indolyl)hydra-
zide-hydrazones 17 in good yields.
Our initial attempts to cyclize intermediate bis-
(indolyl)hydrazide-hydrazone 17a using [bis(trifluor-
oacetoxy)iodo]benzene (BTI) and Dess–Martin period-
Scheme 3. Plausible mechanism for the formation of bis(indolyl)-1,3,4-oxadiazoles (12).
inane (DMP) resulted in poor yields of the desired
bis(indolyl)-1,3,4-oxadiazole 12a. However, the oxida-
tive-cyclization of bis(indolyl)hydrazide-hydrazone 17a was
successful with iodobenzene diacetate (IBD) at room tempera-
ture in acetonitrile to produce bis(indolyl)-1,3,4-oxadiazole 12a
in good yield (Scheme 2). This optimized protocol was used to
synthesize a series of bis(indolyl)-1,3,4-oxadiazoles 12a–m. The
cyclization of intermediate hydrazide-hydrazone 17 to 12 was
confirmed by the disappearance of a carbonyl stretching band
at 1660 cmꢀ1 in the IR spectrum and a characteristic singlet at
d=8.50 ppm (CH=N) in the 1H NMR spectrum. A plausible
mechanism for the formation of product bis(indolyl)-1,3,4-oxa-
diazoles 12 is outlined in Scheme 3. The initial treatment of io-
dobenzene diacetate with hydrazide-hydrazones 17 is suggest-
ed to result in adduct A, which could then undergo an internal
nucleophilic attack to produce adduct B. Finally, elimination of
with 12b and 12c, respectively. However, compound 12 f, with
an additional fluorine atom, retained activity against PC3
cancer cells (IC50 =0.10 mm). In contrast, compound 12g, with
incorporation of an additional fluorine at the C-6 position, ex-
hibited improved activity against multiple cancer cell lines, dis-
playing more than a 100-fold increase in potency for HeLa
cancer cells (IC50 =60 nm) when compared with 12d (IC50 =
6.86 mm). N-Alkylation of compounds 12a, 12b and 12d result-
ed in compounds 12h (N-methyl) and 12i–m (N-chloro/me-
thoxybenzyl). Bis-methylation of both indole nitrogen atoms
(12h) improved the activity against pancreas (AsPC1, IC50 =
0.10 mm) and prostate (PC3, IC50 =0.12 mm) cancer cell lines
when compared with 12a.
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Finally, we investigated the
mechanism of cell death in
MDA-MB-231 cells using three
compounds: 12c, 12g and 12h.
Derivatives 12c and 12g are
highly potent (IC50 =0.90 and
0.21 mm), while compound 12h
is moderately active (IC50 =
15.71 mm) against this cell line.
After incubation for 48 h, MDA-
MB-231 cells were fixed and
stained with propidium iodide,
and their nuclear morphology
was analyzed using fluorescence
microscopy. While DMSO-treated
control cells revealed normal
healthy nuclei, inhibitor-treated
cells showed apoptotic nuclei
(Figure 2), suggesting that apop-
tosis is the major mechanism by
which bis(indolyl)-1,3,4-oxadia-
zoles promote cell death.
Table 1. Cytotoxicity of bis(indolyl)-1,3,4-oxadiazoles 12a–m against a panel of human cancer cell lines.
IC50[a] [mm]
Compd R1
R2 R3
R4 R5
AsPC1 DU145 HeLa MDA-MB-231 OVCAR PC3
12a
12b
12c
12d
12e
12 f
12g
12h
12i
12j
12k
12l
12m
Doxorubicin
H
H
H
H
F
H
H
F
H
H
H
H
F
H
H
H
H
H
H
H
CH3
H
H
H
H
F
H
H
H
H
H
H
H
CH3
H
H
H
H
H
0.46
0.20
0.06
0.31
0.45
1.68
0.20
0.10
2.47
0.05
0.43
1.60
0.07
1.69
0.23
0.02
0.72
9.79
0.08
0.42
0.15
0.52
0.37
0.54
0.11
0.14
0.10
11.59
0.53
0.02
66.79
6.86
0.06
52.90
0.06
4.55
0.73
5.94
8.10
0.96
1.20
12.97
0.09[b]
0.24
0.90
4.34
0.20
6.44
0.21
15.71
126.3
168.9
0.86
2.58
17.22
1.55
0.10
0.15
0.38
0.31
0.23
2.91
0.15
0.97
0.16
0.10
0.27
0.24
0.11
1.05
8.43
0.25
0.11
0.29
4.55
0.10
1.09
0.12
7.11
3.33
0.24
0.05
0.14
9.27
Br
OCH3
H
Br
OCH3
H
H
H
H
Br
H
F
F
H
H
H
H
H
H
4-ClC6H4CH2
4-OCH3C6H4CH2
4-ClC6H4CH2
4-ClC6H4CH2
4-OCH3C6H4CH2
H
F
[a] These experiments were conducted in triplicates at three independent times. IC50 values were obtained
using a dose–response curve by nonlinear regression using GraphPad Prism 5.0 for curve fitting. For all data,
standard error of the mean (SEM) values were ꢁ <10%. [b] IC50 values of less than 0.1 mm are shown in bold.
Human cancer cell lines: pancreas (AsPC1), prostate (DU145 and PC3), cervical (HeLa), breast (MDA-MB-231)
and ovarian (OVCAR).
In summary, we have synthe-
sized a series of novel 2,5-bis-
(indolyl)-1,3,4-oxadiazoles (12a–
Among the derivatives with
para-chlorobenzyl and para-me-
thoxybenzyl substituents at the
N-1 of the parent derivative 12a,
para-methoxybenzyl 12j exhibit-
ed selective cytotoxicity against
pancreas cancer cells (AsPC1,
IC50 =50 nm). Introduction of
a bromine substituent at the C-5
position of compound 12i led to
Figure 2. Propidium iodide staining of MDA-MB-231 cells treated with compounds 12c, 12g and 12h for 48h.
compound 12k with improved
activity against multiple cancer
cell lines, and the most potent
activity against DU145 cells
DMSO was used as a control.
(IC50 =0.11 mm). Similarly, compounds 12l and 12m were ob-
tained by incorporating fluorine into compounds 12i and 12j,
respectively. This led to compounds with improved activities
against multiple cancer cell lines, and compounds 12l and
12m were selectively cytotoxic against prostate (PC3, IC50 =
50 nm) and pancreas (AsPC1, IC50 =70 nm) cancer cell lines,
respectively.
m) by iodobenzene diacetate-mediated oxidative cyclization of
easily accessible bis(indolyl)hydrazide-hydrazones 17, using rel-
atively benign reaction conditions. All of the synthesized oxa-
diazoles showed improved cytotoxicity over previously report-
ed bis(indolyl)heterocycles. Bromo-substituted bis(indolyl)-
1,3,4-oxadiazole 12b was the most active compound in the
series, with IC50 values of 20 nm against prostate (DU145) and
cervical (HeLa) cancer cell lines. The structure–activity relation-
ship study revealed that a bromo substituent is crucial for im-
parting potent cytotoxic activity and that N-alkylation is bene-
ficial for improving the selectivity of the compound towards
a particular cancer type. Preliminary mechanism of action stud-
ies in MDA-MB-231 breast cancer cells indicate that bis-
(indolyl)-1,3,4-oxadiazoles 12a–m induce apoptosis and pro-
mote cell death.
Bis(indolyl)-1,3,4-oxadiazoles 12a–m were found to be supe-
rior over the reference compound, doxorubicin (Table 1). We
also observed that this new series of compounds are several
fold more potent than previously reported bis(indoles) with
various five/six-membered heterocyclic rings[9d–f,12b,38] and
linear hydrazide-hydrazone functionality as spacers.[12a] Table 2
provides a comparison of cytoxicities against several cancer
cell lines of bis(indolyl)-1,3,4-oxadiazoles from this study with
some potent bis(indolyl) heterocycles described in the litera-
ture.[8,9,12]
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Acknowledgements
Table 2. Comparision of cytotoxicity data of bis(indole) analogues synthesized in this study and reported in
the literature.
The authors gratefully acknowl-
edge the Council of Scientific and
Industrial Research (CSIR), New
Delhi (India) for financial support
(grant no.: 01(2398)/10/EMR-II)
and the Sophisticated Analytical
Instrumentation Facility (SAIF) at
Panjab University (Chandigarh,
India) for providing analytical
support.
Compd
IC50[a] [mm]
OVCAR PC3
Reference
MDA
DU145
(12a)
(7)
0.09
0.10
8.43
0.23
this work
83.0
8.06
>100
>100
>100
[9b]
[9e]
Keywords: alkaloids
bis(indoles) · cancer · cytotoxic
agents natural product
derivatives
·
(8b)
>100
8.11
15.6
·
(18)
–
4.68
3.69
2.72
–
[9a]
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12a–m along with details of the MTT assay and nuclear staining
described here are available in the Supporting Information.
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Published online on && &&, 0000
&6
&
www.chemmedchem.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemMedChem 0000, 00, 1 – 6
ÝÝ
These are not the final page numbers!

COMMUNICATIONS
A recipe for potency: A novel series of
bis(indolyl)-1,3,4-oxadiazoles was pre-
pared from the corresponding hydra-
zide-hydrazones via iodobenzene di-
acetate-promoted oxidative cyclization.
Evaluation against a panel of human
cancer cell lines revealed that some
derivatives possess potent cytotoxicity
with tunable selectivity for different
cancer types.
D. Kumar,* V. Arun, N. Maruthi Kumar,
G. Acosta, B. Noel, K. Shah*
&& – &&
A Facile Synthesis of Novel Bis-
(indolyl)-1,3,4-oxadiazoles as Potent
Cytotoxic Agents
ChemMedChem 0000, 00, 1 – 6
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemmedchem.org
&
7
&
ÞÞ
These are not the final page numbers!