Novel synthetic bisbenzimidazole that targets angiogenesis in Ehrlich ascites carcinoma bearing mice

Article abstract of DOI:10.1016/j.bmcl.2015.04.010

Abstract Cancer is a leading cause of death in developed countries and second cause in developing countries. Herein we are reporting the synthesis of novel bisbenzimidazole derivatives and their anticancer properties. Among the newly synthesized bisbenzimidazoles, 3-(4-flurophenylsulfonyl)-1,7-dimethyl-2-propyl-1H,3H-2,5-bibenzo[d]imidazole (FDPB) presented as a potent antiproliferative agent against HeLa, HCT116 and A549 cells with selectivity over normal Vero cells (IC₅₀ >50 μM). Additionally, we evaluated the efficacy of lead compound against Ehrlich ascites tumor (EAT) bearing mice for its antitumor and antiangiogenic properties. Our lead compound significantly reduced the cell viability, body weight, ascites volume and downregulated the formation of neovasculature and production of Vascular Endothelial Growth Factor (VEGF).

Full text of DOI:10.1016/j.bmcl.2015.04.010

Bioorganic & Medicinal Chemistry Letters xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Novel synthetic bisbenzimidazole that targets angiogenesis in Ehrlich
ascites carcinoma bearing mice
Rangaswamy Roopashree a, Chakrabhavi Dhananjaya Mohan a, Toreshettahally Ramesh Swaroop a,
Swamy Jagadish a, Byregowda Raghava a, Kyathegowdanadoddi Srinivas Balaji b, Shankar Jayarama b,
Basappa c, Kanchugarakoppal Subbegowda Rangappa a,
⇑
a Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore 570 006, India
b Department of Biotechnology, Teresian College, Mysore 570 011, India
c Laboratory of Chemical Biology, Department of Chemistry, Bangalore University, Bangalore 560 001, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Cancer is a leading cause of death in developed countries and second cause in developing countries.
Herein we are reporting the synthesis of novel bisbenzimidazole derivatives and their anticancer proper-
ties. Among the newly synthesized bisbenzimidazoles, 3-(4-flurophenylsulfonyl)-1,7-dimethyl-2-propyl-
1H,3H-2,5-bibenzo[d]imidazole (FDPB) presented as a potent antiproliferative agent against HeLa,
Received 20 January 2015
Revised 16 March 2015
Accepted 1 April 2015
Available online xxxx
HCT116 and A549 cells with selectivity over normal Vero cells (IC50 >50 lM). Additionally, we evaluated
the efficacy of lead compound against Ehrlich ascites tumor (EAT) bearing mice for its antitumor and
antiangiogenic properties. Our lead compound significantly reduced the cell viability, body weight,
ascites volume and downregulated the formation of neovasculature and production of Vascular
Endothelial Growth Factor (VEGF).
Keywords:
Bisbenzimidazole
Ehrlich ascites tumor
Angiogenesis
Ó 2015 Published by Elsevier Ltd.
Antiproliferative
Vascular Endothelial Growth Factor
Micro vessel density
Cancer is a most ravaging disease threatening globally with a
leading mortally rate in developed countries.1 Various types of can-
cers have been identified which affects different organs and they
are broadly grouped under the category of carcinoma, sarcoma,
lymphoma or leukemia based on the type of tissue origin.2,3 Most
common striking features of all types of cancer is uncontrolled cell
proliferation, antiapoptosis, enhanced angiogenesis, genomic
instability and metastasis.4 The broad range of devastating charac-
teristics of the cancer makes it a very good therapeutic target for
designing the small molecules. In cancer drug discovery
programme, researchers have contributed many novel synthetic
compounds as anticancer drugs.
Benzimidazoles are the most prominent heterocycles with
diverse biological functions.5–7 Multiple previous reports have sug-
gested that benzimidazoles to be very good cytotoxic agents
against different types of cancer cell lines.8 Recently bisbenzimida-
zole conjugates have been reported to target mitochondria in can-
cer cells and induce their antiproliferative activity by caspase
dependent apoptosis.9 In addition, bisbenzimidazoles bind to
minor groove of the DNA to instigate its anti-proliferative effect
and many DNA minor groove binders have entered clinical trials
in cancer treatment.10,11 Furthermore, bisbenzimidazoles possess
topoisomerase-112 and serine protease inhibition,13 antiviral,14
antileishmanial,15 and several other biological properties.16 In con-
tinuation of our effort in designing small molecules as anticancer
agents, bisbenzimidazoles drawn our interest to synthesize the
novel bisbenzimidazoles and evaluate their anticancer activity
both in vitro and in vivo.17–24 Among the newly synthesized com-
pounds, we selected the most potent cytotoxic compound against
HeLa (Cervical cancer), HCT116 (Colon cancer), A549 (Lung cancer)
and evaluated for its in vivo antitumor and antiangiogenic proper-
ties using Ehrlich ascites tumor (EAT) bearing mice.
A mixture of methyl 3,4-diamino-5-methyl benzoate 1, buta-
noic acid and polyphosphoric acid (PPA) were irradiated in a
microwave flask at 150 °C for 10 min to get methyl 4-methyl-2-
propyl-1H-benzo[d]imidazole-6-carboxylate 2. The key intermedi-
ate 1,70-dimethyl-20-propyl-1H,30H-2,50-bibenzo[d]imidazole
3
was obtained by the reaction of 2 with N-methyl-o-phenylenedi-
amine using PPA at 150 °C for 12 h.25 Finally, key intermediate 3
was subjected to undergo N-sulfonation with various sulfonyl
chlorides 4 to get respective 1,70-dimethyl-30-(arylsulfonyl)-20-
Abbreviation: FDPB, 3-(4-flurophenylsulfonyl)-1,7-dimethyl-2-propyl-1H,3H-
2,5-bibenzo[d]imidazole.
⇑
Corresponding author. Tel.: +91 0821 2419661.
E-mail address: rangappaks@gmail.com (K.S. Rangappa).
http://dx.doi.org/10.1016/j.bmcl.2015.04.010
0960-894X/Ó 2015 Published by Elsevier Ltd.
Please cite this article in press as: Roopashree, R.; et al. Bioorg. Med. Chem. Lett. (2015), http://dx.doi.org/10.1016/j.bmcl.2015.04.010

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R. Roopashree et al. / Bioorg. Med. Chem. Lett. xxx (2015) xxx–xxx
propyl-1H,30H-2,50-bibenzo[d]imidazole 5a–j (Fig. 1A). The struc-
tures of all the synthesised compounds were confirmed by spectral
and micro analytical analysis. All final compounds showed charac-
teristic triplet between 0.8 and 1.1 d for methyl protons, triplet
around 3.1 d, sextet around 1.9 d for methylene protons, singlet
at 2.0 d for aryl methyl protons and singlet at 3.9 d for N-methyl
protons. The structures and yields of the synthesised compounds
are given in Table 1.
FDPB induces its cytotoxic effect in time and dose dependent man-
ner in HeLa cells: We investigated the anti-proliferative effect of
newly synthesized bisbenzimidazoles 5a–j against the panel of cell
lines including HeLa, HCT116 and A549 cells using MTT assay as
described previously and IC50 values are tabulated in
Table 1.18,26,27 We found bisbenzimidazoles 5d and FDPB having
p-methoxy- and p-flurosulfonyl groups exhibited significant cyto-
toxicity towards HeLa and HCT166 cells with the IC50 values rang-
counterparts. Also, strong electron releasing and withdrawing sub-
stituents increased the activity. Notably, the activity decreases
with decrease in electro negativity of halogen at para position of
sulfonyl motif. Finally, halogen substitution at ortho position of
arylsulfonyls is ineffective. Despite the fact that all compounds
are less potent than standard sorafenib, the structure activity rela-
tionship profiles is very interesting. Furthermore, we identified
FDPB as potent cytotoxic agent and tested on HeLa cells at indi-
cated dose and time points and found the substantial decrease in
viable cells (Fig. 1B). The lead compound FDPB is taken for further
in vivo studies.
FDPB interferes with cell cycle and arrest HeLa cells in SubG1
phase: Formation of hypodiploid cells is a hallmark event in cells
undergoing apoptosis which can be detected using propidium
iodide staining.28 We evaluated whether FDPB can effect cell cycle
distribution as described earlier.29 We found the built up of cells in
subG1 phase in the time dependent manner (Fig. 1C). The results
confirmed the cytotoxic effect of FDPB.
FDPB significantly decrease ascites volume, body weight and cell
viability: We further analysed the effect of FDPB on body weight
and ascites volume in the tumor of drug treated and control mice
as described earlier.21 We observed the significant decrease in
the body weight after the administration of FDPB (Fig. 2A and
B). Based on this observation, we quantified the ascites volume
and results confirmed the decrease of ascites fluid (Fig. 2C). In
addition, results of trypan blue assay displayed the substantial
ing from 16.7
bearing tolyl and mesityl sulfonyl groups displayed notable anti-
cancer activity with IC50 values ranging from 20.1 M to 41.6
lM to 19.9 lM. Further, bisbenzimidazoles 5b–c
l
lM
against HeLa and HCT166 cells. Compounds 5h–j substituted with
2,5-dichlro-, 2-chloro and 2-bromophenylsulfonyl groups were
found to be inactive against HeLa cells. On the other hand, most
of the new bisbenzimidazole derivatives displayed least antiprolif-
erative activity against A549 and monkey kidney epithelial (Vero)
cells up to 50
lM. Thus compounds with inductively electron
releasing methyl groups are good inhibitors over unsubstituted
Figure 1. (A) Schematic representation of synthesis of bisbenzimidazoles: (i) butanoic acid, polyphosphoric acid (PPA), MW irradiation 150 °C, 10 min. (ii) N-Methyl-o-
phenylenediamine, PPA, 150 °C, 12 h. (iii) RSO2Cl 4, TBAB, 50% NaOH, C6H6, 5–6 h. (B) FDPB suppresses proliferation of HeLa cells in time and dose dependent manner. (C)
Flow cytometric analysis indicates the arrest of HeLa cells in SubG1 phase in the time dependent manner.
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R. Roopashree et al. / Bioorg. Med. Chem. Lett. xxx (2015) xxx–xxx
3
Table 1
Structures, yield and cytotoxicity (
lM
SD) data of the bisbenzimidazole derivatives 5a–j
Sl no
R (4, 5)
5
% yielda
HeLa (
l
M)
HCT116 (
>50
lM)
A549 (
l
M)
Vero (lM)
1
2
3
4
5
6
7
8
9
C6H5
4-MeC6H4
2,4,6-Me3C6H2
4-MeOC6H4
4-FC6H4
4-ClC6H4
4-BrC6H4
2,5-Cl2C6H3
2-ClC6H4
2-BrC6H4
5a
5b
5c
5d
56
83
90
72
65
67
84
87
62
68
23.8 1.6
20.1 3.1
21 3.9
18.3 2.1
16.7 5.8
21.4 5.4
24.7 5.7
>50
>50
>50
>50
34.7 6.3
32.2 7.5
>50
35.1 9.1
NT
NT
>50
>50
>50
>50
>50
>50
>50
NT
41.6 4.9
29.9 5.9
19.1 10.1
19.9 8.2
36.8 5.4
49.3 6.5
NT
5e (FDPB)
5f
5g
5h
5i
>50
>50
NT
NT
NT
NT
10
5j
NT
NT—not tested.
a
Yield corresponds to the last step of the synthesis.
Figure 2. Evaluation of antitumor activity of compound FDPB on EAT bearing mice. (A) Photographs of FDPB treated, normal and EAT bearing mice. (B) FDPB decreases the
body weight of tumor bearing mice compared to tumor bearing control and Cisplatin administered tumor bearing mice. (C) FDPB decreases the ascites fluid volume in the EAT
mice. (D) Percentage of viable cell count significantly reduced in FDPB treated mice.
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R. Roopashree et al. / Bioorg. Med. Chem. Lett. xxx (2015) xxx–xxx
decrease in number of viable cells in FDPB treated mice (Fig. 2D).
This concludes that our lead molecule possess very good anticancer
property.
Inhibition of peritoneal angiogenesis encouraged us to investigate
whether FDPB can induce its anti-proliferative effect by promoting
apoptosis in Ehrlich ascites cells. We performed DNA fragmenta-
tion assay to detect the intactness of the DNA in cells treated with
our lead compound. The results obtained clearly demonstrate the
extensive degradation of genomic DNA and concluding that FDPB
induces apoptosis (Fig. 3D). Furthermore, morphological changes
of the cells treated with our lead compound was evaluated by
Giemsa staining. Microscopic observation of cells stained with
Giemsa displayed cell shrinkage, formation of small blebs and
apoptotic bodies (Fig. 3E).
FDPB suppresses angiogenesis in EAT bearing mice: Angiogenesis
is associated with tumor expansion by uncontrolled cell prolifera-
tion and metastasis.30 Therefore inhibition of angiogenesis is a
direct measure of increased prognosis. We evaluated whether
FDPB can downregulate neovasculature and micro vessel density
(MVD) in the peritoneal cavity of EAT bearing mice. Figure 3A
clearly shows that FDPB notably suppress the peritoneal angiogen-
esis. Additionally, quantification of MVD in the H & E stained peri-
toneum tissue displayed significant reduction in the number of
In conclusion, an ideal anti-cancer drug should inhibit the pro-
liferation of cancer cells, prevent metastasis, enhance apoptosis
and suppress angiogenesis in tumors.33,34 Designing and synthesis
of novel small molecules that can target cancer cells specifically
and inhibiting their proliferation by disrupting the multiple sur-
vival signals is a prime challenge in cancer drug discovery. In con-
tinuation of our effort to synthesize new anti-cancer agents and
considering the contribution of benzimidazole nucleus in the
development of various drugs, we herein report the synthesis,
characterization, anti-proliferative and anti-angiogenic activity of
novel bisbenzimidazole derivatives. Newly synthesized com-
pounds were evaluated for their cytotoxic efficacy against HeLa,
HCT116 and A549 cells and lead compound was carried forward
for the evaluation of its in vivo antitumor activity. In addition,
the lead compound did not display cytotoxicity towards non-
diseased (Vero) cells. Linlin and colleagues have demonstrated that
bisbenzimidazole derivatives induce cytotoxicity in cancer cells
through both death receptor and mitochondria-mediated apop-
totic pathways.9 Therefore, we are concluding that, our lead com-
pound possibly induce its antiproliferative effect on cancer cells
by activating caspases which are known to induce activation of
caspase-activated DNases (CAD). The activation of CAD proteins
leads to the degradation of genomic DNA into nucleotide oligomers
thereby inducing apoptosis of cancer cells. In summary, FDPB
proved to be an efficient anticancer agent with a therapeutic
potential to combat cancer.
micro vessels (Fig. 3B).
observed in FDPB treated mice compared with 54 6 vessels/
High power field in control mice.
8
2 vessels/high power field were
FDPB downregulates the VEGF in Ehrlich ascites tumor: Based on
the predominant suppression of peritoneal angiogenesis and
MVD, the effect of FDPB on the local production of VEGF in the
peritoneal cavities of EAT bearing mice was investigated using
ELISA based method.31 The levels of VEGF substantially decreased
in the lavage fluid to 225 4 ng in FDPB treated mice (Fig. 3C), In
contrast, the levels of VEGF were found to be 2412 10 ng in the
control mice confirming the anti-angiogenic role of FDPB.
FDPB induces apoptosis in Ehrlich ascites tumor cells: Cellular
morphological changes, shrinkage and fragmentation of genomic
DNA are the hallmark events in the cell undergoing apoptosis.32
Acknowledgments
Authors are grateful to Board of Research in Nuclear Sciences
(BRNS), University Grants Commission (UGC) and Indo-French
Centre for the Promotion of Advance Research (IFCPAR),
Government of India for financial support to KSR under the pro-
jects vide No. 2009/37/40/BRNS/2266 dated 23-11-2009,
F-39-106/2010 (S.R.) dated 24-12-2010 and No. IFC/4303-1/
2010-11 Dated 22-12-2010. R.R. thank University Grants
Commission for Rajiv Gandhi National Fellowship, CDM thank
Department of Science and Technology for Innovation in Science
Pursuit for Inspired Research fellowship and T.R.S. thank Council
of Scientific and Industrial Research for Junior and Senior
Research Fellowship.
Supplementary data
Supplementary data (detailed experimental procedures for the
synthesis and the pharmacological investigations) associated with
this article can be found, in the online version, at http://dx.doi.org/
10.1016/j.bmcl.2015.04.010.
Figure 3. FDPB inhibits neovasculature in EAT bearing mice. (A) FDPB suppress
peritoneal angiogenesis in EAT bearing mice. (B) H & E staining of peritoneum of
FDPB treated mice displayed the substantial decrease of MVD. (C) Profiling of VEGF
in the lavage fluid collected from EAT bearing FDPB treated and control mice. (D)
FDPB induces apoptosis in Ehrlich ascites tumor cells and it is demonstrated by DNA
fragmentation in FDPB treated mice (D—DNA ladder; C—Tumor control). (E)
Morphological changes in cells and formation of apoptotic bodies in EAT cells of
FDPB treated mice.
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