New benzimidazole-2-urea derivates as tubulin inhibitors

Article abstract of DOI:10.1016/j.bmcl.2014.07.035

Emerging drug resistance and other drawbacks limit tubulin inhibitors' therapeutic applications and developing novel tubulin inhibitors still attracts intensive efforts. We describe the discovery and structure-activity relationship study of a series of benzimidazole-2-urea derivatives as novel β tubulin inhibitors. The representative compound 6o potently suppressed the proliferation of a panel of human cancer cells (NCI-H460, Colo205, K562, A431, HepG2, Hela, MDA-MB-435S) with IC₅₀ values of 0.040, 0.050, 0.006, 0.026, 1.774, 0.452 and 0.052 μM, respectively. Compound 6o obviously inhibited NCI-H460 spindles formation and induced cell cycle arrest at G2/M phase at 0.10 μM. Computational study suggested that 6o interacts with β tubulin in a novel binding mode. Our results suggested that benzimidazole-2-urea derivatives might be promising tubulin inhibitors with novel binding mode for further development.

Full text of DOI:10.1016/j.bmcl.2014.07.035

Bioorganic & Medicinal Chemistry Letters 24 (2014) 4250–4253
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
New benzimidazole-2-urea derivates as tubulin inhibitors
Wenna Wang a, , Dexin Kong a, , Huimin Cheng b, , Li Tan b, Zhang Zhang b, Xiaoxi Zhuang b, Huoyou Long b,
b,
Yang Zhou b, Yong Xu b, Xiaohong Yang a, , Ke Ding
⇑
⇑
a College of Pharmacy, Jilin University, Changchun 130021, China
b Institute of Chemical Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, #190 Kaiyuan Avenue, Guangzhou 510530, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Emerging drug resistance and other drawbacks limit tubulin inhibitors’ therapeutic applications and
developing novel tubulin inhibitors still attracts intensive efforts. We describe the discovery and struc-
ture–activity relationship study of a series of benzimidazole-2-urea derivatives as novel b tubulin inhib-
itors. The representative compound 6o potently suppressed the proliferation of a panel of human cancer
cells (NCI-H460, Colo205, K562, A431, HepG2, Hela, MDA-MB-435S) with IC50 values of 0.040, 0.050,
Received 20 February 2014
Revised 20 June 2014
Accepted 11 July 2014
Available online 17 July 2014
0.006, 0.026, 1.774, 0.452 and 0.052
dles formation and induced cell cycle arrest at G2/M phase at 0.10
that 6o interacts with b tubulin in a novel binding mode. Our results suggested that benzimidazole-2-
urea derivatives might be promising tubulin inhibitors with novel binding mode for further development.
Ó 2014 Elsevier Ltd. All rights reserved.
l
M, respectively. Compound 6o obviously inhibited NCI-H460 spin-
M. Computational study suggested
Keywords:
Microtubule
Tubulin inhibitors
Benzimidazole-2-urea derivates
Cell cycle arrest
Ant-cancer
l
Microtubule is an important component of the cytoskeleton
formed by and b tubulin heterodimers, which has been demon-
b tubulin in parasites and inhibit the microtubule polymerization,
while have little effect to mammalian host tubulin protein.22–24
However, a later investigation demonstrated that benzimidazole
5a could be adopted in a novel N-terminal binding site of mamma-
a
strated to be critical in many cellular processes such as cell shape
maintenance, intracellular transport, cell division, cell growth and
mitosis.1–3 As the key structural basis of microtubule, tubulin is
considered as a highly attractive target for anticancer therapy.4–12
Several tubulin inhibitors have been approved as first line chemo-
therapeutic agents for different types of human cancers.13,14 Three
classes of tubulin inhibitors are categorized based on their binding
sites in tubulin protein, including taxol-site inhibitors (i.e., taxol
and epothilones15,16), vinblastine-site inhibitors (i.e., vinblastine
lian b tubulin locating in a 36-amino acid sequence (Ala63-Lys103
)
to display its inhibitory effect.25–27 Therefore, 5a represents a
O
R
O HO
O
O
S
and vincristine17) and colchicines-site inhibitors (i.e., colchicines18
)
HO
O
NH
O
N
(Fig. 1). All of the drugs have achieved significant benefit to cancer
patients by improving the overall survival duration and quality of
life. However, structure related manufactory difficulty, marginal
oral bioavailability and emerging drug resistance limit their thera-
peutic applications.19,20 It is highly valuable to identify tubulin
inhibitors with different binding modes as new anticancer agents.
Benzimidazoles derivatives (BZs), such as albendazole (ABZ), fen-
bendazole (FBZ), mebendazole (MBZ), nocodazole (NZ), oxibendaz-
ole (OBZ), parbendazole (PBZ), and luxabendazole (LBZ) have been
widely used for antinematodal or other therapeutic applications
(Fig. 2).21 It was well recognized that BZs can selectively bind with
O
H
O
O
O
O
OH
OH
O
O
OH
O
O
taxol
Epothilone A (R=H)
Epothilone B (R=Me)
OH
N
MeO
MeO
NHAc
H
N
H
N
H
OMe
MeO2C
O
O
N
R
O
OH
OMe
colchicine
O
⇑
Corresponding authors. Tel.: +86 20 32015255; fax: +86 20 32015299.
E-mail addresses: xiaohongyang88@126.com (X. Yang), ding_ke@gibh.ac.cn
O
vinblastine R=Me
O
vincristine R=CHO
(K. Ding).
These authors contribute equally to this work.
Figure 1. Chemical structures of representative tubulin inhibitors.
http://dx.doi.org/10.1016/j.bmcl.2014.07.035
0960-894X/Ó 2014 Elsevier Ltd. All rights reserved.

W. Wang et al. / Bioorg. Med. Chem. Lett. 24 (2014) 4250–4253
4251
H2N
O2N
F
H2N
O2N
O
H2N
H2N
O
Table 1
R2
R2
a
b
HO
+
R2
Cytotoxic activities of synthesized compounds 5a, 6a–r and 8a–d against NCI-H460
and Colo205
4a-q
O
1
2a-q
3a-q
O
R1
O
N
R1
NH
R2
O
O
O
NH
OMe
N
N
R2
R2
c
d
R1
NH
NH
N
H
+
H2
N
N
H
N
H
5a-v
6a-w
Compounds R1
R2
IC50 (lM)
a
R1= Me; R2=phenyl (for 6w R1=Et); cyclohexyl; 1-naphthyl; benzyl; 2-Cl- phenyl; 3-Cl-
phenyl; 4-Cl-phenyl; 2-OMe-phenyl; 3-OMe-phenyl; 4-OMe-phenyl; 3,4-OMe-phenyl;
3,5-OMe-phenyl; 3,4,5-OMe-phenyl; 3-1,1'-bipheny; 3-CN-phenyl; 3-CF3-phenyl; 3-
isopropyl-phenyl; 3-F-phenyl; 3-Br-phenyl; 3-Me-phenyl; Et-phenyl; 3-alkynyl- phenyl;
NCI-H460
Colo205
5a
6a
6b
6c
6d
6e
6f
6g
6h
6i
OMe
Phenyl
Phenyl
Cyclohexyl
1-Naphthyl
Benzyl
2-Cl-phenyl
3-Cl-phenyl
4-Cl-phenyl
2-OMe-phenyl
3-OMe-phenyl
4-OMe-phenyl
3,4-OMe-
phenyl
3,5-OMe-
phenyl
3,4,5-OMe-
phenyl
0.32 0.12
0.13 0.05
0.56 0.12
7.45 1.13
9.61 2.45
2.02 0.35
1.60 0.66
1.90 0.65
2.61 0.16
0.92 0.43
2.98 1.86
4.98 1.11
0.49 0.14
0.06 0.01
0.17 0.06
1.13 0.32
1.37 0.22
0.58 0.15
0.07 0.01
0.10 0.01
0.32 0.01
0.05 0.03
0.24 0.03
0.48 0.25
NHMe
NHMe
NHMe
NHMe
NHMe
NHMe
NHMe
NHMe
NHMe
NHMe
NHMe
O
O
O
OMe
O
N
N
O
e
R
N
f
NH
NH2
NH
N
H
N
H
N
H
5a
8a-d
7
8a R=Me
8b
8c
R=Et
R=cyclopropyl
8d R=benzyl
6j
6k
Scheme 1. Synthesis of the designed compounds. Reagents and conditions: (a)
DMF, K2CO3, 100 °C, 1.0 h, 12.4–98.5%; (b) 10% Pd/C, H2, rt, 3.0 h, 52.3–75.4%; (c)
ethanol, 1.3-bis(methoxy carbonyl)-2-methyl-thiopseudoeura, reflux, overnight,
65.0%; (d) 33% methylamine ethanol solution, microwave, 140 °C, 2.0 h, 42.5–62.5%;
(e) MeOH/H2O = 2:1, NaOH, reflux, 8 h, 76.8%; (f) CH2Cl2, pyridine, acyl chloride,
0 °C, 47.8–71.2%.
6l
NHMe
NHMe
0.05 0.01
6.42 2.12
0.07 0.01
0.52 0.39
6m
6n
6o
6p
6q
NHMe
NHMe
NHMe
NHMe
3-1,10-Biphenyl
3-CN-phenyl
3-CF3-phenyl
3-Isopropyl-
phenyl
3-F-phenyl
3-Br-phenyl
3-Me-phenyl
3-Et-phenyl
3-Alkynyl-
phenyl
1.72 0.76
0.04 0.02
0.04 0.03
0.04 0.01
0.06 0.02
0.05 0.01
0.05 0.02
0.06 0.02
promising lead compound to discover novel mammalian b tubulin
inhibitors with different binding mode as new anticancer agents.
Herein, we would like to describe our efforts on the structural opti-
mization and biological evaluation on the new benzimidazole based
tubulin inhibitors. The studies help us to successfully identify a
number of benzimidazoles potently suppressing the proliferation
of a panel of human cancer cells with low nM IC50 values.
The general synthetic approach of compound 5a derivatives
was illustrated in Scheme 1. Briefly, compounds 1 and 2 were
heated with K2CO3 in DMF to produce compounds 3 with isolated
yields of 12.4–98.5%. Then the nitro group of compounds 3 was
hydrogenated to yield arylamine derivatives 4, which were further
reacted with 1.3-bis(methoxy carbonyl)-2-methyl-thiopseudoeura
to give the benzimidazole compounds 5.28 The final compounds 6
were readily prepared by reacting 5 with various alkylamines
under microwave conditions. The amide compounds 8 were syn-
thesized by a procedure of standard deprotection and followed
by acylation of compound 5a.
The anti-proliferative activities of the compounds were prelim-
inarily screened by using a standard MTT assay in NCI-H460
human lung cancer cells and Colo205 human colon cancer cells
and the results are summarized in Table 1. Two well known tubu-
lin inhibitors, colchicine and taxol, were used as positive com-
pounds to validate the screening conditions. It was found that
taxol potently inhibited the growth of NCI-H460 and Colo205 can-
cer cells with IC50 values of 10.0 and 3.0 nM, respectively, which is
highly comparable to the reported data.29 Colchicine also displayed
similar anti-proliferative activities. Consistent to its tubulin inhib-
itory effect, compound 5a showed promising cytotoxic effect on
both NCI-H460 and Colo205 cells, with the IC50 values of 0.32
6r
6s
6t
6u
6v
NHMe
NHMe
NHMe
NHMe
NHMe
0.07 0.01
0.20 0.03
0.24 0.05
0.05 0.02
0.12 0.05
0.07 0.02
0.10 0.02
0.07 0.01
0.05 0.03
0.05 0.02
6w
8a
8b
8c
8d
Taxol
Colchicine
NHEt
Me
Et
Phenyl
Phenyl
Phenyl
1.35 0.54
3.47 0.91
1.58 0.84
3.65 0.63
>10
0.18 0.11
1.14 0.45
0.63 0.21
0.58 0.14
11.42 2.45
Cyclopropyl Phenyl
Benzyl Phenyl
0.010 0.005 0.003 0.001
0.021 0.012 0.003 0.001
a
The data are means of three independent experiments performed in duplicate.
O
O
O
O
S
S
O
O
N
N
O
N
NH
NH
NH
N
H
N
H
N
H
albendazole
fenbendazole
mebendazole
N
O
O
O
O
O
O
O
N
O
N
NH
NH
NH
S
N
H
N
H
N
H
pardendazole
nocodazole
oxibendazole
O
O
S
O
O
O
N
O
O
N
NH
O
NH
N
H
N
H
F
5a
luxabendazole
and 0.49 lM, respectively, representing a good starting point for
further structural optimization.
Figure 2. Chemical structures of representative benzimidazoles derivatives.
We first investigated the potential impact of the methoxycar-
bonyl moiety in 5a on its antiproliferative activities by replacing
it with methylaminocarbonyl (6a), ethylaminocarbonyl (6w),
acetyl (8a), propionyl (8b), cyclopropanecarbonyl (8c) and
2-phenylacetyl (8d) groups. It was found that this moiety indeed
obviously affect its biological activity. When the methoxycarbonyl
group was replaced by an aminomethyl moiety (6a), the anti-
proliferative activities were obviously improved to display IC50
values of 0.13 and 0.06 lM, respectively, against NCI-H460 and
Colo205 cancer cells. However, other modified compounds 6w,
8a, 8b, 8c and 8d are less potent. For instance, compound 8d
showed dramatically decreased potency on the proliferation of
NCI-H460 and Colo205 cancer cells and the IC50 values are over
10 lM against both cells.

4252
W. Wang et al. / Bioorg. Med. Chem. Lett. 24 (2014) 4250–4253
Table 2
Cytotoxic activities of compounds 6a, 6f, 6o and 6q against a panel of cancer cells
a
Compounds
IC50 (lM)
K562
A431
HepG2
Hela
MDA-MB-435S
6a
6f
6o
6q
Taxol
Colchicine
0.012 0.006
0.045 0.036
0.006 0.001
0.021 0.001
0.004 0.003
0.001 0.000
0.036 0.012
0.075 0.014
0.026 0.003
0.020 0.008
0.007 0.002
0.008 0.006
2.336 1.160
6.691 1.283
1.774 0.374
8.309 2.915
0.990 0.178
1.710 0.294
1.121 0.1624
0.187 0.052
0.452 0.129
1.613 0.356
0.410 0.106
0.704 0.125
0.055 0.036
0.087 0.058
0.052 0.025
0.052 0.024
0.009 0.001
0.007 0.004
a
The data are means of three independent experiments performed in duplicate.
We further investigated the effects of R2 substitution on the
anti-proliferative activities by fixing R1 as an aminomethyl group.
It was found that R2 also showed great impact on the cytotoxic
activities of the resulting compounds. When R2-phenyl group in
6a was replaced with a cyclohexyl (6b) or 1-naphthyl (6c), or
benzyl (6d) moiety, the potencies were decreased about 4–75
folds. Further investigation suggested that the meta-position of
the phenyl group in 6a could be an optimal position to introduce
different substituent to maintain or improve its antiproliferative
activity. However, a substituted group at the ortho- or para-posi-
tion is detrimental to the potency. For instance, the 3-methoxyl
compound 6i displayed 3–6 times greater potency than that of
the 2-methoxyl (6h) and 4-methoxyl (6j) analogues. The study also
revealed that the 3,5-dimethoxyl compound 6l is significantly
more potent than the 3,4-dimethoxyl (6k) and 3,4,5-trimethoxyl
(6m) compounds.
Arg-2
Asp-251
Glu-71
Other meta-substituted derivatives were also designed and
synthesized, and almost all of them exhibited promising anti-
proliferative activities against NCI-H460 and Colo205 cancer cells
Figure 4. The predicted binding mode of 6o with
a and b tubulin.
with IC50 values ranged from 0.04 to 1.72 lM. Encouragingly, the
3-nitrile (6o), 3-trifluoromethyl (6p), 3-isppropyl (6q) and 3-ethyl
(6u) compounds displayed comparable potencies to that of well
known anticancer agents taxol and colchicines. It was noteworthy
that compounds 6o and 6p contained strong electron withdrawing
groups (i.e., nitrile, 3-trifluoromethyl) and might display greater
metabolic stability than compound 6a.
Further investigation also revealed that these compounds
indeed displayed strong inhibition against the growth of a panel
of various organs sourced human cancer cells (Table 2). For
example, compound 6o potently inhibited the growth of K562,
A431, Hela and MDA-MB-435S cancer cells with IC50 values of
These results support the potential inhibitory function of 6o
against tubulin. A further investigation demonstrated that the
compound dose-dependently induced G2/M phase arrest in NCI-
H460 non-small cell lung cancer cells (Supporting information).
A computational study was also performed to investigate the
potential binding mode of compound 6o with b tubulin. Based on
the previous study by Elias Georges et al.,27 we first fixed the
Ala63-Lys103 in the N-terminal of b tubulin as a centroid of the grid
and used SiteMap to identify the potential binding site of compound
6o. The possible binding poses of the compounds were then gener-
ated by Glide XP (the crystal structure of b tubulin was taken from
PDB (ID: 1SA1)). It was predicted that 6o locates in the interface
0.006, 0.026, 0.452 and 0.052 lM, respectively. However, it was
interestingly found that almost all of the compounds displayed
relatively lower potencies to the HepG2 cancer cells.
of
a
and b tubulin (Fig. 4). The benzimidazole and urea groups in
tubulin)
6o form three critical hydrogen bonds with Arg2, Asp251 (
a
In order to validate the tubulin inhibition of the new benzimid-
azole compounds, we further investigated the 6o’s effect on micro-
tubule skeleton by utilizing an immunofluorescence technique, in
which DMSO was used as blank control. As shown in Figure 3,
exposuring of NCI-H460 cells to different concentrations (25 nM,
50 nM, 100 nM) of 6o for 8 h induced a dose-dependent depoly-
merization of the microtubule cytoskeleton and 6o profoundly
inhibited the spindles formation at the concentration of 100 nM.
and Glu71 (b tubulin) residues, while the phenyl group protrude
toward the solvent-exposed section of the protein and the cyano-
group form another hydrogen bond with Arg2 (a tubulin).
In summary, a series of benzimidazole-2-urea derivatives were
identified as new tubulin inhibitors to potently suppress the prolif-
eration of a panel of human cancer cells with low nM IC50 values.
One of the most promising compounds 6o obviously inhibited
NCI-H460 cancer cells spindles formation and dose-dependent
induced cell cycle arrest at G2/M phase. A computational study
suggested the compound might bind with b tubulin in a new
binding site different from the three well-known ones. The strong
cell growth inhibitory effects support the compounds as new
promising leads for further investigation.
Acknowledgments
We thank the National Natural Science Foundation
(#21302186), and the Key Project on Innovative Drug of Guangdong
Province (#2012A080201014) for their financial support.
Figure 3. Compound 6o disturbs the microtubule skeleton in NCI-H460 cells. Cells
were exposed to various concentrations of 6o for 8 h and stained with anti-
tubulin antibody (green) and DAPI (blue) (scale bar = 20 ms).
a-
l

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Supplementary data associated with this article can be found, in
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