Synthesis and biological evaluation of novel 1-(4-methoxyphenethyl)-1H-benzimidazole-5-carboxylic acid derivatives and their precursors as antileukemic agents

Article abstract of DOI:10.1016/j.bmcl.2009.06.103

We report here the synthesis and preliminary evaluation of novel 1-(4-methoxyphenethyl)-1H-benzimidazole-5-carboxylic acid derivatives 6(a-k) and their precursors 5(a-k) as potential chemotherapeutic agents. In each case, the structures of the compounds w

Full text of DOI:10.1016/j.bmcl.2009.06.103

Bioorganic & Medicinal Chemistry Letters 19 (2009) 4594–4600
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and biological evaluation of novel 1-(4-methoxyphenethyl)-1H-
benzimidazole-5-carboxylic acid derivatives and their precursors
as antileukemic agents
N. R. Thimme Gowda a, C. V. Kavitha b, Kishore K. Chiruvella b, Omana Joy b,
b,
Kanchugarakoppal S. Rangappa a, , Sathees C. Raghavan
*
*
a Department of Studies in Chemistry, University of Mysore, Mysore 570 006, India
b Department of Biochemistry, Indian Institute of Science, Bangalore 560 012, India
a r t i c l e i n f o
a b s t r a c t
Article history:
We report here the synthesis and preliminary evaluation of novel 1-(4-methoxyphenethyl)-1H-benz-
imidazole-5-carboxylic acid derivatives 6(a–k) and their precursors 5(a–k) as potential chemotherapeu-
tic agents. In each case, the structures of the compounds were determined by FTIR, 1H NMR and mass
spectroscopy. Among the synthesized molecules, methyl 1-(4-methoxyphenethyl)-2-(4-fluoro-3-nitro-
phenyl)-1H-benzimidazole-5-carboxylate (5a) induced maximum cell death in leukemic cells with an
Received 13 April 2009
Revised 30 May 2009
Accepted 26 June 2009
Available online 4 July 2009
IC50 value of 3 lM. Using FACS analysis we show that the compound 5a induces S/G2 cell cycle arrest,
Keywords:
which was further supported by the observed down regulation of CDK2, Cyclin B1 and PCNA. The
observed downregulation of proapoptotic proteins, upregulation of antiapoptotic proteins, cleavage of
PARP and elevated levels of DNA strand breaks indicated the activation of apoptosis by 5a. These results
suggest that 5a could be a potent anti-leukemic agent.
Benzimidazole-5-carboxylic acid
Anticancer drugs
Chemotherapy
Cancer therapeutics
Apoptosis
Ó 2009 Elsevier Ltd. All rights reserved.
DNA damage
Among different types of cancers, leukemia is one of the major
causes of cancer related deaths.1,2 Leukemia originates from hema-
topoietic stem cells or cells at different stages of myeloid or ery-
throid differentiation which spread throughout the body.
Although, the success of clinical trials in identifying new agents
and treatment modalities has been significant, current treatments
suffer from many limitations such as side effect of the drugs and
drug resistance. Hence, the identification of novel, efficient and less
toxic anticancer agents remains an important and challenging task
in cancer biology.
The benzimidazole nucleus is the key building block for a vari-
ety of compounds that play crucial roles in the function of a num-
ber of biologically important molecules.3 Benzimidazole
derivatives have shown different therapeutic properties such as
antiulcer,4 antihelminthic,5 antihypertensive,6 anticoagulant,7
antiallergic,8 analgesic,9 anti-inflammatory,10 antimicrobial,11anti-
viral,12 antiparasitic13 and antioxidant.14 It is also reported that,
the benzimidazole nucleus is an essential part of many antineo-
plastic derivatives.15TREANDAÒ (bendamustine hydrochloride)
containing alkylating group and benzimidazole component has
been used for the treatment of patients with chronic lymphocytic
leukemia (CLL) and has been approved by FDA.
Because of their significant medicinal importance, the synthesis
of substituted benzimidazoles has become a focus of synthetic or-
ganic chemistry. Earlier we showed the antiproliferative effect and
mechanism of induction of apoptosis by various bioactive hetero-
cyclic compounds and reported the impact of electron releasing
and withdrawing groups on the induction of apoptosis.16–24 In con-
tinuation with our efforts in search of potential anticancer agents,
we have synthesized a series of novel 1-(4-methoxyphenethyl)-
1H-benzimidazole-5-carboxylic acid derivatives 6(a–k) and their
precursors 5(a–k) by introducing different substituted aryl groups
at 2nd position of benzimidazole nucleus.
Here, we report the synthesis and screening of antiproliferative
activities of a series of novel 1-(4-methoxyphenethyl)-1H-benz-
imidazole-5-carboxylic acid derivatives 6(a–k) and their precur-
sors 5(a–k). Among the compounds, 5a is identified as
a
potential therapeutic agent for leukemia. We find that 5a induces
DNA damage leading to cell cycle arrest at S and G2/M phases cul-
minating into apoptosis.
Synthesis of 1-(4-methoxyphenethyl)-1H-benzimidazole-5-car-
boxylic acid derivatives was outlined in Scheme 1. 4-Fluoro-3-ni-
tro-benzoic acid 1 was dissolved in dichloromethane (MDC).
* Corresponding authors. Tel.: +91 821 2419661; fax: +91 821 2412191 (K.S.R.);
tel.: +91 80 2293 2674; fax: +91 80 2360 0814 (S.C.R.).
E-mail addresses: rangappaks@chemistry.uni-mysore.ac.in (K.S. Rangappa),
sathees@biochem.iisc.ernet.in (S.C. Raghavan).
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.06.103

N. R. Thimme Gowda et al. / Bioorg. Med. Chem. Lett. 19 (2009) 4594–4600
4595
HOOC
NO2
F
H3COOC
NO2
F
a
H3COOC
NO2
b
OCH3
N
H
1
2
3
HOOC
N
N
H3COOC
H3COOC
NH2
NH
N
N
R
d
e
c
f
R
OCH3
OCH3
OCH3
5 (a-k)
6 (a-k)
4
75-85%
75-90%
Scheme 1. Synthesis of benzimidazole derivatives 5(a–k) and 6(a–k). Reagents and conditions: (a) Thionyl chloride, Methanol, MDC, reflux condition; (b) 2-(4-
methoxyphenyl)ethanamine, DIPEA, DMF, rt, 3 h; (c) Fe powder, NH4Cl, IPA, 70 °C, 4 h; (d) R–COCl, TEA, MDC, rt, 3 h; (e) CH3COOH, 90 °C, 8 h; (f) LiOH, THF/water (2:1), reflux
condition.
Methanol and thionyl chloride was added to it, and under reflux
condition the compound 2 was formed. Nucleophilic aromatic sub-
stitution of fluorine group with 2-(4-methoxyphenyl)ethanamine
gave the product 3. The aryl nitro group was then reduced to amine
4 using NH4Cl solution and 20% iron (II) powder. The selective acyl-
ation of primary aromatic amine followed by cyclization gave the
precursors 5(a–k). The hydrolysis of 5(a–k) gave the final com-
pounds 6(a–k). Compounds 5(a–k) and 6(a–k) were obtained in
good yield, purified by column chromatography using hexane
and ethyl acetate, and recrystallized using diethyl ether and hex-
ane. The resulting compounds were characterized by 1H NMR, FTIR,
and LCMS analysis (Fig. 1, Table 1 and Suppl. Fig. S1, S2, S3 and S4).
Trypan blue exclusion assay was the first line of our investigation,
where we assessed the effect of benzimidazole derivatives 5(a–k)
and 6(a–k) on viability of different leukemic cell lines (K562 and
CEM). The leukemic cells were treated with different benzimidazole
derivatives at concentrations of 10, 100 and 250
pounds were dissolved in DMSO, the cells with DMSO (equivalent to
DMSO used in 250 M) were used as vehicle control. The cells were
counted at intervals of 24 h till they attained stationary phase. Re-
sults showed that the addition of benzimidazole derivatives 5(a–k)
and 6(a–k) affected the viability of cells (Suppl. Fig. S5 A–D) in a
dose- and time-dependent manner. In both cell lines tested, the
derivatives, 5a, 5e–g, 5i, 5k, 6–h and 6j showed remarkable effect
lM. Since the com-
l
on cell viability at concentrations of 100 and 250 lM, within 48 h it-
self. However, in the case of other derivatives the effect was limited.
The DMSO control, corresponding to the highest concentrations of
drugs tested did not show any significant toxic effect. The cytotoxic-
ityinduced by benzimidazole derivatives5(a–k) and 6(a–k) was fur-
ther verified using MTTassay (Fig. 2 and Suppl. Fig. S6 A–D). Based on
the trypan blue and MTT assays, IC50 values were calculated for both
K562 and CEM cells (Table 1).
Release of LDH is an indicator of cell injury and hence cell death.
To confirm the cytotoxicity exhibited by some of the compounds (5a,
5i and 6f; Fig. 1) we have carried out an LDH assay. Results showed a
dose- and time-dependent increase in the LDH release upon treat-
ment with the compounds, further confirming the above results
(Fig. 3).
F
NO2
F
H3COOC
H3COOC
N
N
N
N
Studies thus far described clearly show that 5a affects the via-
bility of the cells significantly. Therefore, we were interested in
understanding the mechanism by which 5a induces cell death.
First, we tested whether 5a induces cell death by affecting cell pro-
liferation. Results of tritiated thymidine incorporation assay
showed a time- and dose-dependent decrease in incorporation of
[3H]-thymidine upon treatment with 5a in K562 cells (Fig. 4A).
These studies indicated that 5a could be interfering with DNA rep-
lication affecting cell division and hence proliferation.
OMe
OMe
5a
5i
HOOC
CH3
CH3
CH3
N
N
Many chemotherapeutic compounds have been shown to have
antiproliferative effects by inhibiting cell cycle at certain check-
points.25 Similarly, certain compounds are believed to function
via cell cycle-mediated apoptosis.26,27 In order to study whether
5a could inhibit cell proliferation by cell cycle arrest, FACS analysis
was performed after treatment with 5a. Results showed that the
cell cycle progression was arrested at S and G2 phases (Fig. 4B
and Suppl. Fig. S7). Therefore, our studies suggested that growth
OMe
6f
Figure 1. The structure of the benzimidazole derivative 5a, 5i and 6f.

4596
N. R. Thimme Gowda et al. / Bioorg. Med. Chem. Lett. 19 (2009) 4594–4600
Table 1
IC50 value of 5(a–k) and 6(a–k) compounds on K562 and CEM cells
H3COOC
N
HOOC
N
N
R
R
N
6 (a-k)
5 (a-k)
OCH3
OCH3
Compound
R
IC50
(l
M)
Compound
IC50 (lM)
K562
3
CEM
4
K562
CEM
132
NO2
NH2
5a
6a
135
180
250
>250
200
40
F
5b
5c
5d
5e
5f
78
75
6b
6c
6d
6e
6f
182
245
>250
195
42
F
120
180
136
70
122
175
138
68
NO2
NH2
OCH3
CH3
CH3
CH3
F
5g
5h
5i
84
85
6g
6h
6i
80
85
F
Cl
>250
56
>250
55
110
240
124
>250
102
244
120
>250
Cl
F
Br
5j
>250
64
>250
65
6j
5k
6k

N. R. Thimme Gowda et al. / Bioorg. Med. Chem. Lett. 19 (2009) 4594–4600
4597
Figure 2. Determination of cell proliferation by MTT assay. K562 cells were cultured with different concentrations of 5a, 5i or 6f for 48 and 72 h. After harvesting the cells,
MTT (0.5 mg/ml) was added and processed. The absorbance at 570 nm was measured using ELISA plate reader.
Figure 3. Measurement of LDH release following treatment with 5a, 5i and 6f. After the exposure of K562 cells with different concentrations of 5a, 5i and 6f for 24 and 48 h,
the release of LDH was measured at 490 nm. Results are presented as percentage of LDH release.
Figure 4. Compound 5a affects cell division and progression of cell cycle in leukemic cells. (A) Tritiated thymidine assay. Different concentrations of 5a were treated with
K562 cells for indicated time. Histogram shows the dose-dependent incorporation of tritiated thymidine into DNA. (B) FACS analysis of 5a treated (1, 5, and 10 lM) K562 cells.
DMSO treated cells were used as vehicle control. (C) Treatment of 5a leads to the alteration in the level of replication related proteins. The deregulation of p-Histone 3, PCNA,
Cyclin B1, CDK2 and p21 are studied using western blotting. Tubulin was used as the internal control. Histograms in the right panel show the normalized level of proteins
studied following 5a treatment.

4598
N. R. Thimme Gowda et al. / Bioorg. Med. Chem. Lett. 19 (2009) 4594–4600
Fig 4. (continued)
inhibition observed could be mediated through a DNA replication
defect followed by cell cycle arrest leading to apoptosis.
somal DNA. The extracted DNA was run on agarose gel. The ob-
served smear could be the result of DNA breakage at multiple
positions across the chromosomal DNA (Suppl. Fig. S8). Com-
Since a cell cycle arrest was observed, we were interested in
testing the expression levels of replication related proteins in
K562 cells following treatment with 5a. Western blot analysis
showed that, the levels of p-histone H3 (marker for cell division)
reduced upon treatment with 5a at concentrations of 5 and
pound 5i and 6f showing maximum strand breaks at 100
whereas 5a showed good amount of DNA strand breakage even
at 10 M. In the case of DMSO control, there were only limited
lM
l
strand breaks. These results indicate that 5a is able to induce sig-
nificant amounts of DNA strand breaks including double-strand
breaks (DSBs). Although, we did observe DNA strand breaks, we
could not see DNA fragments of oligonucleosomal size. This sug-
gests that most likely 5a might be inducing damage in the DNA,
leading to strand breaks. However, such a hypothesis needs to be
verified further.
Finally we check the effect of 5a on expression proteins associ-
ated with apoptosis, like BAD, BCL2 and PARP. Results showed that
5a treatment led to the upregulation of proapoptotic protein, BAD
in a time-dependent manner (Fig. 5). In contrast, the expression of
antiapoptotic protein BCL2 went down immediately after 5a treat-
ment (Fig. 5). Poly (ADP-ribosyl) polymerase (PARP) is a single-
strand break repair enzyme (116 kDa). It is known that upon acti-
vation of apoptotic pathway, caspase cleaves PARP into 85 and
27 kDa polypeptides.28 By immunoblotting analysis using anti-
PARP, we found that the addition of 5a led to significant PARP
cleavage, resulting in the accumulation of the 85 kDa product
(Fig. 5). The maximum PARP cleavage was seen after 12 h treat-
ment of 5a. (Fig. 5). Hence, these results suggest that 5a treatment
affects the ratio of proapoptotic:antiapoptotic proteins normally
seen in the cells, and that leads to the activation of apoptosis.
The observed structure–activity relationship indicated that
activity of both the series of compound varied at different levels.
10 lM. However, robust expression was seen in the control
(Fig. 4C). These results indicated that histone H3, (a histone nor-
mally phosphorylated at M phase) was not phosphorylated when
cells were treated with 5a. Moreover, we noted that the levels of
expression of PCNA, another protein required for replication was
reduced upon treatment with 5a (Fig. 4C). In addition to this we
find that 5a treatment leads to a concentration dependent down
regulation of cyclin B1 explaining the observed cell cycle arrest
in G2/M phase. At 10 lM concentration, we also found that 5a
could induce down regulation of CDK2. This is consistent with
the observed S phase arrest. Since earlier reports have shown that
the presence of p21 could lead to the inhibition of PCNA and CDK2,
we were interested to test whether 5a treatment activates p21.
Western blot analysis showed that though the p21 level was very
low in the normal cells, treatment with 5a induced activation of
p21 (Fig. 4C), further justifying the downregulation of PCNA and
CDK2. Hence, our results suggest that 5a downregulates expression
of critical cell cycle related proteins to induce cell cycle arrest.
The formation of distinct DNA fragments of oligonucleosomal
size is a biochemical hallmark of apoptosis in many cells. Hence
we were interested to see whether 5a could induce DNA damage.
To test this, K562 cells treated with 10, 50 and 100
lM of 5a, 5i
or 6f for 72 hr were harvested and used for extraction of chromo-

N. R. Thimme Gowda et al. / Bioorg. Med. Chem. Lett. 19 (2009) 4594–4600
4599
Figure 5. Compound 5a alters expression of apoptotic proteins in K562 cells. Cell lysate was prepared from K562 cells after treating with 30
lM of 5a for 12 and 24 h (labelled
as ‘12’ and ‘24’, respectively). DMSO treated cells grown for 24 h was used as vehicle control (labelled as ‘0’). Approximately, 20
PAGE and transferred to a PVDF membrane. The membrane was probed for the expression of BAD, BCL2 and PARP using specific primary antibody and appropriate secondary
antibody. The -tubulin was used as an internal loading control. The histogram showing quantification of respective gels are shown on the right.
lg of protein per sample was resolved on SDS–
a
When we compare 5(a–k) series (ester) with 6(a–k) series (carbox-
ylic acid) of compounds, we note that most of the compounds in
ester derivatives exhibited better activity than carboxylic acid
derivatives. However, we did not observe any significant difference
in the activity exhibited by these compounds between the cell lines
tested. Among the ester derivatives, it is noteworthy to mention
that, compound 5a, having a fluoro at the para position and a nitro
at the meta position exhibited growth inhibitory activity at an IC50
Acknowledgements
We thank Ms. Mridula Nambiar for her help during cell culture
and manuscript preparation. This work was supported by Lady
Tata Memorial Trust international award for leukemia research
(London) for S.C.R. and by UGC, Govt. of India under the projects
vide No. F. 31-143/2005(SR), UGC-SAP (Phase I) vide No. F. 540/
10/2004-05 (SAP I) and DST-FIST Programmes for K.S.R. N.R.T. is
supported by Senior Research Fellowship from CSIR, India.
value of 3 lM, whereas replacement of the same with only ortho
fluoro group (5i) and nitro group with amine group (5b) decreases
the activity by 19 and 25-fold, respectively (Table 1). Furthermore,
nitro (5c) and amine group (5d) at the para position and methoxy
group (5e) at meta position exhibited low activity with IC50 value
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2009.06.103.
ranging from 75 to 180 lM in both the cell lines (Table 1). When
we introduced tertiary butyl group (5f) and fluorine groups (5g
and 5i) improved cytotoxicity was observed. A significant loss in
the activity was observed when fluorine was replaced with chloro
(5h) and bromo (5j) groups. Although it is difficult to explain the
observed variations in the activity with respect to substituents in
growth inhibition, it is important to point out that phenyl ring
without any substituents in fact exhibited only a moderate activity.
In carboxylic acid derivatives 6(a–k), compound 6f containing ter-
tiary butyl group showed good activity relative to all other com-
pounds of the same series.
In summary, our SAR study shows that both ester and carboxylic
acid derivatives exhibited different levels of antiproliferative activ-
ity upon treatment on leukemic cells. Further studies are underway
to understand the structure-activity relationship of these novel
benzimidazole derivatives. The screening of 22 novel compounds
has led to the discovery of methyl 2-(4-fluoro-3-nitrophenyl)-1-
(4-methoxyphenethyl)-1H-benzimidazole-5-carboxylate (5a), con-
taining electron-withdrawing nitro (–NO2) and fluorine (F) groups,
which showed an excellent inhibition on human leukemic cells with
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