Synthesis of indazole based diarylurea derivatives and their antiproliferative activity against tumor cell lines

Article abstract of DOI:10.1016/j.bmcl.2013.02.034

New series of indazole based diarylureas were synthesized and their anticancer activity against cancer cells H460, A549, OS-RC-2, HT-29, Lovo, HepG2, Bel-7402, SGC-7901 and MDA-MB-231 were examined. These derivatives of diarylureas, except azaindazole based diarylureas 5f, 5l and 5m, showed superior or similar activity against most of these selected cancer cell lines to the reference compound sorafenib. The effect of substituents on the indazole ring was also investigated. Derivatives with trifluoromenthy or halogen substituent on the indazole ring showed higher activity against the selected cancer cell lines than sorafenib. The acute toxicity assay showed that compounds 5a, 5b and 5i possessed lower toxicity than sorafenib. Compound 5i with 4-(trifluoromenthy)-1H-indazole and 4-(trifluoromenthy) benzene moieties exhibited the most potent anticancer activity.

Full text of DOI:10.1016/j.bmcl.2013.02.034

Bioorganic & Medicinal Chemistry Letters 23 (2013) 1989–1992
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis of indazole based diarylurea derivatives and their
antiproliferative activity against tumor cell lines
b,
Cui-rong Zhao a, Rui-qi Wang a, Gang Li b, Xiao-xia Xue b, Chang-jun Sun b, Xian-jun Qu a, , Wen-bao Li
⇑
⇑
a Department of Pharmacology, School of Pharmaceutical Sciences, Shandong University, Wen Hua Xi Rd, Jinan 250012, China
b Haile Pharma Tech Ltd, 2766 Yingxiu Road, Jinan 250101, China
a r t i c l e i n f o
a b s t r a c t
Article history:
New series of indazole based diarylureas were synthesized and their anticancer activity against cancer
cells H460, A549, OS-RC-2, HT-29, Lovo, HepG2, Bel-7402, SGC-7901 and MDA-MB-231 were examined.
These derivatives of diarylureas, except azaindazole based diarylureas 5f, 5l and 5m, showed superior or
similar activity against most of these selected cancer cell lines to the reference compound sorafenib. The
effect of substituents on the indazole ring was also investigated. Derivatives with trifluoromenthy or
halogen substituent on the indazole ring showed higher activity against the selected cancer cell lines than
sorafenib. The acute toxicity assay showed that compounds 5a, 5b and 5i possessed lower toxicity than
sorafenib. Compound 5i with 4-(trifluoromenthy)-1H-indazole and 4-(trifluoromenthy) benzene
moieties exhibited the most potent anticancer activity.
Received 28 October 2012
Revised 2 February 2013
Accepted 6 February 2013
Available online 15 February 2013
Keywords:
Indazole based diarylureas
Antiproliferative activity
Sorafenib
Ó 2013 Elsevier Ltd. All rights reserved.
Cancer is a major public health problem in the world. The
American Cancer Society estimates that one out of every four
deaths in the United States is due to cancers.1 Cancers of lung
and bronchus, prostate, breast, colorectum, kidney and liver have
been the most causes of cancer death.1 Although the immense ef-
forts of innumerable research have been made, the rates of cancer
death are still in its high plateau.
non-small cell lung cancer cells NCI-H460 and A549, colon cancer
cells HT-29 and Lovo, hepatocellular carcinoma cells HepG2 and
Bel-7402, renal cell carcinoma cells OS-RC-2, gastric carcinoma
cells SGC-7901 and breast cancer cells MDA-MB-231.
The synthesis of this series diarylureas is shown in Scheme 1. In
the presence of Cs2CO3, compound 3 was synthesized by reacting
indazoles or azaindazoles with 4-fluoronitrobenzene in DMF. Com-
pound 4 was achieved by reductive of compound 3 with SnCl2 in
concentrated hydrochloric acid. The desired compounds 5a–m
was obtained by slowly adding phenylisocyanate R2 to the solution
of compound 4 in CH2Cl2 under argon atmosphere. With this
reaction route, 13 new indazole and azaindazole based diarylureas
were obtained, and their chemical characteristics and analytic data
are reported in Table 1.
The anticancer activity of these new diarylurea compounds in
human cancer cell lines was evaluated by using the MTT assay.17
The half-maximal inhibitory concentrations (IC50s) were calculated
and summarized in Table 2 with sorafenib as control drug.
Most of these compounds showed potent activity against one or
more of these cell lines. As shown in Table 2, the IC50 of sorafenib
The current treatments for cancers involve surgery, chemother-
apy, radiotherapy, biological therapy (including immunotherapy
and gene therapy), and various combinations.2 Chemotherapies
have been the backbone among these cancer treatments.3 How-
ever, most of the current drugs are cytotoxic agents with the nar-
row therapeutic index and frequently acquired resistance.3 The
development of more effective and lower toxicity drugs is needed.
A considerable number and diversity of diarylureas have been
identified as the promising, effective, and selective anti-cancer
agents.4–7 Sorafenib, for example, the first oral multi-kinase inhib-
itor, has shown good effects in renal cell carcinoma, hepatocellular
carcinoma, non-small cell lung cancer and melanoma,8–12 though
concomitant toxicities13–15 and drug resistance16 cannot be
ignored in clinic. Encouraged by these good effects of diarylurea
derivatives, we designed a new series of diarylurea compounds
containing indazole or azaindazole moiety based on the structural
features of sorafenib (shown in Fig. 1 and Table 1). In this Letter,
we show the synthesis of these new diarylurea derivatives and
their activity against a series of human cancer cell lines including
against MDA-MB-231 was 2.0
lM, which is close to the published
data of 2.6
l
M.18 The newly synthesized compound 5a with 4-triflu-
oromenthy-1H-indazole moiety and compound 5b containing 4-
chloro-1H-indazole moiety showed similar or superior activity
against MDA-MB-231 to sorafenib. Their IC50s in MDA-MB-231
were 2.0 and 1.6 lM, respectively. These two compounds also
showed similar or superior activity to sorafenib in NCI-H460,
A549, HT-29, and Lovo cell lines. These results indicated that both
trifluoromenthy and chloro-substituent at the 4 position of indazole
⇑
Corresponding authors. Tel./fax: +86 531 88382490.
E-mail addresses: qxj@sdu.edu.cn (X .- j .Qu), wbli@sanlugen.com (W.-b. Li).
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2013.02.034

1990
C. Zhao et al. / Bioorg. Med. Chem. Lett. 23 (2013) 1989–1992
Figure 1. Chemical structures of sorafenib and indazole based diarylurea derivatives.
Table 1
Structures for desired compounds
R1
O
R2
N
H
N
H
Compound
no.
R1
R2
Analytic data
CF
Cl
CF3
Cl
3
3
3
HPLC (UV254): 99.6%, LC–MS (C22H13ClF6N4O, MW = 498): M+H = 499, M+Na = 521. 1H NMR (600 MHz, DMSO-d6)
(ppm): d 7.47 (t, J = 7.8 Hz, 1H), 7.58 (d, J = 7.2 Hz, 1H), 7.64 (d, J = 9.0 Hz, 1H), 7.68 (m, 3H), 8.04 (d, J = 9.0 Hz, 1H),
8.14 (m, 3H), 9.17 (s, 1H)
5a
5b
5c
5d
N
N
N
N
N
N
N
N
CF
Cl
HPLC (UV254): 98.5%, LC–MS (C22H13Cl2F3N4O, MW = 464): M+H = 465, M+Na = 487. 1H NMR (600 MHz, DMSO-
d6) (ppm): d 9.26 (s, 1H), 9.14 (s, 1H), 8.42 (s, 1H), 8.14 (d, J = 1.8 Hz, 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.70 (m, 5H), 7.64
(d, J = 8.4 Hz, 1H), 7.48 (m, 1H), 7.35 (d, J = 7.2 Hz, 1H)
CF
Cl
Br
HPLC (UV254): 99%. LC–MS (C21H13BrClF3N4O, MW = 508, 510): M+Na = 531, M+Na = 533. 1H NMR (600 MHz,
DMSO-d6) (ppm): d 7.41 (t, J = 4.2 Hz, 1H), 7.50 (d, J = 7.2 Hz, 1H), 7.63–7.72 (m, 6H), 7.79 (d, J = 8.4 Hz, 1H), 8.14
(s, 1H), 8.32 (d, J = 0.6 Hz, 1H), 9.13 (s, 1H), 9.25 (s,1H)
CF
F
3
HPLC (UV254): 99.8%, LC–MS (C21H13ClF4N4O, MW = 448): M+H = 449, M+Na = 471. 1H NMR (600 MHz, DMSO-d6)
(ppm): d 7.06 (m, 1H), 7.49 (m, 1H), 7.62 (m, 2H), 7.70 (m, 5H), 8.14 (d, J = 2.4 Hz, 1H), 8.47 (s, 1H), 9.13 (s, 1H),
9.25 (s, 1H)
Cl
CF
Cl
CH3
3
HPLC (UV254): 100%, LC–MS (C22H16ClF3N4O, MW = 444): M+H = 44, M+Na = 467. 1H NMR (600 MHz, DMSO-d6)
(ppm): d 2.60 (s, 3H), 7.04 (d, J = 7.2 Hz, 1H), 7.37 (t, J = 7.8 Hz, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.65 (d, J = 8.4 Hz, 1H),
7.68 (m, 5H), 8.14 (d, J = 2.4 Hz, 1H), 8.40 (s, 1H)
5e
5f
N
N
N
N
CF
HPLC (UV254): 99.7%, LC–MS (C22H14ClF3N4O, MW = 430): M+H = 431, M+Na = 453. 1H NMR (600 MHz, DMSO-d6)
(ppm): d 7.27 (t, J = 7.5 Hz, 1H), 7.49 (m, 1H), 7.64 (d, J = 9.0 Hz, 1H), 7.66 (d, J = 2.4 Hz, 1H), 7.69 (m, 4H), 7.79 (d,
J = 8.4 Hz, 1H), 7.89 (d, J = 8.4 Hz, 1H), 8.14 (d, J = 1.8 Hz, 1H), 8.35 (s, 1H)
3
Cl
CF
H
3C
3
NH
HPLC (UV254): 94.8 %, LC–MS (C22H17ClF3N5O, MW = 459): M+H = 459. 1H NMR (600 MHz, DMSO-d6) (ppm): d
2.86 (s, 3H), 6.12 (d, J = 7.8 Hz, 1H), 6.55 (s, 1H), 6.9 (d, J = 8.4 Hz, 1H), 7.22 (t, J = 8.1 Hz, 1H), 7.65 (m, 6H) , 8.14 (d,
J = 2.4 Hz, 1H), 8.34 (s, 1H), 9.05 (s, 1H), 9.22 (s, 1H)
5g
Cl
N
N
H3C
CF
Cl
3
O
HPLC (UV254): 100%, LC–MS (C22H16ClF3N4O2, MW = 460): M+H = 461, M+Na = 483. 1H NMR (600 MHz, DMSO-
d6) (ppm): d 3.97 (s, 3H), 6.71 (d, J = 7.8 Hz, 1H), 7.33 (d, J = 8.4 Hz, 1H), 7.4 (t, J = 16.2 Hz, 1H), 7.60–7.70 (m, 6H),
8.14 (d, J = 1.8 Hz, 1H), 8.28 (s, 1H), 9.08 (s, 1H), 9.23 (s, 1H)
5h
5i
N
N
CF3
HPLC (UV254): 100%, LC–MS (C22H14F6N4O, MW = 464): M+H = 464, M+Na = 486. 1H NMR (600 MHz, DMSO-d6)
(ppm): d 7.47 (t, J = 7.8 Hz, 1H), 7.57 (d, J = 7.2 Hz, 1H), 7.65 (d, J = 8.4 Hz, 2H), 7.69 (d, J = 9.0 Hz, 4H), 8.05 (d,
J = 5.4 Hz, 1H), 8.12 (d, J = 8.4 Hz, 2H), 9.12 (s, 1H), 9.19 (s, 1H), 9.22 (s, 1H)
CF3
N
N

C. Zhao et al. / Bioorg. Med. Chem. Lett. 23 (2013) 1989–1992
1991
Table 1 (continued)
Compound
no.
R1
R2
Analytic data
Cl
HPLC (UV254): 99%, LC–MS (C21H14ClF3N4O, MW = 430): M+H = 431, M+Na = 453, 1H NMR (600 MHz, DMSO-d6)
(ppm): d 9.19 (s, 1H), 9.09 (s, 1H), 8.42 (s, 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.69 (m, 8H), 7.48 (t, J = 7.8 Hz, 1H), 7.35 (d,
J = 7.8 Hz, 1H)
CF3
5j
N
N
CF
Cl
HPLC (UV254): 97.8%, LC–MS (C20H13ClF3N5O, MW = 431): M+H = 432, 1H NMR (600 MHz, DMSO-d6) (ppm): d
7.67 (m, 6H), 7.78 (d, J = 6.0 Hz, 1H), 8.14 (d, J = 2.4 Hz, 1H), 8.47 (d, J = 6.0 Hz, 1H), 8.59 (s, 1H), 9.13 (s, 1H), 9.22
(s, 1H), 9.25 (s, 1H)
3
N
N
N
5k
5l
N
HPLC (UV254): 100%. LC–MS (C20H13ClF3N5O, MW = 431): M+H = 432, 1H NMR (600 MHz, DMSO-d6) (ppm): d
7.64 (d, J = 9.0 Hz, 1H), 7.68 (dd, J1 = 2.4 Hz, J2 = 9.0 Hz, 1H), 7.69 (d, J = 2.4 Hz, 2H), 7.72 (d, J = 1.8 Hz, 2H), 7.90
(dd, J1 = 1.2 Hz, J2 = 5.4 Hz, 1H), 8.14 (d, J = 2.4 Hz, 1H), 8.37 (d, J = 5.4 Hz, 1H), 8.50 (s, 1H), 9.13 (s, 1H), 9.25 (s,
1H), 9.28 (s, 1H)
CF3
N
N
Cl
CF3
HPLC (UV254): 100%. LC–MS (C20H13ClF3N5O, MW = 431): M+H = 432, M+Na = 454, 1H NMR (600 MHz, DMSO-d6)
(ppm): d 7.37 (dd, J1 = 4.2 Hz, J2 = 7.8 Hz, 1H), 7.63 (d, J = 9.0 Hz, 1H), 7.67 (d, J = 9.0 Hz, 3H), 8.15 (dd, J1 = 2.7 Hz,
J2 = 6.9 Hz, 3H), 8.38 (d, J = 1.8 Hz, 1H), 8.40 (s, 1H), 8.67 (dd, J1 = 1.8 Hz, J2 = 4.8 Hz, 1H), 9.05 (s, 1H), 9.22 (s, 1H)
N
5m
N
N
Cl
Scheme 1. Synthesis of indazole based diarylurea derivatives. Reagents and conditions: (a) Cs2CO3, DMF; (b) SnCl2, concentrated HCl, saturated NaHCO3, pH 9, CH2Cl2, MgSO4,
silica gel column chromatography (eluent EtOAc/PE = 2:1); (c) CH2Cl2, Ar, 0 °C, methanol (yields: 5a: 45%, 5b: 33%, 5c: 43%, 5d: 36%, 5e: 50%, 5f: 49%, 5g: 48%, 5h: 52%, 5i: 24%,
5j: 80%, 5k: 80%, 5l: 81%, 5m: 79%).
Table 2
IC50s (lM) for desired compounds in nine human cancer cell lines after 72 h continuous exposure
NO.
NCI-H460
A549
OS-RC-2
HT-29
LOVO
HepG2
Bel-7402
SGC-7901
MDA-MB-231
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
Sorafenib
1.6
1.3
1.3
3.4
2.5
5.5
2.6
2.2
0.8
6.8
1.4
4.8
16.6
3.9
3
>32
3.1
9.9
32
32
32
10.6
28.8
4
4.6
>32
>32
>32
16
2.9
4.6
4
8.2
32
18.2
5.9
>32
3.3
1
10.5
29.5
>32
4
3
8
16
2.5
1.3
16
6.7
10.6
5
2.9
1
8
>32
4.6
16.6
32
14.2
>32
6.9
29.8
4
2
3.1
2.3
3.8
5.5
9.9
4.9
3.7
0.8
6
3.4
10.6
>32
4
3.6
1.7
9.8
3.9
8.7
6.3
>32
2.2
5.1
8
1.9
2.0
29.5
4
8
3
1.6
7.7
3.1
2.3
5
3.6
1.2
2
2.7
16
>32
>32
2
4
1
6.7
4
16
>32
4
6
2.7
4
20.9
5.8
22.6
>32
>32
6.9
7.1
32
3.3
ring are favorable. This inference was supported by another halogen
compound 5c which has 4-bromo-1H-indazole moiety and also
exhibited excellent inhibitory activity against NCI-H460, A549,
HT-29, and Lovo cell lines. Notably, both compounds 5b and 5c
showed stronger activity than sorafenib against hepatocellular car-
cinoma cell lines HepG2 and Bel-7402. The IC50s in HepG2 and Bel-
sorafenib and compound 5b against MDA-MB-231, NCI-H460,
A549, HepG2, and Bel-7402 cell lines, which might be ascribed to
their space effect and electric effect from MeN- or MeO- group.
All above eight diarylurea compounds have 4-chloro-3-(triflu-
oromenthy) benzene moiety as their R2 (Table 1). By replacing this
moiety with 4-(trifluoromenthy) benzene, two novel compounds
5i and 5j were synthesized (Table 1). Compound 5i showed much
more potential anticancer activity against all these cell lines, espe-
cially MDA-MB-231, NCI-H460, A549, HepG2, Bel-7402 and OS-RC-
2, in which the IC50s for compounds 5i were 2.0, 0.8, 0.8, 1.0, 1.0
7402 were 1.9 and 2.0
tively. More encouragingly, compound 5b showed very good activ-
ity against OS-RC-2 with IC50 at 3.1 M and SGC-7901 with IC50 at
4.6 M. In contrast, compounds 5d, 5e or 5f, with F-, Me-, or
lM for 5b and 2.5 and 1.3 lM for 5c, respec-
l
l
none-indazole substitute, respectively, showed less activity than
compounds 5b in most of these cell lines, which might be caused
by their smaller atom space. However, compounds 5g and 5h, with
MeN- and MeO-groups, exhibited similar or superior activity to
and 4.0 lM, respectively. The IC50s of compound 5j were similar
to that of compounds 5a and 5b in most of the cell lines (Table 2).
To investigate the function of the indazole ring, three azaindaz-
oles based diarylurea compounds 5k–m were synthesized

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(Table 1). Their IC50s showed that all these three compounds have
less activity in all these cell lines, indicating that the activity was
diminished while the indazole ring was replaced by the azaindaz-
ole ring. These data suggested that the indazole ring is an impor-
tant moiety for anticancer activity and the trifluoromenthy or
halogen substituent at the 4 position of indazole ring is favorable.
We evaluated the acute toxicity for the representative com-
pounds 5a, 5b and 5i in mice. The highest single oral dose of
2000 mg/kg for these compounds was tolerated without any sign
of toxicity, while the tolerated single oral dose of sorafenib was
1460 mg/kg in mice. These results suggested that these new syn-
thesized diarylurea compounds might have lower toxicity than
sorafenib. Further toxicities of these compounds are currently
underway.
In conclusion, a new series of indazole based diarylurea com-
pounds were synthesized and their activity against human tumor
cell lines was examined. Among them, compounds with trifluoro-
menthy and halogen substituents showed better effect than sorafe-
nib. Compounds 5a, 5b and 5i were found to have lower toxicity
than sorafenib. Compound 5i could be developed as a promising
agent for treatment of cancers.
15. Mir, O.; Coriat, R.; Blanchet, B.; Durand, J. P.; Boudou-Rouquette, P.; Michels, J.;
Ropert, S.; Vidal, M.; Pol, S.; Chaussade, S.; Goldwasser, F. PLoS One 2012, 7,
37563.
16. Villanueva, A.; Llovet, J. M. Clin. Cancer Res. 1824, 2012, 18.
17. NCI-H460, A549, HT-29, Lovo, HepG2, Bel-7402, OS-RC-2, SGC-7901 and MDA-
MB-231 cells were purchased from the American Type Cell Culture Collection
(ATCC, USA) and maintained in RPMI-1640 or DMEM medium supplemented
with 10% (v/v) heat-inactivated fetal bovine serum, penicillin–streptomycin
(100 IU/mL–100 lg/mL), 2 mM glutamine, and 10 mM HEPES buffer at 37 °C in
a humidified atmosphere (5% CO2–95% air). Culture medium was changed
every 2 days. Cells were harvested by brief incubation in 0.02% (w/v) trypsin in
PBS (ICN, Aurora, USA), seeded in 96-well plates (3 Â 103 per well) and then
were incubated in humidified atmosphere for 24 h prior to exposure to various
concentrations of test compounds for 72 h. Cell viability was assessed using the
3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay
Acknowledgment
This project was supported by Jinan ‘5150’ Plan to Dr. Wenbao
Li.
via adding 20 lL of MTT (5 mg/mL, Sigma, USA) and incubating for 4 h. The
absorbance at 570 nm was measured on a microplate reader (Perkin-Elmer,
USA), and the IC50s were calculated.
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