Bioorganic & Medicinal Chemistry Letters
Synthesis and biological evaluation of compounds which contain
pyrazole, thiazole and naphthalene ring as antitumor agents
Ji-Wen Yuan , She-Feng Wang , Zhong-Liang Luo, Han-Yue Qiu, Peng-Fei Wang, Xin Zhang,
⇑
Yong-An Yang, Yong Yin, Fei Zhang, Hai-Liang Zhu
State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of compounds which contain pyrazole, thiazole and naphthalene ring (1a–7a, 1b–7b, 1c–7c,
1d–7d) were firstly synthesized and their anti-proliferative activity, EGFR inhibitory activity, cytotoxicity
and inhibition to Hela cell migration were evaluated. Compound 2-(3-(3,4-dimethylphenyl)-5-(naphtha-
len-2-yl)-4,5-dihydro-1H-pyrazol-1-yl)thiazol-4(5H)-one (7d) displayed the most potent inhibitory
Received 9 January 2014
Revised 5 March 2014
Accepted 24 March 2014
Available online 3 April 2014
activity (IC50 = 0.86 lM for Hela and IC50 = 0.12 lM for EGFR). Structure–activity relationship (SAR) anal-
ysis showed that the anti-proliferative activity was affected by A-ring-substituent (–OCH3 > –CH3 > –H >
–Br > –Cl > –F). Docking simulation of compound 7d into EGFR active site showed that naphthalene ring
Keywords:
EGFR inhibitors
Anti-tumor activity
Cell migration
Structure–activity relationship
of 7d with LYS721 formed two p–
p bonds, which enhanced antitumor activity. Therefore, compound 7d
may be developed as a potential antitumor agent.
Ó 2014 Elsevier Ltd. All rights reserved.
Pyrazole ring was a prominent skeleton motif in a lot of pharma-
ceutically active compounds, and pyrazole derivatives possess a
wide range of biological activities, such as anti-inflammatory,1 anti-
fungal,2,3 antimicrobial,4,5 anticoagulants,6 analgesic,7 antithrom-
bolic,8 anti-tumor activity,9,10 and so on. A series of pyrazoleoxime
ether derivatives were prepared and examined as cytotoxic agents,
among which 5-phenoxypyrazole exhibited very potent
cytotoxicity against XF 498 and HCT15.9 While 1-arylmethyl-3-
aryl-1H-pyrazole-5-carbohydrazide derivatives were showed
inhibitory effects on the growth of A549 cells.10
pyrazole, thiazole and naphthalene ring and evaluated their anti-
proliferative activity. As everyone knows, EGFR (epidermal growth
factor receptor) plays a very important role in cell proliferation,
survival, migration, differentiation and metastasis of many tumors.
EGFR was often used as targets for the development of novel
anticancer agents, such as Gefitinib and Elotinib.26,27 To further
understand the antitumor effect of designed compounds, docking
simulation was performed to position compound 7d into the EGFR
active site to determine the probable binding model.
The synthetic procedures of compounds 1a–7a, 1b–7b, 1c–7c
and 1d–7d were outlined in Scheme 1, Tables 1 and 2 and their
structures were confirmed by one 1H NMR and MS. The structures
of compounds 1d and 5d were demonstrated by X-ray diffraction
analysis. The crystal data were presented in Table 3, Figures 1
and 2 and have been deposited at the Cambridge Crystallographic
Data Centre as supplementary publication Nos. 987465 and
978466.
Thiazole and its derivatives were widely used in pesticides and
medicine. For example, 4-(4-chlorophenyl)-2-(3-(3,4-dimethyl-
phenyl)-5-p-tolyl-4,5-dihydro-1H-pyrazol-1-yl) thiazole displayed
the potent EGFR TK inhibitory activity and anti-proliferative activ-
ity against MCF-7,11 4-substituted methoxybenzoyl-aryl-thiazoles
exhibited anti-proliferative activity of against melanoma and pros-
tate cancer cells from l
M to nM range.12 Besides, thiazole and its
derivatives also showed other biological activities in antimicrobial,5
antifungal,13 antifilarial,14 anti-inflammatory,15 antiviral,16 and so
on. Compounds containing naphthalene ring displayed potent bio-
activity in anti-arrhythmia,17 anti-tumor18 and antioxidant.19
Due to potent biological activities and low toxicities,20,21,4,22–25
we designed and synthesized a series of compounds containing
The title compounds were evaluated for their ability to inhibit
cell proliferation against Hela, BGC823 and HepG2 cell lines using
CCK8 assay. The results in Table 4 showed good anti-proliferative
activities on Hela cancer cell line (IC50 values between 0.86 and
12.35
l
M). Among them, compound 7d showed the most potent
M.
inhibiting activity with IC50 0.86
l
SAR studies were carried out to determine how compounds
affected the anti-proliferative activity. Firstly, compound 7d
⇑
Corresponding author. Tel.: +86 25 83592572; fax: +86 25 83592672.
(IC50 = 0.86
lM) with two -CH3 in A-ring displayed stronger
anti-proliferative activity than those with one -OCH3 (5d,
These authors contributed equally to this work.
0960-894X/Ó 2014 Elsevier Ltd. All rights reserved.