Bioorganic & Medicinal Chemistry Letters
Synthesis, in vitro and in vivo evaluation of novel substituted
N-(4-(2-(4-benzylpiperazin-1-yl)ethoxy)phenyl)-N-methyl-
quinazolin-4-amines as potent antitumor agents
Dong Cao a,y, Xiaoyan Wang a,y, Lei Lei a,y, Liang Ma b, Fang Wang a, Chunyu Wang a, Minghai Tang a,
Wei Xiang a, Taijin Wang a, Hongyang Li a, Lijuan Chen a,
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a State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center of Biotherapy, Chengdu 610041, China
b Division of Nephrology, Kidney Research Institute, West China Hospital of Sichuan University, Chengdu 610041, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A
novel series of substituted N-(4-(2-(4-benzylpiperazin-1-yl)ethoxy)phenyl)-N-methylquinazolin-
4-amines were synthesized and evaluated for their in vitro antiproliferative activity. Among them, com-
pound 7a exhibited the best potency, with IC50 values of 0.029–0.147 M against four types of cancer cell
Received 11 December 2015
Revised 23 February 2016
Accepted 7 March 2016
Available online 7 March 2016
l
lines. In addition, 7a was confirmed that it could arrest the cell cycle at G2/M phase and trigger apoptosis.
Indirect immunofluorescence staining revealed its anti-tubulin property. Importantly, 7a significantly
inhibited tumor growths in HepG2 xenograft models without causing significant loss of body weight,
suggesting that 7a is a promising new anticancer agent to be developed.
Keywords:
4-Anilinoquinazoline derivatives
Anti-proliferation
G2/M arrest
Ó 2016 Elsevier Ltd. All rights reserved.
Chemotherapy agents,1 including paclitaxel and docetaxel, play
a predominant role in the treatment of human cancer, which is
one of the most complicated and capricious diseases.2,3 They are
clinically used to eliminate the remaining tumor population after
surgery, or to cure patients when metastatic diseases were
diagnosed. However, their narrow therapeutic windows and the
emergence of drug resistance have encouraged continued efforts
to find safer and more effective agents capable of treating resistant
cancer phenotypes.4,5
azin-1-yl)ethoxy)phenyl)-N-methylquinazolin-4-amines were
synthesized and evaluated for their cytotoxicity. Among these
compounds, compound 7a exhibited the most potent inhibitory
effect on the proliferation of HepG2, A549, MCF-7, and SW620 cells
(IC50 = 0.029, 0.147, 0.099, and 0.052 lM, respectively). In addition,
7a was confirmed that it could arrest the cell cycle at G2/M phase
and trigger apoptosis. Indirect immunofluorescence staining
revealed its anti-tubulin property. Importantly, 7a significantly
inhibited tumor growths in HepG2 xenograft models without
causing significant loss of body weight, suggesting that 7a is a
promising new anticancer agent to be developed.
4-Anilinoquinazoline derivatives 7a–k were prepared by the
synthesis route outlined in Scheme 1. 2,4-Dichloroquinazoline 1a
and 4-(methylamino) phenol 2 in isopropanol with a little drop
of concentrated HCl were stirred at room temperature to give 3a
in moderate yield.24 3b was obtained by conducting the same pro-
cedure. N-(2-Hydroxyethyl)piperazine 4, 2-fluorobenzyl bromide
5a and potassium carbonate in toluene were refluxed for 4 h, then
mixture was filtrate and the organic phase was treated with freshly
distilled thionyl chloride to obtain 6a in moderate yield. Com-
pounds 6b–g were obtained by conducting the same procedure.
3a and 6a were heated with cesium carbonate in acetonitrile to
produce compound 7a in moderate yield. The absolute configura-
tion of 7a was determined by X-ray analysis.25 Compounds 7a–k
were obtained by conducting the same procedure.
The early discovery of the anticancer agents erlotinib6 and
gefitinib7 prompted intensive research on 4-anilinoquinazoline
compounds,8 leading to the development of new attractive
compounds such as lapatinib,9 vandetanib,10 and afatinib11
(Fig. 1). These therapeutic molecules include the tyrosine kinase
inhibitors,12 b-catenin/Tcf4 inhibitors,13 G9a inhibitors,14 and the
like. Among them, verubulin (MPC-6827) was reported as a potent
apoptosis inducer (Fig. 1). Its corresponding hydrochloride salt is
water-soluble and currently showing promising results in phase
II human cancer clinical trials.15–23
The success of previous research base on 4-anilinoquinazoline
scaffold encouraged us to search for more potential drug candi-
dates. In this paper, a series of substituted N-(4-(2-(4-benzylpiper-
⇑
Corresponding author. Tel.: +86 28 85164063; fax: +86 28 85164060.
These authors contributed equally to this work.
y
0960-894X/Ó 2016 Elsevier Ltd. All rights reserved.