Synthesis and Biological Evaluation of 3-Alkyl-1,5-Diaryl-1H-Pyrazoles as Rigid Analogues of Combretastatin A-4 with Potent Antiproliferative Activity

被引：21

作者：

Xu, Qile ^{[1
]}

Qi, Huan ^{[2
]}

Sun, Maolin ^{[1
]}

Zuo, Daiying ^{[2
]}

Jiang, Xuewei ^{[2
]}

Wen, Zhiyong ^{[1
]}

Wang, Zhiwei ^{[1
]}

Wu, Yingliang ^{[2
]}

Zhang, Weige ^{[1
]}

机构：

[1] Shenyang Pharmaceut Univ, Minist Educ, Dept Key Lab Struct Based Drug Design & Discovery, Shenyang, Peoples R China

[2] Shenyang Pharmaceut Univ, Dept Pharmacol, Shenyang, Peoples R China

来源：

PLOS ONE | 2015年 / 10卷 / 06期

基金：

中国国家自然科学基金;

关键词：

ANTINEOPLASTIC AGENTS; PYRAZOLE DERIVATIVES; INHIBITORS; ANTITUMOR; CYTOTOXICITY; WATER; A4;

D O I：

10.1371/journal.pone.0128710

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

A series of novel 3-alkyl-1,5-diaryl-1H-pyrazoles were synthesized as combretastatin A-4 (CA-4) analogues and evaluated for antiproliferative activity against three human cancer cell lines (SGC-7901, A549 and HT-1080). Most of the target compounds displayed moderate to potent antiproliferative activity, and 7k was found to be the most potent compound. Structure-activity relationships indicated that compounds with a trimethoxyphenyl A-ring at the N-1 position of the pyrazole skeleton were more potent than those with the A-ring at the C-5 position. Tubulin polymerization and immunostaining experiments revealed that 7k potently inhibited tubulin polymerization and disrupted tubulin microtubule dynamics in a manner similar to CA-4. Computational modelling demonstrated that the binding of 7k to the colchicine binding site on microtubules may involve a similar mode as CA-4.

引用

页数：18

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