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

Qile Xu; Huan Qi; Maolin Sun; Daiying Zuo; Xuewei Jiang; Zhiyong Wen; Zhiwei Wang; Yingliang Wu; Weige Zhang

doi:10.1371/journal.pone.0128710

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

PLoS One. 2015 Jun 10;10(6):e0128710. doi: 10.1371/journal.pone.0128710. eCollection 2015.

Authors

Qile Xu¹, Huan Qi², Maolin Sun¹, Daiying Zuo², Xuewei Jiang², Zhiyong Wen¹, Zhiwei Wang¹, Yingliang Wu², Weige Zhang¹

Affiliations

¹ Department Key Laboratory of Structure-Based Drug Design and Discovery Ministry of Education, Shenyang Pharmaceutical University, Shenyang, China.
² Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, China.

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell Line, Tumor
Cell Proliferation / drug effects*
Humans
Models, Molecular
Pyrazoles / chemical synthesis*
Pyrazoles / pharmacology*
Stilbenes / chemical synthesis
Stilbenes / chemistry*
Stilbenes / pharmacology

Substances

Pyrazoles
Stilbenes
fosbretabulin

Grants and funding

This work was supported by the Programme for Innovative Research Team of the Ministry of Education and the Programme for Liaoning Innovative Research Team in University, the National Science and Technology Major Project of the Ministry of Science and Technology of China (1.2012ZX09103101-060, http://www.nmp.gov.cn/zxjs/ WZ, YW), and the National Natural Science Foundation of China (2.30973614,http://www.nsfc.gov.cn/ WZ). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.