2. Academic Validation
  3. Synthesis and bioevaluation of diarylpyrazoles as antiproliferative agents

Synthesis and bioevaluation of diarylpyrazoles as antiproliferative agents

  • Eur J Med Chem. 2019 Jun 1:171:1-10. doi: 10.1016/j.ejmech.2019.02.049.
Chao Wang 1,  Shuang Yang 1,  Jianan Du 2,  Jia Ni 1,  Yue Wu 1,  Junfang Wang 2,  Qi Guan 1,  Daiying Zuo 3,  Kai Bao 4,  Yingliang Wu 2,  Weige Zhang 5
Affiliations

Affiliations

  • 1 Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, China.
  • 2 Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, China.
  • 3 Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, China. Electronic address: zuodaiying@163.com.
  • 4 Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, China. Electronic address: baokai@syphu.edu.cn.
  • 5 Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, China. Electronic address: zhangweige2000@sina.com.
PMID: 30901597 DOI: 10.1016/j.ejmech.2019.02.049
Abstract

Two series of diarylpyrazoles were designed as potential microtubule targeting agents. Twenty-eight target compounds were synthesized and exhibited potent antiproliferative activity. Compound 15e, displayed potent antiproliferative activity against SGC-7901, KB and HT-1080 cell lines, respectively, and was comparable to the positive control, CA-4. Tubulin polymerization experiments indicated that 15e effectively inhibited the tubulin polymerization, and immunostaining assay revealed that it significantly disrupted tubulin microtubule dynamics. Moreover, cell cycle studies revealed that compound 15e dramatically arrested cell cycle progression at G2/M phase and caused microtubule destabilization. Molecular modeling studies showed that 15e could bind to the colchicine binding site on microtubules.

Keywords

CA-4; Colchicine binding site; Pyrazole; Tubulin.

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