Design, synthesis, and biological evaluation of diaryl heterocyclic derivatives targeting tubulin polymerization with potent anticancer activities

Gang Li; Jia-Qiang Wu; Xiaojia Cai; Wen Guan; Zhijun Zeng; Yanghui Ou; Xiaoyun Wu; Jiayu Li; Xiangxiang Fang; Jinling Liu; Yali Zhang; Huamin Wang; Canqiang Yin; Hongliang Yao

doi:10.1016/j.ejmech.2023.115284

Design, synthesis, and biological evaluation of diaryl heterocyclic derivatives targeting tubulin polymerization with potent anticancer activities

Eur J Med Chem. 2023 Apr 5:252:115284. doi: 10.1016/j.ejmech.2023.115284. Epub 2023 Mar 16.

Authors

Gang Li¹, Jia-Qiang Wu², Xiaojia Cai², Wen Guan¹, Zhijun Zeng¹, Yanghui Ou¹, Xiaoyun Wu³, Jiayu Li¹, Xiangxiang Fang¹, Jinling Liu¹, Yali Zhang¹, Huamin Wang¹, Canqiang Yin¹, Hongliang Yao⁴

Affiliations

¹ Guangdong Key Laboratory of Animal Conservation and Resource Utilization, Guangdong Public Laboratory of Wild Animal Conservation and Utilization, Institute of Zoology, Guangdong Academy of Sciences, Guangzhou, Guangdong, 510260, China.
² School of Biotechnology and Health Sciences, Wuyi University, 22 Dongchengcun, Jiangmen, 529020, China.
³ School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China.
⁴ Guangdong Key Laboratory of Animal Conservation and Resource Utilization, Guangdong Public Laboratory of Wild Animal Conservation and Utilization, Institute of Zoology, Guangdong Academy of Sciences, Guangzhou, Guangdong, 510260, China. Electronic address: yaohl@giabr.gd.cn.

PMID: 36940610
DOI: 10.1016/j.ejmech.2023.115284

Abstract

A series of diaryl heterocyclic analogues were designed and synthesized as tubulin polymerization inhibitors. Among them, compound 6y showed the highest antiproliferative activity against HCT-116 colon cancer cell line with an IC₅₀ values of 2.65 μM. Compound 6y also effectively inhibited tubulin polymerization in vitro (IC₅₀ of 10.9 μM), and induced HCT-116 cell cycle arrest in G2/M phase. In addition, compound 6y exhibited high metabolic stability on human liver microsomes (T_1/2 = 106.2 min). Finally, 6y was also effective in suppressing tumor growth in a HCT-116 mouse colon model without apparent toxicity. Collectively, these results suggest that 6y represents a new class of tubulin inhibitors deserving further investigation.

Keywords: Antitumor; CA-4; Colchicine binding site; Tubulin inhibitors.

MeSH terms

Animals
Antineoplastic Agents* / pharmacology
Cell Line, Tumor
Cell Proliferation
Drug Screening Assays, Antitumor
Humans
Mice
Molecular Structure
Polymerization
Structure-Activity Relationship
Tubulin Modulators / pharmacology
Tubulin* / metabolism

Substances

Tubulin
Tubulin Modulators
Antineoplastic Agents