2. Academic Validation
  3. Design, synthesis, and biological evaluation of diaryl heterocyclic derivatives targeting tubulin polymerization with potent anticancer activities

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.
Gang Li 1,  Jia-Qiang Wu 2,  Xiaojia Cai 2,  Wen Guan 1,  Zhijun Zeng 1,  Yanghui Ou 1,  Xiaoyun Wu 3,  Jiayu Li 1,  Xiangxiang Fang 1,  Jinling Liu 1,  Yali Zhang 1,  Huamin Wang 1,  Canqiang Yin 1,  Hongliang Yao 4
Affiliations

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: [email protected].
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 (T1/2 = 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.

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