2. Academic Validation
  3. Design, synthesis of combretastatin A-4 piperazine derivatives as potential antitumor agents by inhibiting tubulin polymerization and inducing autophagy in HCT116 cells

Design, synthesis of combretastatin A-4 piperazine derivatives as potential antitumor agents by inhibiting tubulin polymerization and inducing autophagy in HCT116 cells

  • Eur J Med Chem. 2024 Jun 5:272:116497. doi: 10.1016/j.ejmech.2024.116497.
Hangqi Zhang 1,  Ming Li 1,  Xueming Zhou 1,  Li Tang 1,  Guangying Chen 2,  Yongmin Zhang 3
Affiliations

Affiliations

  • 1 Key Laboratory of Tropical Medicinal Resource Chemistry of Ministry of Education and Key Laboratory of Tropical Medicinal Plant Chemistry of Hainan Province, College of Chemistry and Chemical Engineering, Hainan Normal University, Haikou, Hainan, 571158, China.
  • 2 Key Laboratory of Tropical Medicinal Resource Chemistry of Ministry of Education and Key Laboratory of Tropical Medicinal Plant Chemistry of Hainan Province, College of Chemistry and Chemical Engineering, Hainan Normal University, Haikou, Hainan, 571158, China. Electronic address: chgying123@163.com.
  • 3 Key Laboratory of Tropical Medicinal Resource Chemistry of Ministry of Education and Key Laboratory of Tropical Medicinal Plant Chemistry of Hainan Province, College of Chemistry and Chemical Engineering, Hainan Normal University, Haikou, Hainan, 571158, China; Sorbonne Université, CNRS, Institut Parisien de Chimie Moléculaire, UMR 8232, 4 Place Jussieu, 75005, Paris, France. Electronic address: yongmin.zhang@upmc.fr.
PMID: 38759453 DOI: 10.1016/j.ejmech.2024.116497
Abstract

A series of combretastatin A-4 (CA-4) derivatives were designed and synthesized, which contain stilbene core structure with different linker, predominantly piperazine derivatives. These compounds were evaluated for their cytotoxic activities against four Cancer cell lines, HCT116, A549, AGS, and SK-MES-1. Among them, compound 13 displayed the best effectiveness with IC50 values of 0.227 μM and 0.253 μM against HCT116 and A549 cells, respectively, showing low toxicity to normal cells. Mechanistic studies showed that 13 inhibited HCT116 proliferation via arresting cell cycle at the G2/M phase through disrupting the microtubule network and inducing Autophagy in HCT116 cells by regulating the expression levels of autophagy-related proteins. In addition, 13 displayed antiproliferative activities against A549 cells through blocking the cell cycle and inducing A549 cells Apoptosis. Because of the poor water solubility of 13, four carbohydrate conjugates were synthesized which exhibited better water solubility. Further investigations revealed that 13 showed positive effects in vivo Anticancer study with HCT116 xenograft models. These data suggest that 13 could be served as a promising lead compound for further development of anti-colon carcinoma agent.

Keywords

Antitumor; CA-4; Carbohydrate; Cell cycle; Piperazine derivatives; Synthesis.

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