2. Academic Validation
  3. Design and synthesis of novel 3-amino-5-phenylpyrazole derivatives as tubulin polymerization inhibitors targeting the colchicine-binding site

Design and synthesis of novel 3-amino-5-phenylpyrazole derivatives as tubulin polymerization inhibitors targeting the colchicine-binding site

  • Eur J Med Chem. 2024 Mar 5:267:116177. doi: 10.1016/j.ejmech.2024.116177.
Yang Yang 1,  Yan Cao 2,  Jingwen Yu 2,  Xinyu Yu 2,  Yali Guo 2,  Fei Wang 2,  Qingjia Ren 3,  Caolong Li 4
Affiliations

Affiliations

  • 1 Key Laboratory of Biomedical Functional Materials, School of Science, China Pharmaceutical University, Nanjing, 211198, PR China; Department of Trauma Center, Affiliated Hospital of Nantong University, No.20 Xisi Road, Chongchuan District, Nantong City, Jiangsu Province, 226001, PR China.
  • 2 Key Laboratory of Biomedical Functional Materials, School of Science, China Pharmaceutical University, Nanjing, 211198, PR China.
  • 3 Tibetan Medicine Research Institute, Tibetan Traditional Medical College, Tibet, 850000, PR China. Electronic address: renchen2100@qq.com.
  • 4 Key Laboratory of Biomedical Functional Materials, School of Science, China Pharmaceutical University, Nanjing, 211198, PR China. Electronic address: licl@cpu.edu.cn.
PMID: 38280356 DOI: 10.1016/j.ejmech.2024.116177
Abstract

As the basic unit of microtubules, tubulin is one of the most important targets in the study of anticarcinogens. A novel series of 3-amino-5-phenylpyrazole derivatives were designed and synthesized, and evaluates for their biological activities. Among them, a majority of compounds exerted excellent inhibitory activities against five Cancer cell lines in vitro. Especially, compound 5b showed a strong antiproliferative activity against MCF-7 cells, with IC50 value of 38.37 nM. Further research indicated that compound 5b can inhibit the polymerization of tubulin targeting the tubulin colchicine-binding sites. Furthermore, 5b could arrest MCF-7 cells at the G2/M phase and induce MCF-7 cells apoptotic in a dose-dependent and time-dependent manners, and regulate the level of related proteins expression. Besides, compound 5b could inhibit the Cancer cell migration and angiogenesis. In addition, 5b could inhibit tumor growth in MCF-7 xenograft model without obvious toxicity. All these results indicating that 5b could be a promising antitumor agent targeting tubulin colchicine-binding site and it was worth further study.

Keywords

3-Amino-5-phenylpyrazole derivatives; Antiproliferative activity; Antitumor; Tubulin colchicine-binding site.

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