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

• Published in: European journal of medicinal chemistry Vol. 267; p. 116177
• Main Authors: Yang, Yang, Cao, Yan, Yu, Jingwen, Yu, Xinyu, Guo, Yali, Wang, Fei, Ren, Qingjia, Li, Caolong
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 05.03.2024; Elsevier
• Subjects: 3-Amino-5-phenylpyrazole derivatives; Antiproliferative activity; Antitumor; Chemistry, Medicinal; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Science & Technology; Tubulin colchicine-binding site; Tubulin colchicine-binding site; Antiproliferative activity; 3-Amino-5-phenylpyrazole derivatives; Antitumor; CANCER-CELLS; MICROTUBULES; PACLITAXEL RESISTANCE; DRUGS; BIOLOGICAL EVALUATION; AGENTS; III BETA-TUBULIN; MOLECULAR-MECHANISMS
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2024.116177

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. [Display omitted] •The synthesis of a novel derivative of 3-amino-5-phenylpyrazole.•The compounds were designed and synthesized as potential inhibitors for tubulin polymerization.•Compound 5b exhibited potent against tumor growth in MCF-7 xenograft models.