Synthesis and structure–activity relationships of 5-phenyloxazole-2-carboxylic acid derivatives as novel inhibitors of tubulin polymerization

• Published in: Bioorganic & medicinal chemistry letters 2021-05, Vol.40, p.127968-127968, Article 127968
• Main Authors: Zhang, Ruiqiang, Mo, Hualong, Ma, Yan-Yan, Zhao, Deng-Gao, Zhang, Kun, Zhang, Tingwen, Chen, Xuecheng, Zheng, Xi
• Format: Article
• Language: English
• Subjects: ABT751; Cytotoxicity; Oxazole; Structure–activity relationships; Tubulin polymerization
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2021.127968

[Display omitted] A series of 5-phenyloxazole-2-carboxylic acid derivatives were synthesized, and their structure–activity relationships (SARs) were studied. N,5-diphenyloxazole-2-carboxamides 6, 7, and 9, which mimicked ABT751, showed improved cytotoxicity compared with ABT751. Compound 9 exhibited the highest antiproliferative activities against Hela A549, and HepG2 cancer cell lines, with IC50 values of 0.78, 1.08, and 1.27 μM, respectively. Furthermore, compound 9 showed selectivity for human cancer cells over normal cells, and this selectivity was greater than those of ABT751 and colchicine. Preliminary mechanism studies suggested that compound 9 inhibited tubulin polymerization and led to cell cycle arrest at G2/M phase. Molecular docking studies indicated that compound 9 bound to the colchicine binding site of tubulin. Our findings provided insights into useful SARs for further structural modification of inhibitors of tubulin polymerization.