Synthesis and structure–activity relationships of 5-phenyloxazole-2-carboxylic acid derivatives as novel inhibitors of tubulin polymerization. (15th May 2021)

• Record Type: Journal Article
• Authors: Zhang, Ruiqiang; Mo, Hualong; Ma, Yan-Yan; Zhao, Deng-Gao; Zhang, Kun; Zhang, Tingwen; Chen, Xuecheng; Zheng, Xi
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 40(2021)
• Publication Date: 2021-05-15
• Subjects: Oxazole -- Tubulin polymerization -- Structure–activity relationships -- Cytotoxicity -- ABT751; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2021.127968
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: 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.