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

Bioorg Med Chem Lett. 2021 May 15:40:127968. doi: 10.1016/j.bmcl.2021.127968.

Ruiqiang Zhang ¹, Hualong Mo ¹, Yan-Yan Ma ², Deng-Gao Zhao ³, Kun Zhang ², Tingwen Zhang ¹, Xuecheng Chen ¹, Xi Zheng ¹

Affiliations

1 School of Biotechnology and Health Sciences, Wuyi University, Jiangmen 529020, China.
2 School of Biotechnology and Health Sciences, Wuyi University, Jiangmen 529020, China; International Healthcare Innovation Institute (Jiangmen), Jiangmen 529040, China.
3 School of Biotechnology and Health Sciences, Wuyi University, Jiangmen 529020, China; International Healthcare Innovation Institute (Jiangmen), Jiangmen 529040, China. Electronic address: zhaodenggao@wyu.edu.cn.

PMID: 33753264 DOI: 10.1016/j.bmcl.2021.127968

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.

Keywords

ABT751; Cytotoxicity; Oxazole; Structure–activity relationships; Tubulin polymerization.

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