Design, synthesis and biological evaluation of 1-Aryl-5-(4-arylpiperazine-1-carbonyl)-1H-tetrazols as novel microtubule destabilizers

• Main Authors: Chao Wang, Yuelin Li, Zi Liu, Zeyu Wang, Zihan Liu, Shuai Man, Yujing Zhang, Kai Bao, Yingliang Wu, Qi Guan, Daiying Zuo, Weige Zhang
• Format: Article
• Language: English
• Published: Taylor & Francis Group 2021-01-01
• Series: Journal of Enzyme Inhibition and Medicinal Chemistry
• Subjects: tetrazole; microwave; antiproliferative activity; microtubule destabilizer; molecular docking
• Online Access: http://dx.doi.org/10.1080/14756366.2020.1759582

A series of 1-aryl-5-(4-arylpiperazine-1-carbonyl)-1H-tetrazols as microtubule destabilizers were designed, synthesised and evaluated for anticancer activity. Based on bioisosterism, we introduced the tetrazole moiety containing the hydrogen-bond acceptors as B-ring of XRP44X analogues. The key intermediates ethyl 1-aryl-1H-tetrazole-5-carboxylates 10 can be simply and efficiently prepared via a microwave-assisted continuous operation process. Among the compounds synthesised, compound 6–31 showed noteworthy potency against SGC-7901, A549 and HeLa cell lines. In mechanism studies, compound 6–31 inhibited tubulin polymerisation and disorganised microtubule in SGC-7901 cells by binding to tubulin. Moreover, compound 6–31 arrested SGC-7901cells in G2/M phase. This study provided a new perspective for development of antitumor agents that target tubulin.