Discovery of 6-aryl-2-(3,4,5-trimethoxyphenyl)thiazole[3,2-b][1,2,4]triazoles as potent tubulin polymerization inhibitors

Tubulin/colchicine-binding site inhibitors (CBSIs) co-crystal structures play an important role in the exploration of novel small molecules for oncotherapy. Based on the analysis of the binding models of tubulin and reported CBSIs, a series of 6-aryl-2-(3,4,5-trimethoxyphenyl)thiazole[3,2-b][1,2,4]triazoles were designed as potential tubulin polymerization inhibitors by binding to distinct colchicine domain of tubulin. Among the compounds synthesized, 7w not only shown noteworthy potency against SGC-7901 cancer cell line (IC50 = 0.21 μM) but also exhibited lower cytotoxicity than colchicine in normal cell line (HUVEC). The mechanism studies elucidated that 7w could cause the apoptosis of cancer cells by inhibiting tubulin polymerization to trigger G2/M arrest. In 4T1-xenograft mice model, 7w significantly inhibited tumor growth without losing weight, demonstrating a promising potential for further development with a unique binding mode at the colchicine-binding site. [Display omitted] •SBDD was employed to design novel CBSIs bearing thiazole[3,2-b][1,2,4]triazole.•7w showed noteworthy potency against SGC-7901 cancer cell line (IC50 = 0.21 μM).•7w displayed potent anti-tubulin activity and caused cells arrest in G2/M phase.•7w possessed remarkable in vivo antitumor efficacy.