Design synthesis and structure-activity relationship of 36-diaryl-7H-124triazolo34-b134thiadiazines as novel tubulin inhibitors

摘要

A novel series of 3,6-diaryl-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines were designed, synthesized and biologically evaluated as vinylogous CA-4 analogues, which involved a rigid [1,2,4]triazolo[3,4-b][1,3,4]thiadiazine scaffold to fix the configuration of (Z,E)-butadiene linker of A-ring and B-ring. Among these rigidly vinylogous CA-4 analogues, compounds >4d, >5b, >5i, >6c, >6e, >6g, >6i and >6k showed excellent antiproliferative activities against SGC-7901, A549 and HT-1080 cell lines with IC50 values at the nanomolar level. Compound >6i showed the most highly active antiproliferative activity against the three human cancer cell lines with an IC50 values of 0.011–0.015 µM, which are comparable to those of CA-4 (IC50 = 0.009–0.013 µM). Interestingly, SAR studies revealed that 3,4-methylenedioxyphenyl, 3,4-dimethoxyphenyl, 3-methoxyphenyl and 4-methoxyphenyl could replace the classic 3,4,5-trimethoxyphenyl in CA-4 structure and keep antiproliferative activity in this series of designed compounds. Tubulin polymerization experiments showed that >6i could effectively inhibit tubulin polymerization, which was corresponded with CA-4, and immunostaining experiments suggested that >6i significantly disrupted microtubule/tubulin dynamics. Furthermore, >6i potently induced cell cycle arrest at G2/M phase in SGC-7901 cells. Competitive binding assays and docking studies suggested that compound >6i binds to the tubulin perfectly at the colchicine binding site. Taken together, these results revealed that >6i may become a promising lead compound for new anticancer drugs discovery.