通过化学选择性还原C=N键,已成功实现了一系列新的5-取代/未取代的[1,2,4]三唑并[3,4-b][1,3,4]噻二嗪化合物,根据我们之前的工作。最初的生物学评估表明,最具活性的衍生物7j对MCF-7,A549,HCT116和A2780表现出明显的细胞生长抑制活性,IC50值为0.75,0.94,2.90和4.15μM。分别。最重要的是,所有代表性类似物均未显示针对非肿瘤细胞系HEK-293的明显细胞毒活性(IC50>100μM)。机制研究表明,7j引起G2/M期停滞,以浓度依赖的方式诱导HeLa细胞凋亡,并显示出有效的微管蛋白聚合抑制作用。同时,7j在伤口愈合和管形成测定中发挥了显着的抗血管活性。这些观察结果表明,5-未取代的6,7-二氢-5H-[1,2,4]三唑并[3,4-b][1,3,4]噻二嗪支架可能被认为是抗微管蛋白抑制剂开发高效抗癌剂的潜在线索,其对正常人细胞具有有效的选择性。
A novel series of 5-substituted/unsubstituted [1,2,4]triazolo[3,4-b][1,3,4] thiadiazine compounds has been achieved successfully through chemoselective reduction of the C = N bond, based on our prior work. Initial biological evaluation illustrated that the most active derivative 7j exhibited significant cell growth inhibitory activity toward MCF-7, A549, HCT116, and A2780 with the IC50 values of 0.75, 0.94, 2.90, and 4.15 μM, respectively. Most importantly, all the representative analogs did not demonstrate obvious cytotoxic activity against the non-tumoural cell line HEK-293 (IC50 > 100 μM). The mechanism study revealed that 7j caused the G2 /M phase arrest, induced cell apoptosis in HeLa cells in a concentration-dependent manner, and also showed potent tubulin polymerization inhibitory effect. Meanwhile, 7j exerted significant antivascular activity in the wound-healing and tube formation assays. These observations indicate that 5-unsubstituted 6,7-dihydro-5H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine scaffold might be considered as a potential lead for antitubulin inhibitors to develop highly efficient anticancer agents with potent selectivity over normal human cells.