Building on our prior research, a novel series of trimethoxyphenoxymethyl- and trimethoxybenzyl-substituted triazolothiadiazine compounds has been designed and achieved successfully via a direct ring-closing strategy. Initial biological evaluation illustrated that the most active derivative B₅ exhibited significant cell growth inhibitory activity toward HeLa, HT-29, and A549 giving the IC₅₀ values of 0.046, 0.57, and 0.96 μM, respectively, which are greater or similar with CA-4. The mechanism study revealed that B₅ 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, B₅ exerted significant antivascular activity in the wound-healing and tube formation assays. Most importantly, B₅ remarkably inhibited tumor growth without obvious signs of toxicity in A549-xenograft mice model. These observations indicate that 6-p-tolyl-3-(3,4,5-trimethoxybenzyl)-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine might be considered as the potential lead compound to develop highly efficient anticancer agents with potent selectivity over normal human cells.

在我们之前的研究的基础上，通过直接闭环策略设计并成功实现了一系列新型三甲氧基苯氧基甲基和三甲氧基苄基取代的三唑并噻二嗪化合物。初步生物学评估表明，最活跃的衍生物B ₅对 HeLa、HT-29 和 A549 表现出显着的细胞生长抑制活性，IC ₅₀值分别为 0.046、0.57 和 0.96 μM，这与 CA- 4. 机制研究表明，B ₅引起G ₂ /M期阻滞，以浓度依赖性方式诱导HeLa细胞凋亡，并显示出有效的微管蛋白聚合抑制作用。同时，乙₅在伤口愈合和管形成测定中发挥了显着的抗血管活性。最重要的是， B ₅在A549-异种移植小鼠模型中显着抑制肿瘤生长而没有明显的毒性迹象。这些观察结果表明 6-p-tolyl-3-(3,4,5-trimethoxybenzyl)-7 H -[1,2,4]triazolo[3,4- b ][1,3,4]thiadiazine 可能是被认为是开发对正常人体细胞具有强选择性的高效抗癌剂的潜在先导化合物。