A series of novel anticancer hydrazinotriazolothiadiazine-based derivatives were designed based on the structure–activity relationship of the previously reported anticancer triazolothiadiazines. These derivatives were synthesized and biologically screened against full NCI-60 cancer cell lines revealing compound 5l with a potential antiproliferative effect. 5l was screened over 16 kinases to study its cytotoxic mechanism which showed to inhibit glycogen synthase kinase-3 β (GSK-3β) with IC₅₀ equal to 0.883 μM and 14-fold selectivity over CDK2. Also, 5l increased active caspase-3 levels, induced cell cycle arrest at the G2-M phase, and increased the percentage of Annexin V-fluorescein isothiocyanate-positive apoptotic cells in PC-3 prostate cancer-treated cells. Molecular docking and dynamics were performed to predict the binding mode of 5l in the GSK-3β ATP binding site. 5l can be utilized as a starting scaffold for developing potential GSK-3β inhibitors.

中文翻译：

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新型7H- [1,2,4]三唑并[3,4-b] [1,3,4]噻二嗪抑制剂的设计，合成及生物学评价。

基于以前报道的抗癌三唑并噻二嗪的结构-活性关系，设计了一系列基于肼基三唑并噻二嗪的新型抗癌衍生物。合成了这些衍生物，并针对完整的NCI-60癌细胞系进行了生物学筛选，揭示了具有潜在抗增殖作用的化合物5l。筛选了16种激酶中的5l来研究其细胞毒性机制，该机制显示抑制糖原合酶激酶3β（GSK-3β）的IC ₅₀等于0.883μM，选择性是CDK2的14倍。还有5公升在PC-3前列腺癌治疗的细胞中，增加了活跃的caspase-3水平，诱导了细胞周期阻滞在G2-M期，并增加了膜联蛋白V-异硫氰酸荧光素-异硫氰酸酯阳性细胞的百分比。进行分子对接和动力学以预测5l在GSK-3βATP结合位点的结合模式。5l可用作开发潜在的GSK-3β抑制剂的起始支架。