采用分子叠加法，设计并合成了具有预期细胞毒性和CDK2抑制潜力的三组新的噻唑二氮杂环并嘧啶衍生物。这是首次通过嘧啶与噻唑环的杂联实现的。对所得的噻唑二氮杂环并嘧啶衍生物进行了对肝癌细胞HepG2、乳腺癌细胞MCF-7、前列腺癌细胞PC-3以及正常细胞WI38的细胞毒性评估。在所研究的化合物中，3b和3c对肿瘤细胞表现出显著的抗增殖活性，IC50范围为5.52-17.09µM，相比于Roscovitine（9.32-13.82µM）。此外，这两种化合物在对癌细胞的选择性指数（SI = 3.00-7.15）方面表现出更好的效果。其中，4-氯苯基类似物3b表现出最佳的选择性指数，因此进一步研究了其正确的机制作用。相应地，评估了MCF-7细胞系中该类似物的CDK2抑制潜力、诱导凋亡能力和细胞周期分析。结果显示该类似物具有强效的CDK2抑制潜力，IC50值为0.219µM。研究还显示，3b被认为能够在S期阻滞MCF-7细胞周期，并通过增加Bax、Caspase-8和Caspase-9标志物的表达，同时伴随着Bcl-2表达的下降来诱导细胞凋亡。此外，还通过分子对接研究了3b可能与CDK2结合位点的相互作用。版权所有©2023 Elsevier Inc.。保留所有权利。

Adopting the molecular overlay approach, three novel sets of thiazepinopurines with expected cytotoxicity and CDK2 inhibition potential were designed and synthesized. This was accomplished through the heteroannelation of purines, for the first time, with thiazepine. The obtained thiazepinopurines derivatives were assessed for their cytotoxicity toward tumor cells of three different types, HepG2, MCF-7, and PC-3 as well as one normal cell (WI38). Among the studied compounds, 3b and 3c exhibited significant antiproliferative activity against tumor cells presenting IC50 range of 5.52-17.09 µM in comparison with Roscovitine (9.32-13.82 µM). Additionally, both compounds displayed superior selectivity indices (SI = 3.00-7.15) toward tested cancer cells. The 4-chlorophenyl analog 3b has shown the best selectivity index, and hence it has been subjected to additional investigations to determine its proper mechanistic effect. Accordingly, the CDK2 inhibition potential, apoptosis induction, and cell cycle analysis of MCF-7 were evaluated. Results revealed that this analog displayed a potent CDK2 inhibition potential with an IC50 value of 0.219 µM. Findings also showed that 3b was thought to arrest MCF-7 cell cycle at S phase together with apoptosis induction by the increased expression of Bax, Caspase-8, and -9 markers with a concomitant decrease in Bcl-2 expression. Besides, the probable interaction of 3b with CDK2 binding pocket was investigated by molecular docking.Copyright © 2023 Elsevier Inc. All rights reserved.