Combinations of apoptotic inducers are common clinical practice in breast cancer. However, their efficacy is limited by the heterogeneous pharmacokinetic profiles. An advantageous alternative is merging their molecular entities in hybrid multitargeted scaffolds exhibiting synergistic activities and uniform distribution. Herein, we report apoptotic inducers simultaneously targeting DNA and CDK-2 (cyclin-dependent kinase-2) inspired by studies revealing that CDK-2 inhibition sensitizes breast cancer to DNA-damaging agents. Accordingly, rationally substituted pyrimidines and triazolopyrimidines were synthesized and assayed by MTT against MCF-7, MDA-MB231, and Wi-38 cells compared to doxorubicin. The N-(4-amino-2-((2-hydrazinyl-2-oxoethyl)thio)-6-oxo-1,6-dihydropyrimidin-5-yl)acetamide 5 and its p-nitrophenylhydrazone 8 were the study hits against MCF-7 (IC₅₀ = 0.050 and 0.146 μM) and MDA-MB231 (IC₅₀ = 0.826 and 0.583 μM), induced DNA damage at 10.64 and 30.03 nM, and inhibited CDK-2 (IC₅₀ = 0.172 and 0.189 μM). 5 induced MCF-7 apoptosis by 46.75% and disrupted cell cycle during S phase. Docking and MD simulations postulated their stable key interactions.

中文翻译：

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新型嘧啶酮和 1,2,4-三唑并[4,3-a]嘧啶酮衍生物通过周期蛋白依赖性激酶抑制和 DNA 损伤触发乳腺癌细胞凋亡

细胞凋亡诱导剂的组合是乳腺癌的常见临床实践。然而，它们的功效受到异质药代动力学特征的限制。一种有利的替代方案是将它们的分子实体合并在混合多靶点支架中，表现出协同活性和均匀分布。在此，我们报告了同时靶向 DNA 和 CDK-2（细胞周期蛋白依赖性激酶 2）的细胞凋亡诱导剂，其灵感来自于研究表明 CDK-2 抑制使乳腺癌对 DNA 损伤剂敏感。因此，合成了合理取代的嘧啶和三唑并嘧啶，并通过 MTT 对 MCF-7、MDA-MB231 和 Wi-38 细胞进行了检测，与阿霉素进行了比较。 N - (4-氨基-2-((2-肼基-2-氧代乙基)硫基)-6-氧代-1,6-二氢嘧啶-5-基)乙酰胺5及其对硝基苯腙8是研究的目标MCF-7（IC ₅₀ = 0.050 和 0.146 μM）和 MDA-MB231（IC ₅₀ = 0.826 和 0.583 μM）在 10.64 和 30.03 nM 时诱导 DNA 损伤，并抑制 CDK-2（IC ₅₀ = 0.172 和 0.189 μM）。5诱导MCF-7细胞凋亡46.75%，并扰乱S期细胞周期。对接和 MD 模拟假设了它们稳定的关键相互作用。