嘧啶-5-甲腈类潜在抗癌药物通过抑制白血病 K562 中的 PI3K/AKT 轴诱导细胞凋亡。

Pyrimidine-5-carbonitrile based potential anticancer agents as apoptosis inducers through PI3K/AKT axis inhibition in leukaemia K562.

机构信息

Pharmaceutical Chemistry Department, College of Pharmaceutical Sciences and Drug Manufacturing, Misr University for Science and Technology, 6th of October City, Egypt.

Pharmaceutical Chemistry Department, Faculty of Pharmacy, Heliopolis University, Cairo, Egypt.

出版信息

J Enzyme Inhib Med Chem. 2022 Dec;37(1):895-911. doi: 10.1080/14756366.2022.2051022.

A novel series of 4-(4-Methoxyphenyl)-2-(methylthio)pyrimidine-5-carbonitrile was developed linked to an aromatic moiety -containing bridge and then evaluated for their cytotoxic activity against MCF-7 and K562 cell lines. Seven compounds exhibited the highest activity against both cell lines where compounds and were the most active against K562 cell line. Exploring their molecular mechanisms by enzyme inhibition assay on PI3Kδ/γ and AKT-1 showed that compound was promising more than with IC = 6.99 ± 0.36, 4.01 ± 0.55, and 3.36 ± 0.17 uM, respectively. Also, flowcytometric analysis revealed that caused cell cycle arrest at S-phase followed by caspase 3 dependent apoptosis induction. Mechanistically, compound proved to modulate the expression of PI3K, p-PI3K, AKT, p-AKT, Cyclin D1, and NFΚβ. Furthermore, toxicity study indicated good safety profile for . These findings suggest that the trimethoxy derivative has strong potential as a multi-acting inhibitor on PI3K/AKT axis targeting breast cancer and leukaemia.

开发了一系列新型的 4-(4-甲氧基苯基)-2-(甲硫基)嘧啶-5-甲腈，它们与含芳基部分的桥连接在一起，然后评估其对 MCF-7 和 K562 细胞系的细胞毒性活性。七种化合物对两种细胞系均表现出最高的活性，其中化合物和对 K562 细胞系的活性最高。通过对 PI3Kδ/γ 和 AKT-1 的酶抑制测定来探索其分子机制表明，化合物比更有前途，其 IC = 6.99 ± 0.36、4.01 ± 0.55 和 3.36 ± 0.17 μM。此外，流式细胞术分析显示导致细胞周期在 S 期停滞，随后 caspase 3 依赖性凋亡诱导。在机制上，化合物被证明可以调节 PI3K、p-PI3K、AKT、p-AKT、Cyclin D1 和 NFΚβ 的表达。此外，毒性研究表明具有良好的安全性。这些发现表明，三甲氧基衍生物具有作为针对乳腺癌和白血病的 PI3K/AKT 轴的多作用抑制剂的强大潜力。