新型 2H-苯并[b][1,4]恶嗪-3(4H)-酮和 2H-苯并[b][1,4]恶嗪骨架衍生物作为 PI3Kα 抑制剂的设计、合成与生物评价。
Design, synthesis and biological evaluation of novel series of 2H-benzo[b][1,4]oxazin-3(4H)-one and 2H-benzo[b][1,4]oxazine scaffold derivatives as PI3Kα inhibitors.
机构信息
Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China; School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, China.
Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
出版信息
Bioorg Med Chem. 2018 Aug 7;26(14):3982-3991. doi: 10.1016/j.bmc.2018.06.022. Epub 2018 Jun 18.
The abnormal activation of PI3K signaling pathway leads to the occurrence of various cancers. The PI3Kα is frequently mutated and overexpressed in many human cancers. Therefore, the PI3Kα was considered as a promising target in therapeutic treatment of cancer. In this study, two series of compounds containing 2H-benzo[b][1,4]oxazin-3(4H)-one and 2H-benzo[b][1,4]oxazine scaffold were synthesized and evaluated antiproliferative activities against three cancer cell lines, including HCT-116, MDA-MB-231 and SNU638. Compound 7f with the most potent antiproliferative activity was selected for further evaluation on normal cells and PI3K kinase. Studies indicated that compound 7f could decrease the phospho-Akt (T308) in a dose-dependent manner. Four key hydrogen bonding interactions were found in the docking of 7f with PI3K enzyme. All the results suggested that 7f was a potent PI3Kα inhibitor.
PI3K 信号通路的异常激活导致了各种癌症的发生。PI3Kα 在许多人类癌症中经常发生突变和过表达。因此，PI3Kα 被认为是癌症治疗的一个有前途的靶点。在这项研究中，合成了两个系列的含有 2H-苯并[b][1,4]恶嗪-3(4H)-酮和 2H-苯并[b][1,4]恶嗪骨架的化合物，并评估了它们对三种癌细胞系 HCT-116、MDA-MB-231 和 SNU638 的增殖活性。具有最强增殖活性的化合物 7f 被选择用于进一步评估正常细胞和 PI3K 激酶。研究表明，化合物 7f 可以剂量依赖性地降低磷酸化 Akt(T308)。在 7f 与 PI3K 酶的对接中发现了四个关键氢键相互作用。所有结果表明，7f 是一种有效的 PI3Kα 抑制剂。
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