Design, synthesis and biological evaluation of novel chromeno[4,3-c] pyrazol-4(2H)-one derivates containing sulfonamido as potential PI3K alpha inhibitors
Design, synthesis and biological evaluation of novel chromeno[4,3-c] pyrazol-4(2H)-one derivates containing sulfonamido as potential PI3K alpha inhibitors
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作为潜在 PI3K α 抑制剂的新型含磺酰胺基苯并[4,3-c]吡唑-4(2H)-一衍生物的设计、合成和生物学评价
DOI：
10.1016/j.bmc.2019.04.021
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发表时间：
2019
影响因子：
3.5
通讯作者：
Zhu Hai Liang
中科院分区：
文献类型：
--
作者：
Yin Yong;Hu Jia Qin;Wu Xu;Sha Shao;Wang She Feng;Qiao Fang;Song Zhong Cheng;Zhu Hai Liang
设计合成了一系列新型磺胺类[4,3-c]吡唑-4(2H)- 1衍生物，并对其体外抗癌效果进行了评价，以期开发出新的PI3Kα抑制剂。大多数化合物对4种肿瘤细胞系的抗增殖活性均优于LY294002。其中，化合物40对PI3Kα蛋白具有较强的抗增殖活性和高选择性，并能诱导HCT116细胞凋亡，且呈剂量依赖性。Western blot检测结果显示，复方40明显下调p-Akt （S473）的表达。进行分子对接以阐明化合物40与PI3Kα之间可能的结合模式。这些结果表明化合物4可能是PI3Kα的潜在抑制剂。
A series of novel chromeno[4,3-c]pyrazol-4(2H)-one derivates contained sulfonamido were designed and synthesized, and their anticancer effects in vitro was evaluated to develop some new PI3Kα inhibitors. Most of desired compounds exhibited the better antiproliferative activities against four cancer cell lines than that of LY294002. Out of them, compound4odisplayed the potent antiproliferative activity and high selectivity against the PI3Kα protein and it can induce apoptosis of HCT116 in a dose-dependent manner. Western blot assay indicated that compound4oobviously down-regulated expression of p-Akt (S473). Molecular docking was performed to clarify the possible binding mode between compound4oand PI3Kα. All these results indicated that compound4ocould be a potential inhibitor of PI3Kα.