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首页> 外文期刊>European Journal of Medicinal Chemistry: Chimie Therapeutique >Development of novel chromeno[4,3-c]pyrazol-4(2H)-one derivates bearing sulfonylpiperazine as antitumor inhibitors targeting PI3K alpha
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Development of novel chromeno[4,3-c]pyrazol-4(2H)-one derivates bearing sulfonylpiperazine as antitumor inhibitors targeting PI3K alpha

机译：新型Chromeno [4,3-C]吡唑-4（2H） - 酮衍生含磺酰哌嗪作为靶向PI3Kα的抗肿瘤抑制剂

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摘要

PI3K signal pathway plays a vital role in cellular functions and becomes an attractive approach for cancer therapy. Herein, a new series of novel chromeno[4,3-c]pyrazol-4(2H)-one derivatives bearing sulfonylpiperazine based on the PI3K inhibitors and our previous research. They were screened for their PI3K inhibitory activities and anticancer effects in vitro. Biological studies indicated that compound 7m revealed the remarkable antiproliferative activity (IC50 ranging from 0.03 to 0.09 mu M) against four cancer cell lines (A549, Huh7, HL60 and HCT-116). Besides, compound 7m displayed a certain selective for PI3K alpha (IC50 = 0.009 mu M) over PI3K beta, gamma and delta, and meanwhile, it can remarkable decreased the expression level of p-Akt (Ser473) and p-S6K. In addition, compound 7m could not only induce HCT-116 cell arrest at G1 phase in a dose-dependent manner, but also induce cell apoptosis via upregulation of Bax and cleaved-caspase 3/9, and downregulation of Bcl-2. Besides, compound 7m can remarkably inhibit the growth of tumor in vivo. The above results suggested that compound 7m could be considered as a promising PI3K alpha inhibitor. (C) 2019 Elsevier Masson SAS. All rights reserved.
机译：PI3K信号途径在蜂窝功能中起着至关重要的作用，成为癌症治疗的有吸引力的方法。这里，基于PI3K抑制剂的磺酰基哌嗪和我们以前的研究，新的一系列新的Chromeno [4,3-C]吡唑-4（2H）-ONE衍生物。他们在体外筛选它们的PI3K抑制活动和抗癌效果。生物学研究表明，化合物7M针对四种癌细胞系（A549，HUH7，HL60和HCT-116）显示出显着的抗增殖活性（IC50为0.03至0.09μm）。此外，化合物7M通过PI3Kβ，γ和δ的PI3Kα（IC50 =0.009μm）显示了一定选择性，同时，它可以显着降低P-AKT（SER473）和P-S6K的表达水平。此外，化合物7M不能以剂量依赖性方式在G1相时诱导HCT-116细胞停滞，而且还通过上调Bax和Cleaved-Caspase 3/9和Bcl-2的下调诱导细胞凋亡。此外，化合物7M可以显着抑制体内肿瘤的生长。上述结果表明，化合物7M可以被认为是有前途的PI3Kα抑制剂。 （c）2019年Elsevier Masson SAS。版权所有。

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