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 μM) against four cancer cell lines (A549, Huh7, HL60 and HCT-116). Besides, compound 7m displayed a certain selective for PI3Kα (IC50 = 0.009 μM) over PI3Kβ, γ and δ, 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 PI3Kα inhibitor.

中文翻译：

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新型磺酰基哌嗪的chromeno [4,3-c]吡唑-4（2H）-one衍生物的开发作为靶向PI3Kα的抗肿瘤抑制剂。

PI3K信号通路在细胞功能中起着至关重要的作用，并成为癌症治疗的一种有吸引力的方法。在这里，基于PI3K抑制剂和我们以前的研究的一系列新的带有磺酰基哌嗪的新的chromeno [4,3-c] pyrazol-4（2H）-one衍生物。筛选了它们的PI3K抑制活性和体外抗癌作用。生物学研究表明，化合物7m对四种癌细胞系（A549，Huh7，HL60和HCT-116）具有显着的抗增殖活性（IC50为0.03至0.09μM）。此外，化合物7m对PI3Kα（IC50 = 0.009μM）相对于PI3Kβ，γ和δ具有一定的选择性，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不仅可以剂量依赖的方式诱导HCT-116细胞停滞在G1期，而且还可以通过上调Bax和半胱天冬酶3/9以及下调Bcl-2来诱导细胞凋亡。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可以被认为是有希望的PI3Kα抑制剂。