Development of novel chromeno[4,3-c]pyrazol-4(2H)-one derivates bearing sulfonylpiperazine as antitumor inhibitors targeting PI3K alpha
Development of novel chromeno[4,3-c]pyrazol-4(2H)-one derivates bearing sulfonylpiperazine as antitumor inhibitors targeting PI3K alpha
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开发带有磺酰哌嗪的新型色并[4,3-c]吡唑-4(2H)-酮衍生物作为靶向 PI3K α 的抗肿瘤抑制剂
DOI：
10.1016/j.ejmech.2019.111630
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发表时间：
2019
影响因子：
6.7
通讯作者：
Zhu Hai-Liang
中科院分区：
文献类型：
--
作者：
Yin Yong;Sha Shao;Wu Xun;Wang She-Feng;Qiao Fang;Song Zhong-Cheng;Zhu Hai-Liang
PI3K信号通路在细胞功能中发挥着至关重要的作用，并成为癌症治疗的一种有吸引力的方法。在此，基于PI3K抑制剂和我们之前的研究，一系列新的带有磺酰哌嗪的新型色并[4,3-c]吡唑-4(2H)-酮衍生物。对它们的 PI3K 抑制活性和体外抗癌作用进行了筛选。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范围为0.03至0.09μM）。此外，compound7m对PI3Kα（IC50=0.009μM）表现出一定的选择性（IC50=0.009μM），高于PI3Kβ、γ和δ，同时能显着降低p-Akt（Ser473）和p-S6K的表达水平。此外，compound7m不仅能够以剂量依赖性方式诱导HCT-116细胞阻滞在G1期，而且还可以通过上调Bax和cleaved-caspase 3/9以及下调Bcl-2来诱导细胞凋亡。此外，化合物7m还能显着抑制体内肿瘤的生长。上述结果表明compound7m可以被认为是一种有前途的PI3Kα抑制剂。
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 effectsin vitro. Biological studies indicated that compound7mrevealed the remarkable antiproliferative activity (IC50ranging from 0.03 to 0.09 μM) against four cancer cell lines (A549, Huh7, HL60 and HCT-116). Besides, compound7mdisplayed a certain selective for PI3Kα (IC50= 0.009 μM) over PI3Kβ, γ andδ, and meanwhile, it can remarkable decreased the expression level of p-Akt (Ser473) and p-S6K. In addition, compound7mcould not only induce HCT-116 cell arrest at G1 phase in a dose-dependent manner, but also induce cell apoptosisviaupregulation of Bax and cleaved-caspase 3/9, and downregulation of Bcl-2. Besides, compound7mcan remarkably inhibit the growth of tumorin vivo. The above results suggested that compound7mcould be considered as a promising PI3Kα inhibitor.