Development of novel chromeno[4,3-c]pyrazol-4(2H)-one derivates containing piperazine as inhibitors of PI3K alpha
Development of novel chromeno[4,3-c]pyrazol-4(2H)-one derivates containing piperazine as inhibitors of PI3K alpha
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开发含有哌嗪的新型色并[4,3-c]吡唑-4(2H)-酮衍生物作为 PI3K α 抑制剂
DOI：
10.1016/j.bioorg.2019.103238
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发表时间：
2019
影响因子：
5.1
通讯作者：
Zhu Hai Liang
中科院分区：
文献类型：
--
作者：
Yin Yong;Zhou Yang;Sha Shao;Wu Xun;Wang She Feng;Qiao Fang;Song Zhong Cheng;Zhu Hai Liang
PI 3 K通路已被大量研究，并且是各种癌症治疗的最有潜力的靶点之一。本文在前人研究的基础上，设计并合成了一系列含哌嗪的色烯并[4，3-c]吡唑-4（2 H）-酮衍生物。评价了它们的PI 3 K α野生型和H1047 R突变体抑制活性和体外抗癌作用。这些化合物对4种肿瘤细胞株（HCT-116、A549、Huh 7和HL 60）均表现出潜在的抗增殖活性。其中，化合物4具有显著的抗增殖活性，并被选择用于进一步的生物学评价。化合物4p对PI 3 K α野生型和H1047 R突变体均表现出较强的活性，且对PI 3 K α的选择性高于对PI 3 K β、γ和δ的选择性，同时对Akt的磷酸化水平有明显的下调作用。此外，发现化合物4p通过上调Bax和裂解的半胱天冬酶3/9以及下调Bcl-2诱导细胞凋亡。上述结果表明化合物4p是一种很有前途的PI 3 K α抑制剂。
PI3K pathway has been heavily studied and is one of the most potential targets for various cancer treatment. Herein, we designed and synthesized a series of novel chromeno[4,3-c]pyrazol-4(2H)-one derivates contained piperazine based on our previous research. They were evaluated for their PI3Kα wild-type and H1047R mutant inhibitory activities and anticancer effects in vitro. Most of these compounds displayed the potential antiproliferative activities against four cancer cell lines (HCT-116, A549, Huh7 and HL60). Among them, Compound4prevealed the remarkable antiproliferative activity and was selected for further biological evaluation. Compound4pdisplayed the potent activity against both PI3Kα wild-type and H1047R mutant, and a certain degree of selectivity for PI3Kα over PI3Kβ, γ and δ, and meanwhile it can remarkable down-regulate the phosphorylation of Akt. In addition, compound4pwas found to induce cell apoptosisviaupregulation of Bax and cleaved-caspase 3/9, and downregulation of Bcl-2. The above results suggested that compound4pcould be considered as a promising PI3Kα inhibitor.