Design, synthesis and evaluation of some 1,6-disubstituted-1H-benzo[d]imidazoles derivatives targeted PI3K as anticancer agents

被引：21

作者：

Ding, Huai-Wei ^{[1
]}

Yu, Lu ^{[2
]}

Bai, Meng-xuan ^{[1
]}

Qin, Xiao-Chun ^{[2
]}

Song, Man-tong ^{[3
]}

Zhao, Qing-Chun ^{[2
]}

机构：

[1] Shenyang Pharmaceut Univ, Key Lab Struct Based Drug Design & Discovery, Minist Educ, Shenyang 110016, Liaoning, Peoples R China

[2] Shenyang Pharmaceut Univ, Sch Tradit Chinese Mat Med, Shenyang 110016, Liaoning, Peoples R China

[3] Shenyang Med Coll, Sch Publ Hlth, Shenyang 110034, Liaoning, Peoples R China

来源：

BIOORGANIC CHEMISTRY | 2019年 / 93卷

关键词：

Benzo[d]imidazole; Antitumor; PI3K; HIGHLY POTENT; BIOLOGICAL EVALUATION; INHIBITOR; PATHWAY; OPTIMIZATION; DISCOVERY; APOPTOSIS; CANCER;

D O I：

10.1016/j.bioorg.2019.103283

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Phosphatidylinositol 3-kinase (PI3K) pathway regulates various cellular processes, such as proliferation, growth, autophagy and apoptosis. Class I PI3K is frequently mutated and overexpressed in a lot of human cancers and PI3K was considered as a target for therapeutic treatment of cancer. In this study, we designed and synthesized a series of 1,6-disubstituted-1H-benzo[d]imidazoles derivatives and evaluated their anticancer activity and the compound 8i was identified as a lead compound. Compound 8i with the most potent antiproliferative activity was selected for further biological mechanism. The PI3K kinase assay have shown potent efficiency against four subtypes of PI3K with an IC50 of 0.5-1.9 nM. Molecular docking showed a possible formation of H-bonding with essential amino acid residues. Meanwhile, western blot assay indicated that 8i inhibited cell proliferation via suppression of PI3K kinase activity and subsequently blocked PI3K/Akt pathway activation in HCT116 cells. In addition, 8i could inhibit the migration and invasion ability of HCT116 cells and could induce apoptosis of HCT116 cells.

引用

页数：13

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