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

• Published in: Bioorganic chemistry Vol. 93; p. 103283
• Main Authors: Ding, Huai-Wei, Yu, Lu, Bai, Meng-xuan, Qin, Xiao-Chun, Song, Man-tong, Zhao, Qing-Chun
• Format: Journal Article
• Language: English
• Published: SAN DIEGO Elsevier Inc 01.12.2019; Elsevier
• Subjects: Antitumor; Benzo[d]imidazole; Biochemistry & Molecular Biology; Chemistry; Chemistry, Organic; Life Sciences & Biomedicine; Physical Sciences; PI3K; Science & Technology; PI3K; Benzo[d]imidazole; Antitumor; APOPTOSIS; PATHWAY; BIOLOGICAL EVALUATION; OPTIMIZATION; HIGHLY POTENT; INHIBITOR; CANCER; DISCOVERY
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2019.103283

[Display omitted] •Synthesis of 1,6-disubstituted-1H-benzo[d]imidazoles derivatives.•Cytotoxicity evaluation.•Evaluation of PI3K inhibition.•Study on anti-tumor mechanisms. 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.