Design, synthesis, and biological evaluation of novel 3-substituted imidazo[1,2- a ]pyridine and quinazolin-4(3H)-one derivatives as PI3Kα inhibitors

摘要

Abstract Phosphatidylinositol 3-kinase (PI3K) is a pivotal regulator of intracellular signaling pathways and considered as a promising target in the development of a therapeutic treatment of cancer. Among the different PI3K subtypes, the PIK3CA gene encoding PI3K p110α is frequently mutated and overexpressed in majority of human cancers. Therefore, the inhibition of PI3Kα has been considered to be an efficient approach for the treatment of cancer. In this study, two series compounds containing hydrophilic group in imidazo[1,2- a ]pyridine and quinazolin-4(3H)-one were synthesized and their antiproliferative activities against five cancer cell lines, including HCT-116, SK-HEP-1, MDA-MB-231, SNU638 and A549, were evaluated. Compound 1i with most potent antiproliferative activity was selected for further biological evaluation. PI3K kinase assay showed that 1i has selectivity for PI3Kα distinguished from other isoforms. The western blot assay indicated that 1i is more effective than HS-173, an imidazopyridine-based PI3Ka inhibitor, in reducing the levels of phospho-Akt. All these results suggested that 1i is a potent PI3Kα inhibitor and could be considered as a potential candidate for the development of anticancer agents. Graphical abstract Display Omitted Highlights ? Imidazo[1,2- a ]pyridine and quinazolin-4(3H)-one derivatives were synthesized. ? Their antiproliferative activities against cancer cell lines were evaluated. ? 1i exhibited an IC 50 value of 10?nM against HCT116 and SNU638?cells. ? The compounds 1b , 1i and 10b were evaluated for their PI3K inhibitory activity and selectivity. ? Compound 1i is considered as a potent PI3Kα inhibitor with IC 50 of 0.5?nM.