Synthesis and anticancer evaluation of novel 1H-benzo[d]imidazole derivatives of dehydroabietic acid as PI3Kα inhibitors

Phosphatidylinositol 3-kinase (PI3K) is one of the most attractive therapeutic targets for Cancer treatment. In this study, a series of new 2-arylthio- and 2-arylamino-1H-benzo[d]imidazole derivatives of dehydroabietic acid were designed, synthesized and characterized by ¹H NMR, ¹³C NMR, IR and MS spectra analyses. In the in vitro Anticancer assay, some title compounds showed significant inhibitory activities against four Cancer cell lines (HCT-116, MCF-7, HeLa and HepG2). Among them, compound 9g exhibited the most potent activity with IC₅₀ values of 0.18 ± 0.03, 0.43 ± 0.05, 0.71 ± 0.08 and 0.63 ± 0.09 μM against four Cancer cell lines, and considerably lower cytotoxicity to human gastric mucosal cell line Ges-1 (IC₅₀: 21.95 ± 0.73 μM). Besides, compound 9g displayed a certain selective activity to PI3Kα (IC₅₀ = 0.012 ± 0.002 μM) over PI3Kβ, γ and δ, and meanwhile, it can remarkably decrease the expression level of p-Akt (Ser473). In addition, compound 9g could increase intracellular Reactive Oxygen Species level, decrease mitochondrial membrane potential, upregulate Bax and cleaved Caspase-3/9 levels, downregulate Bcl-2 level and thus induce the Apoptosis of HCT-116 cells in a dose-dependent manner. The results suggested that compound 9g could be considered as a promising PI3Kα Inhibitor.