Design, synthesis, biological evaluation and molecular docking study of novel chalcone-based hydroxamic acids possessing a central 2, 4-dimethy pyrrole linker as potential HDAC (Histone Deacetylase) inhibitors and anticancer agents

Abstract

A new series of chalcone-based compounds possessing pharmacophoric elements of HDAC (histone deacetylase) inhibitors with a central 2, 4-dimethyl pyrrole bridge linked to hydroxamic acid as ZBG (Zn binding group) were designed, synthesized, and evaluated as HDAC inhibitors and anticancer agents. The MTT assay revealed that most of the compounds have strong anti-proliferative activity against three cancer cell lines (HT-29, HCT-116 and HEK293) and low cytotoxicity on normal cell line (NIH). Among the compounds, a chalcone-based hydroxamic acid derivative possessing a methyl substituent on the chalcone moiety (9d) showed significant anti-proliferative activity against HCT-116 cancer cells (IC50=0.22 µM) more than the reference drug vorinostat (IC50=4.17 µM). In the enzyme activity inhibition test, 9d showed excellent inhibitory activity against pan-HDAC. Compounds 9d also inhibited HDAC1 strongly with IC50 values of 0.14 μM, which is comparable to vorinostat (IC50 = 0.38 μM). Compound 9d can also induce apoptosis in HCT116 cancer cells strongly. Furthermore, 9d had ex vivo diminished new neovascularization (anti-angiogenic effect) in the chick chorioallantoic membrane (CAM) model at concentration of 15 µM in a mode similar to that of vorinostat. Molecular docking was performed with 9d in the active site of HDAC1 enzyme. In silico docking study confirmed that compound 9d fitted in the substrate binding pocket of HDAC1. Taken together, compound 9d possesses the potential to be a new potent HDAC inhibitor and anticancer agent.