Design and synthesis of imidazole based zinc binding groups as novel small molecule inhibitors targeting Histone deacetylase enzymes in lung cancer

Abstract

Histone deacetylase enzymes are involved in the remodelling of chromatin and have a pivotal role in balancing acetylation and deacetylation status of chromatin eventually ensures the epigenetic regulation of gene expression. Its aberrant activity was reported in several forms of cancer considering it as a potential target for cancer treatment. Histone deacetylase inhibitors emerged as new class of antineoplastic drugs. Recent developments in understanding the mechanism of interaction between drug and targeted molecule encourages rational development of new class of HDAC inhibitors directing global or gene specific histone acetylation. In the present study, we designed 14 imidazole based derivatives abiding the common pharmacophore structure like CAP, Spacer, and Zinc binding group (ZBG) shared among the established HDAC inhibitors and was explored for its epigenetic modulator candidature targeting histone modifying enzymes through docking experiments. Among them the compound ethyl (2,5-diphenyl-1H-imidazole-4-yl)acetate (C3) was tightly bound to the isoforms of the HDAC enzymes at their receptor regions with high binding score. C3 was synthesized and have been characterized experimentally by IR and NMR techniques. The C3 inhibit cell proliferation of A549 lung cancer cell by inducing cytotoxicity and increased levels of ROS generation by disrupting mitochondrial permeability as evidenced from deflection in (Δψm). From this study we revealed that C3 a novel imidazole derivative inhibit highly expressed HDAC enzyme in non-small cell lung cancer cell lines by chromatin remodelling. Further findings may validate the identified compound C3 as an effective epigenetic modulator.