Synthesis, biological evaluation, and molecular dynamic studies of novel quinoline-based hydroxamic acid derivatives as HDAC inhibitor and anticancer agents
摘要
In this study, novel quinoline-based hydroxamic acid derivatives, both with and without linkers, were synthesized to act as potential histone deacetylase (HDAC) inhibitors and anticancer agents. The cytotoxicity and pan-HDAC inhibitory activity of these compounds were assessed using the HCT116 human colon cancer cell line. The results indicated that the inclusion of a linker in the molecular structures significantly improved both the cytotoxicity and pan-HDAC inhibitory activity of the synthesized derivatives. The cytotoxicity of the linker-containing compounds ranged from 6.99 to 18.92 μM for compounds 13a-d and 13g, which was notably higher than that of compounds 9a-b, 9e-k, and 10, which lacked a linker. Among these, compound 13b exhibited the highest cytotoxicity, while compound 9a showed the lowest. Compound 13b, with an IC50 of 1.76 μM, exhibited the most significant pan-HDAC inhibitory activity, correlating with its cytotoxic effects. Docking studies conducted on all synthesized compounds against various HDAC isoforms revealed favorable docking scores for nearly all linker-containing compounds (13a-d and 13g). Conversely, the compounds without linkers (9a-b, 9e-k, and 10) generally received the lowest docking scores against class I HDACs, while achieving better scores against class IIA and sirt4 from class III (sirtuins) HDACs. Molecular dynamics simulations were carried out between HDAC1 and compound 13b, as well as vorinostat, indicating greater stability in the 13b-HDAC1 complex. Overall, predictions made using the pkCSM and SwissADME free web tools suggested that the drug-likeness, physicochemical properties, and pharmacokinetics of the synthesized compounds were favorable.