Cancer is the second leading cause of death in the United States of America and the entire world and the disease burden is exacerbated due to resistance to drugs that are currently in clinical use.<br/>Histone deacetylase (HDAC) enzymes are highly expressed in cancer cells and they are considered viable targets for drug intervention. Four HDAC inhibitors have been approved by the US FDA as anticancer drugs for clinical use, but these drugs have numerous side effects, at least partly due to their low HDAC isoform selectivity. Most of these drugs have hydroxamic acid group as the metal-binding group. Hydroxamates are promiscuous in their metal-binding ability and also have poor pharmacokinetic properties. In this study, we used molecular modeling studies to design and develop a new class of HDAC inhibitors incorporating a new imidazole-based metal-binding group. The compounds showed promising cell growth inhibitory activity comparable to or better than that of the clinically used HDAC inhibitor SAHA and a cell phenotype which is distinctly different from what was observed with SAHA. The design, synthesis and biological activity of these compounds will be presented. <br/>

Synthesis and biological evaluation of HDAC inhibitors with an imidazole-based metal-binding group

255th National Meeting (2018)

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