Unlocking Histone Deacetylase Inhibition with Chalcone Chemistry

Abstract: Chalcone, a prominent scaffold, is well recognized for its anticancer properties. The overexpression of epigenetic regulatory enzymes such as histone deacetylases (HDACs) has been associated with tumour progression and cancer development. The role of the chalcone scaffold in the inhibition of HDACs has been explored over the years. This study investigated the research progress reported on HDAC inhibition by compounds with a chalcone scaffold and evaluated their potential in medicinal chemistry. The research articles were sourced from multiple databases, such as SCOPUS, Google Scholar and PubMed, via the keywords ‘chalcone’, ‘histone deacetylase inhibitor’, ‘HDACi’, ‘HDAC’ and ‘chalcone HDAC inhibitor’. The articles are classified into two main categories according to their structural features. First, HDAC inhibition is achieved via zinc chelation of the carbonyl functional group of the chalcone scaffold. Second, zinc chelation is shown by known zinc-binding groups (ZBGs), and the chalcone scaffold enhances the interaction with the target. In each category, there are subdivisions on the basis of the presence or absence of heterocycles, dual inhibition, and any other modifications. Chalcone compounds with hydroxyl (-OH) and methoxy (-OCH3) substituents have shown therapeutic relevance. Although the inhibition of HDACs by chalcone scaffold metal chelation has been shown, it is comparable to or less effective than known ZBGs, such as hydroxamic acids and benzamides. These findings increase the understanding of the ability of the chalcone scaffold to inhibit HDAC activity and explain its effect on cytotoxicity. Analysis of the influence of substituents offered insight into structural optimization. Further research on structural modifications may reveal improved metal chelation and enhanced cytotoxicity.