Design, Synthesis, and Biological Characterization of Largazole Analogues

Abstract

Histone deacetylases (HDACs) have been shown to play key roles in tumorigenesis, andhave been validated as effective enzyme target for cancer treatment. Largazole, a marine naturalproduct isolated from the cyanobacterium Symploca, is an extremely potent HDAC inhibitor thathas been shown to possess high differential cytotoxicity towards cancer cells along with excellentHDAC class-selectivity. However, improvements can be made in the isoform-selectivity andpharmacokinetic properties of largazole.In attempts to make these improvements and furnish a more efficient biochemical probeas well as a potential therapeutic, several largazole analogues have been designed, synthesized,and tested for their biological activity. Three different types of analogues were prepared. First,different chemical functionalities were introduced at the C2 position to probe the class Iselectivity profile of largazole. Additionally, docking studies led to the design of a potentialHDAC8-selective analogue. Secondly, the thiol moiety in largazole was replaced with a widevariety of othe zinc-binding group in order to probe the effect of Zn2+ affinity on HDACinhibition. Lastly, three disulfide analogues of largazole were prepared in order to utilize adifferent prodrug strategy to modulate the pharmacokinetic properties of largazole.Through these analogues it was shown that C2 position can be modified significantlywithout a major loss in activity while also eliciting minimal changes in isoform-selectivity. Whilethe Zn2+-binding group plays a major role in HDAC inhibition, it was also shown that the thiolcan be replaced by other functionalities while still retaining inhibitory activity. Lastly, the use ofa disulfide prodrug strategy was shown to affect pharmacokinetic properties resulting in varyingfunctional responses in vitro and in vivo.vLargazole is already an impressive HDAC inhibitor that shows incredible promise.However, in order to further develop this natural product into an anti-cancer therapeutic as well asa chemical probe, improvements in the areas of pharmacokinetics as well as isoform-selectivityare required. Through these studies we plan on building upon existing structure–activityrelationships to further our understanding of largazole’s mechanism of inhibition so that we mayimprove these properties and ultimately develop largazole into an efficient HDAC inhibitor thatmay be used as an anti-cancer therapeutic as well as a chemical probe for the studying ofbiochemical systems.