Design, Synthesis, and Biological Characterization of Largazole Analogues

<p>Histone deacetylases (HDACs) have been shown to play key roles in tumorigenesis, and</p><p>have been validated as effective enzyme target for cancer treatment. Largazole, a marine natural</p><p>product isolated from the cyanobacterium Symploca, is an extremely potent HDAC inhibitor that</p><p>has been shown to possess high differential cytotoxicity towards cancer cells along with excellent</p><p>HDAC class-selectivity. However, improvements can be made in the isoform-selectivity and</p><p>pharmacokinetic properties of largazole.</p><p>In attempts to make these improvements and furnish a more efficient biochemical probe</p><p>as well as a potential therapeutic, several largazole analogues have been designed, synthesized,</p><p>and tested for their biological activity. Three different types of analogues were prepared. First,</p><p>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 potential</p><p>HDAC8-selective analogue. Secondly, the thiol moiety in largazole was replaced with a wide</p><p>variety of othe zinc-binding group in order to probe the effect of Zn2+ affinity on HDAC</p><p>inhibition. Lastly, three disulfide analogues of largazole were prepared in order to utilize a</p><p>different prodrug strategy to modulate the pharmacokinetic properties of largazole.</p><p>Through these analogues it was shown that C2 position can be modified significantly</p><p>without a major loss in activity while also eliciting minimal changes in isoform-selectivity. While</p><p>the Zn2+-binding group plays a major role in HDAC inhibition, it was also shown that the thiol</p><p>can be replaced by other functionalities while still retaining inhibitory activity. Lastly, the use of</p><p>a disulfide prodrug strategy was shown to affect pharmacokinetic properties resulting in varying</p><p>functional responses in vitro and in vivo.</p><p>v</p><p>Largazole is already an impressive HDAC inhibitor that shows incredible promise.</p><p>However, in order to further develop this natural product into an anti-cancer therapeutic as well as</p><p>a chemical probe, improvements in the areas of pharmacokinetics as well as isoform-selectivity</p><p>are required. Through these studies we plan on building upon existing structure–activity</p><p>relationships to further our understanding of largazole’s mechanism of inhibition so that we may</p><p>improve these properties and ultimately develop largazole into an efficient HDAC inhibitor that</p><p>may be used as an anti-cancer therapeutic as well as a chemical probe for the studying of</p><p>biochemical systems.</p>Dissertatio