Design, Synthesis, and Biological Characterization of Largazole Analogues
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Histone deacetylases (HDACs) have been shown to play key roles in tumorigenesis, and
have been validated as effective enzyme target for cancer treatment. Largazole, a marine natural
product isolated from the cyanobacterium Symploca, is an extremely potent HDAC inhibitor that
has been shown to possess high differential cytotoxicity towards cancer cells along with excellent
HDAC class-selectivity. However, improvements can be made in the isoform-selectivity and
pharmacokinetic properties of largazole.
In attempts to make these improvements and furnish a more efficient biochemical probe
as 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 potential
HDAC8-selective analogue. Secondly, the thiol moiety in largazole was replaced with a wide
variety of othe zinc-binding group in order to probe the effect of Zn2+ affinity on HDAC
inhibition. Lastly, three disulfide analogues of largazole were prepared in order to utilize a
different prodrug strategy to modulate the pharmacokinetic properties of largazole.
Through these analogues it was shown that C2 position can be modified significantly
without a major loss in activity while also eliciting minimal changes in isoform-selectivity. While
the Zn2+-binding group plays a major role in HDAC inhibition, it was also shown that the thiol
can be replaced by other functionalities while still retaining inhibitory activity. Lastly, the use of
a disulfide prodrug strategy was shown to affect pharmacokinetic properties resulting in varying
functional responses in vitro and in vivo.
Largazole 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 as
a chemical probe, improvements in the areas of pharmacokinetics as well as isoform-selectivity
are required. Through these studies we plan on building upon existing structure–activity
relationships to further our understanding of largazole’s mechanism of inhibition so that we may
improve these properties and ultimately develop largazole into an efficient HDAC inhibitor that
may be used as an anti-cancer therapeutic as well as a chemical probe for the studying of
Kim, Bumki (2016). Design, Synthesis, and Biological Characterization of Largazole Analogues. Dissertation, Duke University. Retrieved from https://hdl.handle.net/10161/12114.
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