Tropolones As Lead-Like Natural Products: The Development
of Potent and Selective Histone Deacetylase Inhibitors
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Abstract
Natural
products have long been recognized as a rich source of potent therapeutics
but further development is often limited by high structural complexity
and high molecular weight. In contrast, at the core of the thujaplicins
is a lead-like tropolone scaffold characterized by relatively low
molecular weight, ample sites for diversification, and metal-binding
functionality poised for targeting a range of metalloenzyme drug targets.
Here, we describe the development of this underutilized scaffold for
the discovery of tropolone derivatives that function as isozyme-selective
inhibitors of the validated anticancer drug target, histone deacetylase
(HDAC). Several monosubstituted tropolones display remarkable levels
of selectivity for HDAC2 and potently inhibit the growth of T-cell
lymphocyte cell lines. The tropolones represent a new chemotype of
isozyme-selective HDAC inhibitors