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7083259 
Journal Article 
Tropolones As Lead-Like Natural Products: The Development of Potent and Selective Histone Deacetylase Inhibitors 
Ononye, SN; Vanheyst, MD; Oblak, EZ; Zhou, W; Ammar, M; Anderson, AmyC; Wright, DL; , 
2013 
Yes 
ACS Medicinal Chemistry Letters
ISSN: 1948-5875 
AMER CHEMICAL SOC 
WASHINGTON 
757-761 
24900743 
WOS:000323081800018 
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.