Tropolones As Lead-Like Natural Products: The Development of Potent and Selective Histone Deacetylase Inhibitors

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 molecula...

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Bibliographic Details
Published in:ACS medicinal chemistry letters 2013-08, Vol.4 (8), p.757-761
Main Authors: Ononye, Sophia N, VanHeyst, Michael D, Oblak, E. Zachary, Zhou, Wangda, Ammar, Mohamed, Anderson, Amy C, Wright, Dennis L
Format: Article
Language:English
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Letter
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Summary: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.
ISSN:1948-5875
1948-5875
DOI:10.1021/ml400158k