Tropolones As Lead-Like Natural Products: The Development of Potent and Selective Histone Deacetylase Inhibitors
Tropolones As Lead-Like Natural Products: The Development of Potent and Selective Histone Deacetylase Inhibitors
复制标题
DOI：
10.1021/ml400158k
复制
发表时间：
2013-08-01
影响因子：
4.2
通讯作者：
Wright, Dennis L.
中科院分区：
文献类型：
--
作者：
Ononye, Sophia N.;VanHeyst, Michael D.;Wright, Dennis L.
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.
