Design and Synthesis of Dual-Action Inhibitors Targeting Histone Deacetylases and 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase for Cancer Treatment
Design and Synthesis of Dual-Action Inhibitors Targeting Histone Deacetylases and 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase for Cancer Treatment
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DOI：
10.1021/jm400179b
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发表时间：
2013-05-09
影响因子：
7.3
通讯作者：
Fang, Jim-Min
中科院分区：
文献类型：
--
作者：
Chen, Jhih-Bin;Chern, Ting-Rong;Fang, Jim-Min
我们设计了一系列针对组蛋白去乙酰化酶（HDAC）和3-羟基-3-甲基戊二酰辅酶A还原酶（HMGR）的双效化合物，这些化合物中的羟酰胺基团是与HDAC活性位点的锌离子螯合所必需的，而他汀的关键结构元素则是与这两种蛋白结合所必需的。在我们的研究中，通过融合策略制备的他汀类羟肟酸在癌症治疗中最有前景。这些化合物对 HDACs 和 HMGR 具有很强的抑制活性，其 IC50 值在纳摩尔范围内。这些化合物还能有效降低 HMGR 活性，促进癌细胞中组蛋白和微管蛋白的乙酰化，但对正常细胞无毒性。
A series of dual-action compounds were designed to target histone deacetylase (HDAC) and 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) by having a hydroxamate group essential for chelation with the zinc ion in the active site of HDAC and the key structural elements of statin for binding with both proteins. In our study, the statin hydroxamic acids prepared by a fused strategy are most promising in cancer treatments. These compounds showed potent inhibitory activities against HDACs and HMGR with IC50 values in the nanomolar range. These compounds also effectively reduced the HMGR activity as well as promoted the acetylations of histone and tubulin in cancer cells, but were not toxic to normal cells.