Department of Chemistry, National Taiwan University, Taipei 106, Taiwan.
J Med Chem. 2013 May 9;56(9):3645-55. doi: 10.1021/jm400179b. Epub 2013 Apr 22.
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.
一系列双作用化合物被设计用来靶向组蛋白去乙酰化酶（HDAC）和 3-羟基-3-甲基戊二酰辅酶 A 还原酶（HMGR），通过具有羟肟酸基团，该基团对于与 HDAC 活性位点中的锌离子以及他汀类药物与两种蛋白质结合的关键结构元素螯合至关重要。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 HDAC 和 HMGR 表现出很强的抑制活性，IC50 值在纳摩尔范围内。这些化合物还能有效降低 HMGR 的活性，并促进癌细胞中组蛋白和微管蛋白的乙酰化，但对正常细胞没有毒性。
