College of Pharmacy, Nankai University, 94 weijin Road, Nankai District, Tianjin 300071, China.
Eur J Med Chem. 2011 Aug;46(8):3190-200. doi: 10.1016/j.ejmech.2011.04.027. Epub 2011 Apr 29.
Previously, we reported a click-chemistry based approach to the synthesis of a novel class of histone deacetylase (HDAC) inhibitors [1]. The lead compound NSC746457 was found to be as potent as SAHA (Vorinostat). Further optimization of NSC746457 by using the HDAC2-TSA crystal structure is described herein. Docking of NSC746457 into HDAC2 binding domain suggested that the hydrophobic residue Phe210 flanking the cap-group binding-motif could be exploited for structural optimization. Substitution on the methylene group of cinnamic cap region led to identification of more potent HDAC inhibitors: isopropyl derivative 5 and tert-butyl derivative 6, with an IC(50) value of 22 nM and 18 nM, respectively.
此前，我们报道了一种基于点击化学的方法来合成新型组蛋白去乙酰化酶 (HDAC) 抑制剂[1]。先导化合物 NSC746457 的活性与 SAHA（伏立诺他）相当。本文进一步描述了使用 HDAC2-TSA 晶体结构对 NSC746457 的优化。将 NSC746457 对接至 HDAC2 结合域表明，位于帽基团结合基序侧翼的疏水性残基 Phe210 可用于结构优化。肉桂酸帽区亚甲基上的取代导致发现了更有效的 HDAC 抑制剂：异丙基衍生物 5 和叔丁基衍生物 6，其 IC50 值分别为 22 nM 和 18 nM。
