组蛋白去乙酰化酶抑制剂的结构要求：在异羟肟酸相邻位置官能化的SAHA类似物。
Structural requirements of HDAC inhibitors: SAHA analogs functionalized adjacent to the hydroxamic acid.
作者信息
Bieliauskas Anton V, Weerasinghe Sujith V W, Pflum Mary Kay H
机构信息
Department of Chemistry, Wayne State University, Detroit, MI 48202, USA.
出版信息
Bioorg Med Chem Lett. 2007 Apr 15;17(8):2216-9. doi: 10.1016/j.bmcl.2007.01.117. Epub 2007 Feb 8.
Abstract
Inhibitors of histone deacetylase (HDAC) proteins such as suberoylanilide hydroxamic acid (SAHA) have emerged as effective therapeutic anti-cancer agents. To better understand the structural requirements of HDAC inhibitors, a small molecule library with a variety of substituents attached adjacent to the metal binding hydroxamic acid of SAHA was synthesized. The presence of a substituent adjacent to the hydroxamic acid led to an 800- to 5000-fold decrease in inhibition compared to SAHA. The observed results have implications for drug design, suggesting that HDAC inhibitors with substituents near the metal binding moiety will have inhibitory activities in the micromolar rather than nanomolar range.
摘要
诸如辛二酰苯胺异羟肟酸（SAHA）等组蛋白脱乙酰酶（HDAC）蛋白抑制剂已成为有效的治疗性抗癌药物。为了更好地理解HDAC抑制剂的结构要求，合成了一个小分子文库，该文库在SAHA的金属结合异羟肟酸相邻位置连接了各种取代基。与SAHA相比，异羟肟酸相邻位置存在取代基导致抑制作用降低了800至5000倍。观察到的结果对药物设计具有启示意义，表明在金属结合部分附近带有取代基的HDAC抑制剂将具有微摩尔而非纳摩尔范围内的抑制活性。
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