源自核定位信号肽的新型组蛋白去乙酰化酶抑制剂的设计与合成
Design and synthesis of novel histone deacetylase inhibitor derived from nuclear localization signal peptide.
作者信息
Canzoneri Joshua C, Chen Po C, Oyelere Adegboyega K
机构信息
School of Chemistry and Biochemistry, Parker H Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332-0400, USA.
出版信息
Bioorg Med Chem Lett. 2009 Dec 1;19(23):6588-90. doi: 10.1016/j.bmcl.2009.10.028. Epub 2009 Oct 13.
Abstract
We describe herein the synthesis and characterization of a new class of histone deacetylase (HDAC) inhibitors derived from conjugation of a suberoylanilide hydroxamic acid-like aliphatic-hydroxamate pharmacophore to a nuclear localization signal peptide. We found that these conjugates inhibited the histone deacetylase activities of HDACs 1, 2, 6, and 8 in a manner similar to suberoylanilide hydroxamic acid (SAHA). Notably, compound 7b showed a threefold improvement in HDAC 1/2 inhibition, a threefold increase in HDAC 6 selectivity and a twofold increase in HDAC 8 selectivity when compared to SAHA.
摘要
我们在此描述了一类新型组蛋白脱乙酰酶（HDAC）抑制剂的合成与表征，这类抑制剂是通过将辛二酰苯胺异羟肟酸样脂肪族异羟肟酸药效基团与核定位信号肽缀合而成。我们发现，这些缀合物抑制HDAC 1、2、6和8的组蛋白脱乙酰酶活性的方式与辛二酰苯胺异羟肟酸（SAHA）相似。值得注意的是，与SAHA相比，化合物7b在HDAC 1/2抑制方面提高了三倍，在HDAC 6选择性方面提高了三倍，在HDAC 8选择性方面提高了两倍。
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