2-羟基异喹啉-1,3-二酮类似物作为HIV逆转录酶相关核糖核酸酶H和聚合酶抑制剂的合成、生物学评价及分子模拟
Synthesis, biological evaluation and molecular modeling of 2-Hydroxyisoquinoline-1,3-dione analogues as inhibitors of HIV reverse transcriptase associated ribonuclease H and polymerase.
作者信息
Tang Jing, Vernekar Sanjeev Kumar V, Chen Yue-Lei, Miller Lena, Huber Andrew D, Myshakina Nataliya, Sarafianos Stefan G, Parniak Michael A, Wang Zhengqiang
机构信息
Center for Drug Design, Academic Health Center, University of Minnesota, Minneapolis, MN 55455, USA.
Department of Microbiology & Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219, USA.
出版信息
Eur J Med Chem. 2017 Jun 16;133:85-96. doi: 10.1016/j.ejmech.2017.03.059. Epub 2017 Mar 29.
Abstract
Human immunodeficiency virus (HIV) reverse transcriptase (RT) associated ribonuclease H (RNase H) remains the only virally encoded enzymatic function not clinically validated as an antiviral target. 2-Hydroxyisoquinoline-1,3-dione (HID) is known to confer active site directed inhibition of divalent metal-dependent enzymatic functions, such as HIV RNase H, integrase (IN) and hepatitis C virus (HCV) NS5B polymerase. We report herein the synthesis and biochemical evaluation of a few C-5, C-6 or C-7 substituted HID subtypes as HIV RNase H inhibitors. Our data indicate that while some of these subtypes inhibited both the RNase H and polymerase (pol) functions of RT, potent and selective RNase H inhibition was achieved with subtypes 8-9 as exemplified with compounds 8c and 9c.
摘要
人类免疫缺陷病毒（HIV）逆转录酶（RT）相关的核糖核酸酶H（RNase H）仍然是唯一未在临床上被验证为抗病毒靶点的病毒编码酶功能。已知2-羟基异喹啉-1,3-二酮（HID）可对依赖二价金属的酶功能产生活性位点定向抑制作用，如HIV核糖核酸酶H、整合酶（IN）和丙型肝炎病毒（HCV）NS5B聚合酶。我们在此报告了几种C-5、C-6或C-7取代的HID亚型作为HIV核糖核酸酶H抑制剂的合成及生化评估。我们的数据表明，虽然其中一些亚型同时抑制了RT的核糖核酸酶H和聚合酶（pol）功能，但以化合物8c和9c为例的8-9亚型实现了对核糖核酸酶H的强效和选择性抑制。
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