丙型肝炎病毒复制的强效抑制剂2'-脱氧-2'-氟-2'-C-甲基胞苷的设计、合成及抗病毒活性
Design, synthesis, and antiviral activity of 2'-deoxy-2'-fluoro-2'-C-methylcytidine, a potent inhibitor of hepatitis C virus replication.
作者信息
Clark Jeremy L, Hollecker Laurent, Mason J Christian, Stuyver Lieven J, Tharnish Phillip M, Lostia Stefania, McBrayer Tamara R, Schinazi Raymond F, Watanabe Kyoichi A, Otto Michael J, Furman Phillip A, Stec Wojciech J, Patterson Steven E, Pankiewicz Krzysztof W
机构信息
Pharmasset, Inc., 303-A College Road East, Princeton, New Jersey 08540, USA.
出版信息
J Med Chem. 2005 Aug 25;48(17):5504-8. doi: 10.1021/jm0502788.
The pyrimidine nucleoside beta-d-2'-deoxy-2'-fluoro-2'-C-methylcytidine (1) was designed as a hepatitis C virus RNA-dependent RNA polymerase (HCV RdRp) inhibitor. The title compound was obtained by a DAST fluorination of N(4)-benzoyl-1-(2-methyl-3,5-di-O-benzoyl-beta-d-arabinofuranosyl]cytosine to provide N(4)-benzoyl-1-[2-fluoro-2-methyl-3,5-di-O-benzoyl-beta-d-ribofuranosyl]cytosine. The protected 2'-C-methylcytidine was obtained as a byproduct from the DAST fluorination and allowed for the preparation of two biologically active compounds from a common precursor. Compound 1 and 2'-C-methylcytidine were assayed in a subgenomic HCV replicon assay system and found to be potent and selective inhibitors of HCV replication. Compound 1 shows increased inhibitory activity in the HCV replicon assay compared to 2'-C-methylcytidine and low cellular toxicity.
嘧啶核苷β - d - 2'-脱氧-2'-氟-2'-C -甲基胞苷（1）被设计为一种丙型肝炎病毒RNA依赖性RNA聚合酶（HCV RdRp）抑制剂。通过用DAST对N(4)-苯甲酰基-1-(2-甲基-3,5-二-O-苯甲酰基-β - d -阿拉伯呋喃糖基]胞嘧啶进行氟化反应得到标题化合物，从而得到N(4)-苯甲酰基-1-[2-氟-2-甲基-3,5-二-O-苯甲酰基-β - d -核糖呋喃糖基]胞嘧啶。受保护的2'-C -甲基胞苷是DAST氟化反应的副产物，可从一个共同前体出发制备两种生物活性化合物。在亚基因组HCV复制子检测系统中对化合物1和2'-C -甲基胞苷进行了检测，发现它们是HCV复制的有效且选择性抑制剂。与2'-C -甲基胞苷相比，化合物1在HCV复制子检测中显示出增强的抑制活性，且细胞毒性较低。
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