Design, synthesis, and antiviral activity of 2′-deoxy-2′-fluoro-2′-C-methylcytidine, a potent inhibitor of hepatitis C virus replication
Design, synthesis, and antiviral activity of 2′-deoxy-2′-fluoro-2′-C-methylcytidine, a potent inhibitor of hepatitis C virus replication
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DOI：
10.1021/jm0502788
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发表时间：
2005-08-25
影响因子：
7.3
通讯作者：
Pankiewiez, KW
中科院分区：
文献类型：
--
作者：
Clark, JL;Hollecker, L;Pankiewiez, KW
嘧啶核苷 β-D-2'-脱氧-2'-氟-2'-C-甲基胞苷 (1) 被设计为丙型肝炎病毒 RNA 依赖性 RNA 聚合酶 (HCV RdRp) 抑制剂。通过 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 (6) 的 DAST 氟化得到标题化合物，得到 N-4-苯甲酰基-1-[2-氟-2-甲基-3,5-二-O-苯甲酰基-β-D-呋喃核糖基]胞嘧啶 (7a)。 2'-C-甲基胞苷 (7c) 是 DAST 氟化的副产物，可用于从共同前体制备两种生物活性化合物。化合物 1 和 2'-C-甲基胞苷在亚基因组 HCV 复制子测定系统中进行测定，发现与 2'-C-甲基胞苷相比，化合物 1 在 HCV 复制子测定中显示出更高的抑制活性。毒性。
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 (6) to provide N-4-benzoyl-1-[2-fluoro-2-methyl-3,5-di-O-benzoyl-beta-D-ribofuranosyl]cytosine (7a). The protected 2'-C-methylcytidine (7c) 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.