Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB, Canada.
Bioorg Med Chem Lett. 2012 Oct 15;22(20):6475-80. doi: 10.1016/j.bmcl.2012.08.042. Epub 2012 Aug 21.
Hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are major health threats worldwide leading to liver cirrhosis, liver cancer and mortality. Herein, we report a new category of dideoxy pyrimidine nucleosides possessing a 4'-carboxyl (or carboxymethyl) function (7-9, 13, 16, 17), which are discovered as potential antiviral agents. For the first time, these nucleosides are recognized to be inhibitors of HBV and/or HCV replication. Among 4'-carboxy compounds, 3',4'-didehydrothymidine (16) was most effective against DHBV, HBV and HCV. Modification of the 4'-position in compound 7 from a carboxyl to carboxymethyl group (17) did not affect the anti-HBV activity but greatly increased the anti-HCV activity. Importantly, 17 yielded synergistic antiviral effect when combined with ribavirin without toxicity. The activity exhibited by a single agent towards both hepatitis viruses and no detectable in vitro cytotoxicity make this new class of compounds of interest.
乙型肝炎病毒（HBV）和丙型肝炎病毒（HCV）感染是全球主要的健康威胁，可导致肝硬化、肝癌和死亡。在此，我们报告了一类具有 4'-羧基（或羧甲基）功能的新的双脱氧嘧啶核苷（7-9、13、16、17），它们被发现是有潜力的抗病毒药物。这些核苷首次被认为是 HBV 和/或 HCV 复制的抑制剂。在 4'-羧基化合物中，3',4'-二氢胸苷（16）对 DHBV、HBV 和 HCV 的抑制作用最强。化合物 7 中 4'-位的羧基修饰为羧甲基（17）不影响抗 HBV 活性，但大大增强了抗 HCV 活性。重要的是，17 与利巴韦林联合使用时具有协同抗病毒作用，且无毒性。该类化合物对两种肝炎病毒均有活性，且体外无明显细胞毒性，具有潜在的应用价值。
