Antiviral Activity of Various 1-(2′-Deoxy-β-d-lyxofuranosyl), 1-(2′-Fluoro-β-d-xylofuranosyl), 1-(3′-Fluoro-&#

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• 作者：Naveen C. Srivastav ; Neeraj Shakya ; Michelle Mak ; Babita Agrawal ; D. Lorne Tyrrell ; Rakesh Kumar
• 刊名：Journal of Medicinal Chemistry
• 出版年：2010
• 出版时间：October 14, 2010
• 年：2010
• 卷：53
• 期：19
• 页码：7156-7166
• 全文大小：964K
• 年卷期：v.53,no.19(October 14, 2010)
• ISSN：1520-4804

文摘

Despite the existence of successful vaccine and antiviral therapies, infection with hepatitis B virus (HBV) continues to be a major global cause of acute and chronic liver disease and high mortality. We synthesized and evaluated several lyxofuranosyl, 2′-fluoroxylofuranosyl, 3′-fluoroarabinofuranosyl, and 2′-fluoro-2′,3′-didehydro-2′,3′-dideoxyribose pyrimidine nucleoside analogues for antiviral activities against hepatitis B virus. Among the compounds examined, 1-(2-deoxy-β-d-lyxofuranosyl)thymine (23), 1-(2-deoxy-β-d-lyxofuranosyl)-5-trifluoromethyluracil (25), 1-(2-deoxy-2-fluoro-β-d-xylofuranosyl)uracil (38), 1-(2-deoxy-2-fluoro-β-d-xylofuranosyl)thymine (39), 2′,3′-dideoxy-2′,3′-didehydro-2′-fluorothymidine (48), and 2′,3′-dideoxy-2′,3′-didehydro-2′-fluoro-5-ethyluridine (49) were found to possess significant anti-HBV activity against DHBV in primary duck hepatocytes with EC₅₀ values of 4.1, 3.3, 40.6, 3.8, 0.2, and 39.0 μM, respectively. Compounds 23, 25, 39, 48, and 49 (EC₅₀ = 41.3, 33.7, 19.2, 2.0−4.1, and 39.0 μM, respectively) exhibited significant activity against wild-type human HBV in 2.2.15 cells. Intriguingly, 25, 39, 48, and 49 retained sensitivity against lamivudine-resistant HBV containing a single mutation (M204I) and 48 emerged as an effective inhibitor of drug-resistant HBV with an EC₅₀ of 4.1 μM. In contrast, 50% inhibition could not be achieved by lamivudine at 44 μM concentration in the drug-resistant strain. The compounds investigated did not show cytotoxicity to host cells up to the highest concentrations tested.