科研之友
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摘要
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 13 virus. Among the compounds examined, 1-(2-deoxy-beta-D-lyxofuranosyl)thymine (23), 1-(2-deoxy-beta-D-lyxofuranosyl)-5-trifluoromethyluracil (25), 1-(2-deoxy-2-fluoro-beta-D-xylofuranosyl)uracil (38), 1-(2-deoxy-2-fluoro-beta-D-xylofluranosyl)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 EC(50) values of 4.1, 3.3, 40.6, 3.8, 0.2, and 39.0 mu M respectively. Compounds 23, 25, 39, 48, and 49 (EC(50) = 41.3, 33.7, 19.2, 2.0-4.1, and 39.0 mu M, 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 (M2041) and 48 emerged as an effective inhibitor of drug-resistant HBV with an EC(50) of 4.1 mu M. In contrast, 50% inhibition could not be achieved by lamivudine at 44 mu M concentration in the drug-resistant strain. The compounds investigated did not show cytotoxicity to host cells up to the highest concentrations tested.
- 出版日期2010-10-14
