von Janta-Lipinski M, Costisella B, Ochs H, Hübscher U, Hafkemeyer P, Matthes E
Max-Delbrück-Centrum für Molekulare Medizin, Robert-Rössle-Strasse 10, D-13125 Berlin-Buch, Germany.
J Med Chem. 1998 Jun 4;41(12):2040-6. doi: 10.1021/jm9704210.
Novel beta-L-2',3'-dideoxy-3'-fluoro nucleosides were synthesized and further converted to their 5'-triphosphates. Their inhibitory activities against hepatitis B virus (HBV) and duck hepatitis B virus (DHBV) DNA polymerases, human immunodeficiency virus (HIV) reverse transcriptase (RT), and the cellular DNA polymerases alpha, beta, gamma, delta, and epsilon were investigated and compared with those of the corresponding 3'-fluoro-modified beta-d-analogues. The 5'-triphosphates of 3'-deoxy-3'-fluoro-beta-L-thymidine (beta-L-FTTP), 2',3'-dideoxy-3'-fluoro-beta-L-cytidine (beta-L-FdCTP), and 2',3'-dideoxy-3'-fluoro-beta-l-5-methylcytidine (beta-L-FMetdCTP) emerged as effective inhibitors of HBV/DHBV DNA polymerases (IC50 = 0.25-10.4 microM). They were either equally (FTTP) or less (FMetdCTP, FdCTP) effective than their beta-d-counterparts. Also the 5'-triphosphate of beta-L-thymidine (beta-L-TTP) was shown to be a strong inhibitor of these two viral enzymes (IC50 = 0.46/1.0 microM). However, all beta-L-FdNTPs (also beta-L-TTP) were inactive against HIV-RT, a result which contrasts sharply with the high efficiency of the beta-D- FdNTPs against this polymerase. Between the cellular DNA polymerases only the beta and gamma enzymes displayed a critical susceptibility to beta-D-FdNTPs which is largely abolished by the beta-L-enantiomers. These results recommend beta-L-FTdR, beta-L-FCdR, and beta-L-FMetCdR for further evaluation as selective inhibitors of HBV replication at the cellular level.
合成了新型β-L-2',3'-二脱氧-3'-氟核苷，并进一步将其转化为它们的5'-三磷酸酯。研究了它们对乙型肝炎病毒（HBV）和鸭乙型肝炎病毒（DHBV）DNA聚合酶、人类免疫缺陷病毒（HIV）逆转录酶（RT）以及细胞DNA聚合酶α、β、γ、δ和ε的抑制活性，并与相应的3'-氟修饰的β-D-类似物进行了比较。3'-脱氧-3'-氟-β-L-胸苷（β-L-FTTP）、2',3'-二脱氧-3'-氟-β-L-胞苷（β-L-FdCTP）和2',3'-二脱氧-3'-氟-β-L-5-甲基胞苷（β-L-FMetdCTP）的5'-三磷酸酯成为HBV/DHBV DNA聚合酶的有效抑制剂（IC50 = 0.25 - 10.4 microM）。它们与相应的β-D-类似物相比，效力相当（FTTP）或更低（FMetdCTP、FdCTP）。此外，β-L-胸苷的-5'-三磷酸酯（β-L-TTP）也被证明是这两种病毒酶的强抑制剂（IC50 = 0.46/1.0 microM）。然而，所有β-L-FdNTPs（包括β-L-TTP）对HIV-RT均无活性，这一结果与β-D-FdNTPs对该聚合酶的高效性形成鲜明对比。在细胞DNA聚合酶中，只有β和γ酶对β-D-FdNTPs表现出显著敏感性，而β-L-对映体在很大程度上消除了这种敏感性。这些结果推荐β-L-FTdR、β-L-FCdR和β-L-FMetCdR作为细胞水平上HBV复制的选择性抑制剂进行进一步评估。
