Jie L, Van Aerschot A, Balzarini J, Janssen G, Busson R, Hoogmartens J, De Clercq E, Herdewijn P
Laboratory of Pharmaceutical Chemistry, Rega Institute for Medical Research, Leuven, Belgium.
J Med Chem. 1990 Sep;33(9):2481-7. doi: 10.1021/jm00171a023.
5'-O-Phosphonomethylation of different pyrimidine 2',3'-dideoxynucleosides was accomplished by reaction of the latter with diethyl [(p-toylsulfonyl)oxy]methanephosphonate (1) in the presence of sodium hydride. The base-phosphonomethylated (15-19) and sugar-phosphonomethylated (8-12) derivatives could be readily distinguished by 1H and 13C NMR and MS analysis. Protection of the uracil or thymine residue with a N3-benzoyl group failed to prevent base modification. However, O4-methyl-protected 2',3'-dideoxyuridine readily afforded the 5'-O-phosphonomethylated derivative 12, which was converted to both the 2',3'-didoxyuridine analogue 27 and the 2',3'-dideoxycytidine counterpart 29. The 5'-O-phosphonomethyl derivatives of 3'-deoxythymidine (23), 2',3'-dideoxyuridine, (27), 2',3'-dideoxycytidine (29), 3'-O-methylthymidine (26), and 3'-amino-3'-deoxythymidine (28) did not show an appreciable anti-HIV activity in MT-4 cells. In contrast, the 5'-O-phosphonomethyl derivatives of 3'-deoxy-3'-fluorothymidine (24) and 3'-azido-3'-deoxythymidine (25) inhibited HIV-1 cytopathogenicity by 50% at a concentration of approximately 1 microM.
通过不同嘧啶2'，3'-二脱氧核苷与二乙基[(对甲苯磺酰基)氧基]甲基膦酸酯(1)在氢化钠存在下反应，实现了其5'-O-膦酰甲基化。通过1H和13C NMR以及MS分析，可以很容易地区分碱基膦酰甲基化(15 - 19)和糖膦酰甲基化(8 - 12)衍生物。用N3-苯甲酰基保护尿嘧啶或胸腺嘧啶残基不能防止碱基修饰。然而，O4-甲基保护的2'，3'-二脱氧尿苷很容易得到5'-O-膦酰甲基化衍生物12，它可转化为2'，3'-二脱氧尿苷类似物27和2'，3'-二脱氧胞苷对应物29。3'-脱氧胸苷(23)、2'，3'-二脱氧尿苷(27)、2'，3'-二脱氧胞苷(29)、3'-O-甲基胸苷(26)和3'-氨基-3'-脱氧胸苷(28)的5'-O-膦酰甲基衍生物在MT-4细胞中未显示出明显的抗HIV活性。相比之下，3'-脱氧-3'-氟胸苷(24)和3'-叠氮基-3'-脱氧胸苷(25)的5'-O-膦酰甲基衍生物在浓度约为1 microM时可抑制HIV-1细胞病变效应达50%。
