Stuart A L, Ayisi N K, Tourigny G, Gupta V S
J Pharm Sci. 1985 Mar;74(3):246-9. doi: 10.1002/jps.2600740305.
The antiviral activity, effect on cellular DNA and RNA synthesis, and cytotoxicity toward mammalian cells of 5-fluoro-2'-deoxyuridine, 5-methoxymethyl-2'-deoxyuridine, 2'-deoxythymidine, and their corresponding 3'-p-nitrophenylphosphate and 3'-p-aminophenylphosphate derivatives were determined. The 3'-p-aminophenylphosphate-2'-deoxy-5-methoxymethyluridine derivative was as potent as 5-methoxy-methyl-2'-deoxyuridine in inhibiting herpes simplex viruses; however, 3'-p-aminophenylphosphate-2'-deoxy-5-fluorouridine was less potent than 5-fluoro-2'-deoxyuridine in inhibiting viral replication. The results suggest that the deoxypyrimidine ribonucleoside kinase has bulk tolerance for substituents at the 3-position of the ribofuranose moiety. The effect on cellular DNA and RNA synthesis and cytotoxicity toward mammalian cells were monitored by studying the incorporation of radioactive precursors. 5-Methoxymethyl-2'-deoxyuridine and 3'-p-aminophenylphosphate-2'-deoxy-5-methoxymethyluridine failed to inhibit DNA or RNA synthesis. 5-Fluoro-2'-deoxyuridine and 3'-p-aminophenylphosphate-2'-deoxy-5-fluorouridine decreased incorporation of [3H]deoxyuridine by 50% at 1.0 and 40 microM, respectively. Cytotoxicity (microscopic lesions using monolayer cells) on exposure to 5-methoxymethyl-2'-deoxyuridine, 3'-p-aminophenylphosphate-2'-deoxy-5-methoxymethyluridine, 5-fluoro-2'-deoxyuridine, and 3'-p-aminophenylphosphate-2'-deoxy-5-fluorouridine was observed at 3800, 1600, 1.6, and 110 microM, respectively.
测定了5-氟-2'-脱氧尿苷、5-甲氧基甲基-2'-脱氧尿苷、2'-脱氧胸苷及其相应的3'-对硝基苯磷酸酯和3'-对氨基苯磷酸酯衍生物的抗病毒活性、对细胞DNA和RNA合成的影响以及对哺乳动物细胞的细胞毒性。3'-对氨基苯磷酸酯-2'-脱氧-5-甲氧基甲基尿苷衍生物在抑制单纯疱疹病毒方面与5-甲氧基甲基-2'-脱氧尿苷一样有效；然而，3'-对氨基苯磷酸酯-2'-脱氧-5-氟尿苷在抑制病毒复制方面比5-氟-2'-脱氧尿苷效力低。结果表明，脱氧嘧啶核糖核苷激酶对呋喃核糖部分3位的取代基具有较大的耐受性。通过研究放射性前体的掺入来监测对细胞DNA和RNA合成的影响以及对哺乳动物细胞的细胞毒性。5-甲氧基甲基-2'-脱氧尿苷和3'-对氨基苯磷酸酯-2'-脱氧-5-甲氧基甲基尿苷未能抑制DNA或RNA合成。5-氟-2'-脱氧尿苷和3'-对氨基苯磷酸酯-2'-脱氧-5-氟尿苷分别在1.0和40 microM时使[3H]脱氧尿苷的掺入减少50%。暴露于5-甲氧基甲基-2'-脱氧尿苷、3'-对氨基苯磷酸酯-2'-脱氧-5-甲氧基甲基尿苷、5-氟-2'-脱氧尿苷和3'-对氨基苯磷酸酯-2'-脱氧-5-氟尿苷时，细胞毒性（使用单层细胞的显微镜损伤）分别在3800、1600、1.6和110 microM时观察到。
