McGuigan C, Pathirana R N, Balzarini J, De Clercq E
Department of Chemistry, University of Southampton, Highfield, U.K.
J Med Chem. 1993 Apr 16;36(8):1048-52. doi: 10.1021/jm00060a013.
Novel aryl phosphate derivatives of the anti-HIV nucleoside analogue AZT have been prepared by phosphorochloridate chemistry. These materials were designed to act as membrane-soluble prodrugs of the bioactive free nucleotides. In vitro evaluation revealed the compounds to have a pronounced, selective anti-HIV activity in CEM cells; the magnitude of the biological effect varied considerably depending on the nature of the phosphate blocking group. Moreover, several of the compounds retain marked antiviral activity in TK- (thymidine kinase-deficient) mutant CEM cells in which AZT was virtually inactive. These data strongly support the hypothesis that the AZT phosphate derivatives exert their biological effects via intracellular release of AZT nucleotide forms and suggest that the potential of nucleoside drugs in antiviral chemotherapy may be enhanced by suitable nucleotide delivery strategies.
通过磷酰氯化学方法制备了抗艾滋病毒核苷类似物齐多夫定（AZT）的新型芳基磷酸酯衍生物。这些物质被设计用作生物活性游离核苷酸的膜溶性前药。体外评估显示，这些化合物在CEM细胞中具有显著的、选择性抗艾滋病毒活性；生物效应的大小因磷酸酯阻断基团的性质而有很大差异。此外，几种化合物在TK-（胸苷激酶缺陷型）突变CEM细胞中仍保留显著的抗病毒活性，而在这些细胞中AZT几乎没有活性。这些数据有力地支持了这样一种假说，即AZT磷酸酯衍生物通过细胞内释放AZT核苷酸形式发挥其生物学效应，并表明合适的核苷酸递送策略可能会增强核苷类药物在抗病毒化疗中的潜力。
