McGuigan C, Perry A, Yarnold C J, Sutton P W, Lowe D, Miller W, Rahim S G, Slater M J
Welsh School of Pharmacy, University of Wales Cardiff, UK.
Antivir Chem Chemother. 1998 May;9(3):233-43. doi: 10.1177/095632029800900304.
A number of symmetric and asymmetric 5'-phosphate esters of the potent anti-varicella-zoster virus (VZV) agent 1-(beta-D-arabinofuranosyl)-5-prop-1-ynyluracil (882C; netivudine) were prepared as potential lipophilic, membrane-soluble prodrugs of the bio-active phosphate forms. The compounds were prepared by the base-catalysed coupling of various phosphorochloridates with the free nucleoside analogue. Compounds were fully characterized by a range of spectroscopic and analytical methods and were studied for their inhibition of several viruses in tissue culture. All of the phosphate esters were inactive against human cytomegalovirus, herpes simplex virus type 2, VZV, human immunodeficiency virus type 1 and influenza A virus (EC50 > 100 microM) except the 5'-(4-nitrophenyl phenyl) phosphate, which inhibited influenza A virus. The relative rate of esterase-mediated hydrolysis of one of the lead target structures was measured in order to rationalize the poor antiviral action, and data were collected on possible metabolites in support of this analysis. Cell-specific esterases are implicated as key determinants of the antiviral potency of prodrugs of this type.
制备了强效抗水痘带状疱疹病毒（VZV）药物1-(β-D-阿拉伯呋喃糖基)-5-丙-1-炔基尿嘧啶（882C；奈替夫定）的多种对称和不对称5'-磷酸酯，作为生物活性磷酸形式的潜在亲脂性、膜溶性前药。这些化合物通过各种氯代磷酸酯与游离核苷类似物的碱催化偶联反应制备。通过一系列光谱和分析方法对化合物进行了全面表征，并研究了它们在组织培养中对几种病毒的抑制作用。除了抑制甲型流感病毒的5'-(4-硝基苯基苯基)磷酸酯外，所有磷酸酯对人巨细胞病毒、单纯疱疹病毒2型、VZV、人类免疫缺陷病毒1型和甲型流感病毒均无活性（半数有效浓度>100μM）。测定了一种主要目标结构的酯酶介导水解的相对速率，以解释其抗病毒作用不佳的原因，并收集了可能代谢物的数据以支持该分析。细胞特异性酯酶被认为是这类前药抗病毒效力的关键决定因素。
