无环核苷膦酸双（新戊酰氧甲基）前药的代谢及体外抗逆转录病毒活性
Metabolism and in vitro antiretroviral activities of bis(pivaloyloxymethyl) prodrugs of acyclic nucleoside phosphonates.
作者信息
Srinivas R V, Robbins B L, Connelly M C, Gong Y F, Bischofberger N, Fridland A
机构信息
Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee.
出版信息
Antimicrob Agents Chemother. 1993 Oct;37(10):2247-50. doi: 10.1128/AAC.37.10.2247.
Abstract
Bis(pivaloyloxymethyl) [bis(pom)] derivatives of various acyclic nucleoside phosphonates--9-(2-phosphonylmethoxyethyl)adenine (PMEA), 9-(2-phosphonylmethoxypropyl)adenine (PMPA), and 9-(2-phosphonylmethoxypropyl)diaminopurine (PMPDAP)--were found to exhibit 9- to 23-fold greater antiviral activity than their corresponding unmodified compounds. The cytotoxicity of the bis(pom) analogs was also increased by various degrees, thus altering the therapeutic indexes of these compounds. Metabolic studies using [3H]bis(pom)PMEA and [3H]PMEA as model compounds suggested a > 100-fold increase in the cellular uptake of the bis(pom) derivative and formation of active diphosphorylated metabolite. However, the bis(pom) derivatives were chemically unstable and highly susceptible to serum-mediated hydrolysis, factors which limit their potential utility for intracellular drug delivery.
摘要
各种无环核苷膦酸酯的双（新戊酰氧甲基）[双（pom）]衍生物——9-（2-膦酰甲氧基乙基）腺嘌呤（PMEA）、9-（2-膦酰甲氧基丙基）腺嘌呤（PMPA）和9-（2-膦酰甲氧基丙基）二氨基嘌呤（PMPDAP）——被发现其抗病毒活性比相应的未修饰化合物高9至23倍。双（pom）类似物的细胞毒性也有不同程度的增加，从而改变了这些化合物的治疗指数。以[3H]双（pom）PMEA和[3H]PMEA作为模型化合物的代谢研究表明，双（pom）衍生物的细胞摄取增加了100倍以上，并形成了活性二磷酸化代谢物。然而，双（pom）衍生物化学性质不稳定，极易受到血清介导的水解作用，这些因素限制了它们在细胞内药物递送方面的潜在用途。
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