THE ANALYTICAL CHEMISTRY OF ANTI-AIDS AGENTS

本项目的目标是研究和开发适合 分析方法：（1）确定结构和纯度 潜在的抗艾滋病药物和新的抗病毒药物，（2）确定 物理、化学和生物化学性质，包括辛醇-水 分配系数，这些化合物及其代谢物，和（3） 测量生物样品中的这些药物及其代谢物， 阐明药理学并确定药代动力学。 高性能 重点介绍了质谱、液相色谱和质谱 技术. 糖氟化双脱氧核苷，包括 2 ′-F-dd-ara-A、2 ′-F-dd-ara-I和6-取代的-2 ′-F-dd-嘌呤是 目前主要关注的化合物。 高效液相色谱法 测量血浆、尿液和血浆中的2 '-F-ara-ddA和2'-F-dd-ara-I， 脑脊液已经被开发、验证并应用于 测定猴和大鼠的血浆和CSF药代动力学。 2 '-F-ara-ddA表现出增强的中枢神经系统渗透， 在这两个物种中的肌苷类似物。 腺苷的作用 脱氨酶在前药活化中的作用正在研究中。

The objective of this project is the research and development of suitable analytical methods to: (1) establish the structure and purity of potential anti-AIDS agents and new antiviral drugs, (2) determine physical, chemical and biochemical properties, including octanol-water partition coefficients, of these compounds and their metabolites, and (3) measure these drugs and their metabolites in biological samples to elucidate pharmacology and to determine pharmacokinetics. High-perfor- mance liquid chromatography and mass spectrometry are emphasized techniques. Sugar-fluorinated dideoxynucleosides, including 2'-F-dd-ara-A, 2'-F-dd-ara-I, and 6-substituted-2'-F-dd-Purines, are currently the compounds of primary interest. An HPLC method for measuring both 2'-F-ara-ddA and 2'-F-dd-ara-I in plasma, urine and cerebrospinal fluid has been developed, validated and applied to determine plasma and CSF pharmacokinetics in monkeys and rats. 2'-F-ara-ddA exhibits enhanced central nervous system penetration with respect to its inosine analogue in both species. The role of adenosine deaminase in prodrug activation is under investigation.