Applications of New Mass Spectral Techniques

该项目的目标是开发新的质谱技术，以便为涉及(1)化学结构测定，(2)复杂混合物分析和(3)生物系统中痕量成分测量的问题提供创新和/或更快速的解决方案。电喷雾电离质谱法（ESI/MS）、串联质谱法（MS/MS）、液相色谱-质谱联用法（LC/MS）和基质辅助激光解吸电离质谱法（MALDI）是目前研究的热点技术。窄孔（2毫米直径，0.200毫升/分钟）反相液相色谱系统，其流量可以自动转移用于在线样品脱盐，正在与串联质谱联用来测量II期抗艾滋病药物2'-b-氟-2',3'-二脱氧腺苷（lodenosine, F-ddA），其抗hiv活性脱胺代谢物2'-b-氟-2',3'-二脱氧腺苷（F-ddI）和伴生抗逆转录病毒药物司他夫定（2'-脱氧胸苷）。d4T)在人血浆中具有高特异性和敏感性。在一项接受抗逆转录病毒联合治疗的艾滋病患者的I期临床试验中，该方法已被应用于确定口服f - da的药代动力学、代谢和处置。快速原子轰击质谱（FAB/MS）通过对新化合物和合成中间体的结构表征来支持LMC的合成工作。质谱研究正在进行中，通过三维数据库搜索来确认被鉴定为HIV-1整合酶抑制剂的化合物的结构特征。一项利用质谱和核磁共振分析对NCI化学数据库中的化合物进行结构表征和纯度测定的质量评估项目已经启动。正在使用统计和聚类方法来选择具有数据库结构多样性代表性的化合物进行分析。题目：新的质谱方法在抗艾滋病药物分析中的应用

The objective of this project is development of new mass spectral techniques in order to provide innovative and/or more rapid solutions to problems involving (1) chemical structure determination, (2) complex mixture analysis and (3) measurement of trace components in biological systems. Electrospray ionization mass spectrometry (ESI/MS), tandem mass spectrometry (MS/MS), combined liquid chromatography-mass spectrometry (LC/MS) and matrix-assisted laser desorption ionization (MALDI) mass spectrometry are the techniques of current interest. A narrow-bore (2 mm i.d., 0.200 ml/min), reversed-phase liquid chromatography system, whose flow can be automatically diverted for on-line sample desalting, is being used in combination with tandem mass spectrometry to measure the Phase II anti-AIDS drug 2'-b-fluoro-2',3'-dideoxyadenosine (lodenosine, F-ddA), its anti-HIV-active deaminated metabolite 2'-b-fluoro-2',3'-dideoxyinosine (F-ddI) and the companion antiretroviral agent stavudine (2'-deoxythymidinene, d4T) in human plasma with high specificity and sensitivity. This methodology has been applied to determine the pharmacokinetics, metabolism and disposition of oral F-ddA during a Phase I clinical trial of this agent in AIDS patients receiving combination antiretroviral therapy. Fast atom bombardment mass spectrometry (FAB/MS) is employed to support the LMC synthetic effort through structural characterization of new compounds and synthetic intermediates. Mass spectrometric studies to confirm the structural identity of compounds identified as HIV-1 integrase inhibitors through 3-dimensional database searching are ongoing. A project to evaluate the quality of the compounds in the NCI chemical database using MS and NMR analysis for structural characterization and determination of purity has been initiated. Statistical and clustering methods are being used to select compounds representative of the the structural diversity of the database for analysis. AIDS Title: Application of New Mass Spectral Methods for the Analysis of Anti-AIDS Agents