Applications of New Mass Spectral Techniques

该项目的目标是开发新的质谱技术，以提供创新和/或更快速的解决方案，解决涉及（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的测量。电喷雾离子化质谱（ESI/MS）、串联质谱（MS/MS）、液相色谱-质谱联用（LC/MS）和基质辅助激光解吸电离（MALDI）质谱是当前感兴趣的技术。一个窄孔（2 mm内径，0.200 ml/min），反相液相色谱系统，其流动可自动转向，用于在线样品分离，与串联质谱联用测定II期抗艾滋病药物2 '-b-氟-2'，3 '-双脱氧腺苷（碘腺苷，F-ddA），其抗HIV活性脱氨基代谢物2 ′-b-氟-2 ′，3 ′-双脱氧肌苷（F-ddI）和伴随抗逆转录病毒药物司他夫定（2 '-脱氧胸苷烯，d4 T），具有高特异性和灵敏度。这种方法已被应用于确定口服F-ddA的药代动力学，代谢和处置过程中的I期临床试验，这种药物在艾滋病患者接受联合抗逆转录病毒治疗。采用快速原子轰击质谱法（FAB/MS）通过新化合物和合成中间体的结构表征来支持LMC合成工作。通过三维数据库检索确认HIV-1整合酶抑制剂化合物结构特性的质谱研究正在进行中。已经启动了一个项目，利用质谱和核磁共振分析进行结构表征和纯度测定，以评价NCI化学数据库中化合物的质量。 正在使用统计和聚类方法来选择代表数据库结构多样性的化合物进行分析。 AIDS题目：新型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