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）、毛细管电泳-质谱联用（CE/MS）和基质辅助激光解吸电离（MALDI）质谱是当前感兴趣的技术。窄口径，反相液相色谱法已与串联质谱法相结合，以开发一个通用的系统，用于表征和测量生物样品中的核苷类药物。在接受联合抗逆转录病毒治疗的晚期艾滋病患者口服F-ddA的I-II期临床试验期间，该方法已被应用于确定2 '-b-氟-2'，3 '-双脱氧腺苷（碘腺苷，F-ddA）及其抗HIV活性脱氨基代谢物2'-b-氟-2 '，3'-双脱氧肌苷（F-ddI）的药代动力学、代谢、处置和生物利用度。在线样品浓缩技术正在研究的前奏接口毛细管电泳纳米电喷雾电离质谱分析细胞内的核苷酸代谢物。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仍在继续。目前正在进行一个项目，利用质谱和核磁共振分析来评价国家化学研究所化学数据库中化合物的质量，以确定其结构特征和纯度。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), combined capillary electrophoresis-mass spectrometry (CE/MS) and matrix-assisted laser desorption ionization (MALDI) mass spectrometry are the techniques of current interest. Narrow-bore, reversed-phase liquid chromatography has been combined with tandem mass spectrometry to develop a general purpose system for characterizing and measuring nucleoside-based drugs in biological samples. This methodology has been applied to determine the pharmacokinetics, metabolism, disposition and bioavailability of 2'-b-fluoro-2',3'-dideoxyadenosine (lodenosine, F-ddA) and its anti-HIV-active deaminated metabolite 2'-b-fluoro-2',3'-dideoxyinosine (F-ddI) during a Phase I-II clinical trial of oral F-ddA in advanced AIDS patients receiving combination antiretroviral therapy. On-line sample concentration techniques are being investigated as a prelude to interfacing capillary electrophoresis to nano-electrospray ionization mass spectrometry for the analysis of intracellular nucleotide metabolites. 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 continue. 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 is ongoing. Statistical and clustering methods are being used to select compounds representative of the structural diversity of the database for analysis. AIDS Title: Application of New Mass Spectral Methods for the Analysis of Anti-AIDS Agents