Applications of New Mass Spectral Techniques

该项目的目标是开发新的质谱学技术，以便为涉及(1)化学结构确定、(2)复杂混合物分析和(3)生物系统中痕量组分测量的问题提供创新和/或更快速的解决方案。电喷雾质谱(ESI/MS)、串联质谱(MS/MS)、液质联用(LC/MS)、毛细管电泳质谱(CE/MS)和基质辅助激光解吸电离(MALDI)是目前研究的热点。窄口径反相液相色谱与串联质谱仪相结合，开发了一种生物样品中核苷类药物的通用表征和测量系统。在接受联合抗逆转录病毒治疗的晚期艾滋病患者口服2‘-b-氟-2’，3‘-二脱氧腺苷(F-Dda)的I-II期临床试验中，应用该方法学测定了2’-b-氟-2‘，3’-二脱氧腺苷(F-Dda)及其抗HIV活性脱氨代谢物2‘-b-氟-2’，3‘-二脱氧肌苷(F-DDI)的药代动力学、代谢、处置和生物利用度。在线样品浓缩技术是毛细管电泳联用纳米电喷雾电离质谱仪分析细胞内核苷酸代谢物的前奏。通过对新化合物和合成中间体的结构表征，快原子轰击质谱仪(FAB/MS)被用于支持LMC的合成工作。通过三维数据库搜索确认被确认为HIV-1整合酶抑制剂的化合物的结构同一性的质谱学研究仍在继续。目前正在进行一个项目，利用MS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，以评估化合物的质量。正在使用统计和分组方法来选择代表数据库结构多样性的化合物进行分析。 艾滋病：新的质谱学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