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。电喷雾电离质谱仪(ESI/MS)、串联质谱仪(MS/MS)、液-质联用(LC/MS)和基质辅助激光解吸电离(MALDI)是目前研究的热点。窄口径(2 mm内径，0.200毫升/分钟)反相液相色谱系统，其流动可自动分流用于在线样品脱盐，与串联质谱仪相结合，用于检测人血浆中II期抗艾滋病药物2‘-b-氟-2’，3‘-二脱氧腺苷(lodenosine，F-Dda)及其抗艾滋病毒活性脱氨代谢物2’-b-氟-2‘，3’-二脱氧肌苷(F-DDI)和伴随的抗逆转录病毒药物司他夫定(2‘-脱氧胸腺苷，d4T)，具有高特异性和灵敏度。这一方法学已被应用于在接受联合抗逆转录病毒治疗的艾滋病患者的I期临床试验中确定口服F-Dda的药代动力学、代谢和处置。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正在进行中。已经启动了一个项目，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，以评估这些化合物的质量。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) 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