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），采用反相液相色谱串联质谱技术，建立了快速测定抗艾滋病药物2-b-氟-2，3-二脱氧腺苷的方法（碘腺苷，F-ddA），其抗HIV活性脱氨基代谢物2-b-氟-2，3-二脱氧肌苷（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。这种方法正在应用于确定口服F-ddA的药代动力学，代谢和处置过程中，这种药物在艾滋病患者接受联合抗逆转录病毒治疗的I期临床试验。快速原子轰击质谱法（FAB/MS）用于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。FAB液相基质反应涉及离子配对、还原、脱卤和自由基阳离子/阴离子的形成，这些反应将继续被研究和表征，以确保这些分析的可解释性和可靠性。质谱新方法在抗艾滋病药物分析中的应用--电喷雾离子化、液相色谱-质谱、质谱、药代动力学、串联质谱，2 '-β-氟-2'，3 '-二脱氧腺苷，-人体组织、液体、细胞等

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 employed to develop a rapid method utilizing tandem mass spectrometry for measuring 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 is being 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 used 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. FAB liquid matrix reactions involving ion pairing, reduction, dehalogenation and radical cation/anion formation continue to be studied and characterized to ensure the interpretability and reliability of these analyses.AIDS Title: Application of New Mass Spectral Methods for the Analysis of Anti-AIDS Agents - electrospray ionization, liquid chromatography - mass spectrometry, mass spectrometry, pharmacokinetics, tandem mass spectrometry, 2'-beta- fluoro-2',3'-dideoxyadenosine, - Human Tissues, Fluids, Cells, etc.