Applications of New Mass Spectral Techniques

该项目的目标是开发新的质谱技术，以便为涉及(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（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）质谱联用是目前关注的技术。窄孔反相液相色谱法已与串联质谱法相结合，开发了一种通用系统，用于表征和测量生物样品中的核苷类药物。在线样品浓缩技术正在被研究，作为将CE与纳米电喷雾电离质谱相结合，用于分析细胞内核苷酸代谢物的前奏。制备规模的CE也正在被研究作为一种离线方法，将CE与高分辨率MALDI/MS和源后衰变碎片分析相结合。快速原子轰击质谱（FAB/MS）通过对新化合物和合成中间体的结构表征来支持LMC的合成工作。通过三维数据库搜索确认HIV-1整合酶抑制剂化合物结构特性的研究仍在继续。一项利用质谱和核磁共振分析对NCI化学数据库中的化合物进行结构表征和纯度测定的质量评估项目即将完成。统计和聚类方法已被用于选择化合物的结构多样性代表这个公开访问的，超过250,000个结构的小分子数据库进行分析。由于检测的化合物中有31%被评为不可接受（没有光谱证据表明存在所需化合物或污染物超过样品的50%），因此在使用该数据库中的化合物时必须谨慎。

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. On-line sample concentration techniques are being investigated as a prelude to interfacing CE to nano-electrospray ionization mass spectrometry for the analysis of intracellular nucleotide metabolites. Preparative-scale CE is also being investigated as an off-line method for combining CE with high resolution MALDI/MS and post-source decay fragmentation analysis. Fast atom bombardment mass spectrometry (FAB/MS) is employed to support the LMC synthetic effort through structural characterization of new compounds and synthetic intermediates. 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 compounds in the NCI chemical database using MS and NMR analysis for structural characterization and determination of purity is nearing completion. Statistical and clustering methods have been used to select compounds representative of the structural diversity of this publically accessible, small molecule database of over 250,000 structures for analysis. Since 31% of the compounds examined have been rated as unacceptable (no spectral evidence for the presence of the desired compound or contaminants exceed 50% of the sample), care must be exercised in using compounds from this database. AIDS Title: Application of New Mass Spectral Methods for the Analysis of Anti-AIDS Agents