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. Matrix-assisted laser desorption ionization (MALDI) mass spectrometry, 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 accurate mass measurement are the techniques of current interest. 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. A collaborative mass spectrometric and molecular modeling study has been initiated to investigate the factors controlling alkali metal ion cationization during ionization from the liquid phase (ESI/MS and FAB/MS). Under normal circumstances, alkali metal ion cationization is not desirable because it can decrease sensitivity and/or complicate spectral interpretation. However, for certain classes of compounds, such as oligosaccharides and sesquiterpenoids, selective and controlled cationization can confer an analytical advantage. Derivatives of the antimarial natural product artemisinin (qinghaosu), including a series of trioxane dimers with antitumor activity, are being used as model compounds since they require alkali metal ion cationization to obtain useful mass spectra. Our initial investigation focusing on dihyroartemisinin shows that adduct formation is cation and ionization technique selective. Molecular modeling calculations for this compound indicate binding energies for gas phase cationization that are the opposite of what is observed in the mass spectra. A consideration of cation solvation in the liquid matrix is required before the predicted results correspond to the potassium ion complex formation that is observed. Thus it appears that cation adducts formed during ionization from a liquid phase represent at least partially the state of the analyte in the matrix. Fast atom bombardment mass spectrometry (FAB/MS) is employed to support the LMC synthetic effort through structural characterization of new compounds and synthetic intermediates. Strategies for the rapid mass spectral characterization of combinatorial libraries of synthetic analogues based on the diacylglycerol cyclic lactone template are being evaluated and implemented using FAB/MS. The goal is the structural characterization of all 96 library components in a single day. 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 has been completed. Statistical and clustering methods have been used to select 300 compounds representative of the structural diversity of this publically accessible, small molecule database of over 250,000 structures for analysis. A validation set consisting of 38 of these compounds that are commercially available has also been obtained and analyzed as an internal quality control. 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. A series of novel cytotoxic isoquinoline quinones and iminoquinones isolated from the marine bryozoan Caulibugula intermis have been characterized by accurate mass analysis as part of their structural elucidation.
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