The reduction of selected redox indicator dyes during fast atom bombardment mass spectrometry was investigated in several different matrices. Reduction is indicated by the incorporation of one or more hydrogens into the cation of the dye. The extent of reduction of the analyte can be related to the E 1/2 value of the reduction potential of the dye. Selection of matrix also influences the reduction, the reducing power decreasing in the order glycerol greater than sulfolane greater than thioglycerol greater than hydroxyethyl disulfide greater than nitrobenzyl alcohol. Evidence is given suggesting that reduction is initiated by exposure of the analyte-matrix mixture to atom bombardment. It is shown that reduction can be controlled by the addition of metal ions with a very low reduction potential to the matrix to act as electron scavengers.
In this Section, we review the applications of mass spectrometry for the analysis and purification of new chemical entities (NCEs) for pharmaceutical discovery. Since the speed of synthesis of NCEs has dramatically increased over the last few years, new high throughput analytical techniques have been developed to keep pace with the synthetic developments. In this Section, we review both novel, as well as modifications of commonly used mass spectrometry techniques that have helped increase the speed of the analytical process. Part of the review is devoted to the purification of NCEs, which has undergone significant development in recent years, and the close integral association between characterization and purification to drive high throughput operations. At the end of the Section, we review potential future directions based on promising and exciting new developments.
High-throughput parallel synthesis of library compounds for early drug discovery requires high-throughput analytical methods to confirm synthesis, identify reaction products, and determine purity. An ultrafast 1.0-min HPLC/UV/ELSD/MS method was developed and compared to our standard 2.5- and 5.0-min methods in order to determine if the faster method was appropriate to evaluate compound synthesis and determine purity. In addition to using standard test mixtures, a 400-member library produced by high-throughput parallel synthesis was used for comparing the various methods. Mass spectrometric detection was used for compound identification, while UV and ELSD data offered purity assessment. Compared to our longer separations, chromatographic separation achieved using the 1.0-min method was sufficient for compound evaluation and purity assessment. This ultrafast 1.0-min HPLC/UV/ELSD/MS method is expected to increase analytical throughput tremendously, provide important information faster, and reduce the overall cycle time from synthesis to screening.
The fast atom bombardment mass spectra of mixtures of peptide ligands exhibit well-defined peaks corresponding to protonated molecular Ions of ligand complexes. Quantitative selectivity in complex formation between ligands is indicated. A split-probe-tlp experiment has been designed in which individual ligand solutions are placed one on each half of the probe tip and exposed simultaneously to the atom beam. In systems where complexatlon requires interaction at several sites, no protonated complex formation is observed under these conditions. Complexes formed by simple single-site ionic Interactions, on the other hand, are readily formed in this system. The data suggest that complexatlon Is, at least in part, the result of solution (or possibly selvedge-induced) interactions as opposed to a vapor-phase phenomenon.
Orthoquinone diazides, which are widely used in microlithography, have attracted considerable attention, especially in terms of their application in the production of high-contrast resists. Previous electron impact mass spectrometric results have confirmed that the primary fragmentation process of these compounds is the elimination of N, to form an indenoketene ion. This is analogous to the photodecomposition pathway which makes them effective in the lithographic process. Those results also revealed the occurrence of an alternative process, which involves a twohydrogen reduction of the intermediate species formed prior to conversion to the ketene. The present study investigates the behaviour of the orthoquinone diazides when there is an abundance of protons available to form the reduction product. Several different types of diazonaphthalenone sulfonyl esters, ranging in complexity from the monosubstituted phenol esters to disubstituted dihydroxybenzophenones, were examined using fast atom bombardment mass spectrometry. Although reduction was the primary process in the hydrogen-rich matrices, the extent of reduction was characteristic of the particular isomer as well as the matrix used.
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