Current application of mass spectrometry to combinatorial chemistry.

During the past decade, combinatorial chemistry has become an integral component of nearly all drug discovery efforts (1-4). Mass spectrometry (MS) has played a key role in the advancement of combinatorial chemistry efforts: in reaction monitoring and optimization of library synthesis, in the purification of libraries synthesized in a parallel format, and in the assessment of library compound quality, as well as in screening for bioaffinity or pharmaceutical properties of the above. A number of useful books or book chapters (5-8) and review articles (9-18) have been published recently on the application of mass spectrometry to combinatorial chemistry. A few words about the scope of this review article. As nearly all of the pharmaceutical industry now synthesizes and screens single pure entities generated in a parallel format as opposed to combinatorial mixtures (19), this review will deal primarily with parallel synthesis applications. Classical combinatorial libraries made with one-bead-one-compound or split synthesis methods are not reviewed here as efforts in this area are only minimally continued at present. For the interested reader, good recent reviews can be found encompassing the mixture library analysis by MS (5-16, 18). Further, as the vast majority of combinatorial libraries currently being synthesized are small organic molecules (20), this review will not include efforts in peptide and oligonucleotide library synthesis. Relevant references on the analysis of oligomer libraries can be found in reviews (5-16, 18). Small-molecule libraries synthesized in the parallel format may be those directed toward either lead discovery or lead optimization and may be synthesized either on a solid support or in solution. The large numbers of discrete compounds generated require analysis and, most frequently purification. This review will focus upon how mass spectrometry assists in those efforts. High-performance liquid chromatography (HPLC) is an important tool in the analysis and purification of discrete library compounds, often coupled with mass spectrometry (LC/MS). For the interested reader, a good review (21) of HPLC, including equipment, columns, and detectors, is available by LaCourse. A list of abbreviations used in this review may be found at the end of the article.