The central objective of this project is to increase the range, repertoire, and ease of use of mixture-based synthetic combinatorial libraries. The use of carefully prepared mixtures of compounds enable the timely and economical identification of active leads in the majority of bioassays. All of the libraries will be generated in positional scanning format. The positional scanning deconvolution process, also developed in the Principal Investigator's laboratory, allows the most active chemical group(s) at each position of the molecule to be identified direct from the initial screening data. Two synthetic strategies will be used for expanding the library diversities. Thus, Specific Aim 1 will be based on the """"""""libraries from libraries"""""""" approach, developed in the Principal Investigator's laboratory, for the transformation of existing peptide, peptidomimetic, and heterocyclic combinatorial libraries into new diversities often having completely different physicochemical properties relative to the original libraries. Such chemical modifications, including reduction, oxidation, alkylation, dehydration, cyclization, etc., will allow the generation of libraries of bicyclic guanidines, cyclic ureas, hydantoins, indole imidazoles, polyamines, hydroxylamines, nitrosamines, etc. As described in Specific Aim 2, the second strategy will involve the step-wise solid phase synthesis of new pharmacophores in combinatorial formats. These will include the generation of thiomorpholinones, stryl quinazolinones, and diazepines. The chemical alterations described in Specific Aim 1, as well as the development of new solid phase synthetic routes to heterocyclic compounds (described in Specific Aim 2) will continually expand the diversities of compounds available for screening programs. In particular, the driving force for the generation of such new libraries will be primarily focused on the need for projects III and IV. In addition to the monomeric compound libraries mentioned above, Specific Aim 3 will address the development of non-natural polymeric combinatorial libraries. These will initially entail the preparation of poly 1,2-diketo 3-substituted piperazines, poly 3-substituted piperazines, as well as a combination of these two. These polymeric compound libraries will be screened in Projects II, III, and IV. The diversity of the chemical structures proposed for development, as well as the large number of compounds for each class of structures, is expected to greatly increase the probability of identifying highly active compounds having potential therapeutic utility.
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