We plan to use our collective long standing expertise in the diversity oriented synthesis of small molecule compounds for the preparation of a range of 20-26 structurally unique pharmacophores. The proposed strategies and synthetic approaches will lead in a predictable fashion to diversities of multiple chemical probes and will generate a variety of compound types. We will employ both solid and solution phase methods. The synthetic approaches to be pursued while direct and productive, are highly practical and reproducible. The target compounds will therefore be unique and will capitalize on our strength in the utilization of synthetic """"""""simplicity"""""""" for the design and the successful parallel synthesis of large numbers of compounds. Thus, we will use different strategies for the diversity-oriented synthesis of a variety of unique heterocyclic compounds that will enrich the MLSMR collection of small molecules. Compounds will include differing diaza and triazacyclic compounds and diverse fused heterocyclic compounds such as triazinobenzimidazoles and novel fused tetra and pentacyclic o-carbolines [sic]. In addition, one of the approaches we will use in this application is to target libraries of Favored Pharmacophores and employ the Heteroatom Incorporation Strategy (HIS) to generate novel libraries using diversity-oriented synthesis. The libraries are designed in a manner to balance size, diversity, complexity and purity. This is essential to avoid false positives during the screening process. All proposed small molecule libraries are designed with regard to known drug-likeness rules including 'Lipinski's Rule of Five'. All structurally unique libraries will consist of 100-200 individual compounds each and will be prepared with purity equal or higher than 90%. As required by the RFA, 10 to 20 mg of each compound will be prepared and transferred to the NIH small Molecule Repository with the detailed synthetic experimental information and solubility properties. The libraries proposed are designed in a manner which balances molecular weight, diversity, complexity and purity. These have been chosen in a manner which does not overlap in chemical space with molecules currently in the PubChem database. The majority of the chemistries are well established in the PI's and Co-PI's laboratories. There has been and continues to be, a longstanding collaborative interaction between the PIs at Torrey Pines Institute for Molecular Studies and the Burnham Institute for Medical Research, which is part of the Molecular Library Screening Center Network (MLSCN). We thus have ready access to equipment and personnel at both organizations and to the MLSCN.
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