Function and Informatics Driven Assembly of New Pilot Scale Libraries

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DESCRIPTION (provided by applicant): The objective of this project is to assemble a series of pilot-scale heterocyclic libraries to enable the discovery of new bioactive chemotypes by accessing the regions of chemical diversity space, which are not represented in the PubChem database and absent in the NIH Molecular Libraries Small-Molecule Repository (MLSMR). The design of such libraries will be guided by three main considerations, including (a) validated biological activity of closely related chemotypes; (b) rigorous computational analysis of favorable physicochemical properties; and (c) development of concise, parallel synthetic protocols to enable efficient assembly of parent libraries, resupply of active compounds and construction of focused libraries. The project is divided into four specific aims, including (a) construction of libraries based on dihydroquinolone and quassinoids; (b) assembly of scaffold-diversified pyrrolidinone libraries; (c) synthesis of tricyclic benzodiazepine-fused library; and (d) assembly of polycyclic amino guanidine-based libraries. We will prepare seven heterocyclic libraries (3,600 new compounds), which are designed to expand the MLSMR collection with sophisticated, natural product-like compounds in order to enable identification of new small- molecule modulators of diverse biological functions. PUBLIC HEALTH RELEVANCE: The objective of this project is to assemble a series of chemical libraries which are not represented in the PubChem database and absent in the NIH Molecular Libraries Small-Molecule Repository. Subsequent high-throughput biological screening of such compound libraries will produce new chemical tools, large amount of publicly accessible information, and will facilitate basic biomedical research and development of new therapeutic agents.