The rapid assembly of complex molecules continues to be of great interest in diversity-oriented synthesis (DOS) as a means to discover novel chemotypes and pharmacological tools. Synthesis of chemical libraries in this manner has employed both stereochemical and skeletal diversity. A distinct approach to obtain molecules with novel pharmacological properties involves library synthesis based on various core scaffolds derived from natural products. This proposal outlines specific plans for a Pilot Libraries (P41) initiative to generate a number of stereochemically and structurally complex chemical libraries for inclusion in the National Institutes of Health (NIH) Molecular Repository. Five library projects are planned reflecting the Principal Investigator's (PI's) and Co-Principal Investigators' (Co-PIs') continued interest in the design of natural product-like molecules using stereochemical and positional variation within the molecular framework. A total of 16 complex libraries are outlined which are distinct from ongoing and planned Center for Chemical Methodology and Library Development (CMLD-BU) library projects. Target pilot libraries include complex dihydropyrimidones, azaphilone-derived libraries, tetracyclic alkaloid-type libraries, exo-methylene scaffolds and derived spirocycles, and macrocyclic lactam frameworks. In addition, all planned libraries have been designed to include unique structures that do not overlap in chemical space with molecules currently in the PubChem database. In order to facilitate synthesis and timely delivery of libraries to the NIH repository, emphasis has been placed on utilization of chemistries previously established in the Pi's and co-PIs' laboratories. A central mechanism for data sharing for the Pilot Library initiative involves using an internet-based structure-searchable database of synthesis protocols. Inclusion of the target libraries that will be developed in this effort in the NIH repository is anticipated to facilitate discovery of new pharmacological tools for investigation of cellular processes. ? ?
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