In the last funding period we developed a platform to allow post-docs and graduate students to construct libraries of potentially biologically active small molecules in a format that allows efficient screening. In this funding period, we will capitalize on the investment already made by developing libraries based on two approaches in which cycloaddition is followed by specific bond breakage: (1) a macrocyclic scaffold derived from a steroid ring system by sequential cycloaddition and retrocycloaddition; and (2) a library of biaryl macrocycles derived from a cycloaddition/fragmentation strategy. We also plan to perform follow-up chemistry on a number of dihydropyrancarboxamides identified as inhibitors of mitosis during the previous funding period. A second set of technologies developed in the previous funding period allows our library molecules to be arrayed on glass slides and probed with labelled proteins. We plan to exploit these fast, cheap binding assays as a general route to target identification for compounds identified as biologically active in a phenotypic assay.
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