In the previous funding period we developed a standardized library format and a technology platform that allows synthetic molecules to be tested against a wide range of biological assays. We have also developed a wide range of novel reaction pathways on the solid phase, and have used these to produce libraries that are now entering biological testing, with promising results. In the next funding period, we propose to greatly extend the variety of small molecules available to the biology projects by exploring three new concepts for achieving diversity in the skeleton of the small molecule, as opposed to the functionality that it displays. We propose to explore (1) the diverse chemical reactivity of organoboron species; (2) the use of """"""""folding"""""""" pathways to generate a variety of different-sized rings using common reaction conditions; and (3) a novel approach to stereochemically diverse structures based on the spirooxindole skeleton (a family of molecules with proven relevance for the study of cancer biology). Related concepts will also be explored in Project 3. As we receive information on the biological activity of libraries from the previous funding period, and the new libraries we will make this period, from Projects 1 and 2 we will work with Core B to develop sets of molecular descriptors that will help us develop new libraries with improved biological activity.
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