The primary aim of the Core C facility is synthesis of chemical building blocks (or intermediates) to facilitate the generation of Focused Chemical Libraries in Projects 1, 2, 3, 4 &5 of the P01 program and to assist Projects 1, 2, 3, 4 and 5 with multi-gram scale re-synthesis of lead compounds for their in-vivo animal studies. The specific functions of Core C will include: ? The synthesis of unique chemical building blocks that are not commercially available for use by the projects for combinatorial and parallel chemistry. The chemical space explored by Projects 1, 2, 3, 4 and 5, via the synthesis of combinatorial libraries, will therefore be expanded in an efficient and exclusive manner. ? The multi-gram scale re-synthesis of lead and key compounds for advanced drug property studies within the projects to evaluate in-vivo activity, toxicity, selectivity, metabolism and molecular mechanism. The compounds chosen as leads from Projects 1, 2, 3, 4 and 5 need to be re-synthesized with the highest levels of purities (at least 99% pure by HPLC) possible. It is time consuming to validate the reaction conditions, purification and analytical techniques (HPLC and LCMS) necessary to provide pure materials. Researchers whose primary responsibility is lead discovery and optimization would have to devote a considerable amount of time to the re-synthesis of a particular target compound, which could have an adverse effect on their primary goal. Molecular diversity within a combinatorial library is created by attaching chemical building blocks to scaffolds or intermediates. This diversity is highly dependent upon the quality of the building block set used within the library. By providing new building blocks, novel chemical and biological space can be probed, thereby increasing the chances of discovering new highly potent anticancer agents. Flexible synthetic routes will be developed that provide novel building blocks designed to incorporate drug-like properties. Wherever possible the building blocks and their derivatives will be shared across the projects. For these reasons, chemical building block synthesis and multi-gram scale re-synthesis support will play a key role in both integrating the different projects and in achieving the goals of the P01 in identifying a number of potent and selective compounds as tools to fully investigate the biological significance of their signal transduction targets in Projects 1, 2, 3, 4 and 5 and for pre-clinical evaluation as anticancer drugs.
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