This research program aims to develop efficient chemical methods for preparing complex organic molecules. If the aims of this application are achieved, biomedical researchers will have new tools for preparing and modifying the structure of stereochemically complex, polycyclic organic molecules. In the long term, the availability of this new organic synthesis methodology will facilitate discovery and production of improved chemical agents for treating medical disorders. The chemical focus of this project is to invent and develop new methods for constructing complex ring systems. One component of the project focuses on ring constructions involving cyclization and rearrangement cascades of charged intermediates. As part of this effort, total syntheses of several rare natural products will be pursued: asparagamine A, a powerful anti-abortifacient, sclerophytin A, a powerful (1ng/mL) cytotoxic agent, briarellin E, asbestinin-17 and shahamin K. A second component of this project is a comprehensive program to synthesize lead members of the recently reported adociasulfate family of kinesin motor inhibitors and to develop more potent and selective kinesin inhibitors based on this structural model. In the neurological system, kinesins power the transport of most materials from the cell body, where they are synthesized, to the axon and synapse. Kinesins are also necessary for cell division (mitotic and meiotic spindle organization) and for other vesicle and organelle transport. Selective kinesin inhibitors should be useful antimitotic or antitransport drugs as well as important tools for studying kinesin function in vivo.
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