The overall goal of the chemistry section of this Program Project grant application is the demonstration of new strategies for mechanism-based cancer drug discovery using solid-phase and novel fluorous phase combinatorial synthesis as well as phase-switching methods. Lead structure identification is derived from natural products and target-based array design. High quality, single-compound libraries will provide the broad structure-activity relationship necessary for rational lead optimization. Specifically, we have two major synthetic goals: . to optimize solid phase and fluorous phase synthesis protocols for the preparation of a library of ca. 5,000 potential phosphatase inhibitors derived from the natural products microcystin LR and calyculin A; . to apply a combined solid-phase/fluorous phase strategy for the preparation of libraries containing ca. 1,000 analogs of the anti-mitotic cyanobacterium metabolite curacin A and ca. 500 analogs of the structurally complex anti-mitotic marine natural product discodermolide. The proposed program represents a multi-dimensional effort to improve current methodologies for the combinatorial synthesis of libraries of organic molecules, establish new strategies for the use of natural products as lead structure for drug discovery, and identify novel mechanism-based anti-cancer agents.
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