The natural products under study in this project possess potent biological activities including antibacterial and anticancer effects. Our continued synthetic studies made possible by this Administrative Supplement, combined with the proposed biological studies of our collaborators, will contribute to basic science aimed at intervention of human disease, including bacterial infection and cancer while also opening avenues for novel therapeutics. A recent discovery that we would like to fully explore is a direct synthesis of cyclic guanidines (2-amino imidazolines) through 1,3-dipolar cycloadditions of a 2-amido 1,3-diamino allyl cation with alkenes. In addition, we seek to further demonstrate an innovative strategy for total synthesis that we term ?pharmacophore-directed retrosynthesis (PDR).? This strategy begins with a hypothesized pharmacophore for a bioactive natural product which informs and directs the retrosynthetic strategy. Stepwise, methodical introduction of complexity to this pharmacophore enables concurrent structure-activity relationship (SAR) studies that in turn informs bioactive probe synthesis useful for cellular target identification. This proposal focuses on application of PDR to several compelling bioactive natural products including: (i) the b-lactone containing antitumor/antibiotic oxazolomycin A to enable comparative proteomics studies by the Sieber Lab (Tech. Univ. of Munich) with increasingly complex side-chains attached to the presumed spiro-b-lactone pharmacophore; (ii) the potent antiproliferative agent salarin C through chemo- and site-selective elaboration of proposed more stable bioactive macrocycles that preclude Wasserman rearrangement, possess the proposed reactive allylic epoxide, and enable SAR studies and target identification studies by the Liu Lab (Johns Hopkins); (iii) the potent cancer stem cell and glioblastoma antiproliferative agent, ophiobolin A, and simplified keto aldehyde-containing, pyrrole forming derivatives to be assayed by the Taube (Baylor) and Kornienko (Texas State) Labs while alkynylated versions will be subjected to proteomics studies by the Cravatt Lab (Scripps). The proposed studies made possible by this Supplement, in addition to further demonstrating the utility of PDR and the newly discovered 1,3-dipoloar cycloaddition, will enable continuation of our research momentum ultimately leading to the identification of novel, simplified bioactive natural product derivatives, cellular targets or novel binding sites of known cellular targets critical for disease intervention, and define the potential of these novel natural product derivatives as drug leads.
The proposed studies will open new avenues for small molecule intervention against cancer, and infectious disease through development of new synthetic methodologies. The natural products to be synthesized and simplified potent derivatives identified in route to the natural product, along with derived cellular probes, will lead to identification of novel therapeutic targets or novel binding sites of known therapeutic targets that will impact the treatment of human disease. The identification of novel small molecule-protein interactions is critical for the development of the next generation of human therapeutics and the proposed research will contribute significantly to this arena.
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