Synthesis and Study of Complex Antiproliferative and Antimalarial Natural Products

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 DESCRIPTION (provided by applicant): This proposal describes the synthesis and studies of the ocimyquines and gukulenins, natural products that exhibit potent antimalarial and antiproliferative effects, respectively. Ocimyquines are nanomolar inhibitors of malaria parasites that are equally potent against drug-sensitive and -resistant strains, and have demonstrated high therapeutic indices in cell culture. In addition, they display prophylactic and curative activty in mouse models, without measurable toxicity. The gukulenins are low nanomolar inhibitors of several cancer cell lines and are very promising candidates for the treatment of colorectal cancer, the second-leading cause of cancer-related deaths in the United States. Both families of natural products possess molecular architectures that are unique. The ocimyquines contain a tetrasubstituted aminocyclopropane embedded within a pentacyclic carbon skeleton whereas the gukulenins are dimeric a-tropolone natural products containing six carbocyclic rings. Although these two families of compounds are unique among anti-infectives and anti-proliferative compounds, and show potent and potentially clinically-useful activities, no syntheses or synthetic studies have been reported. In addition, little is known about their structure-function relationships, and the mechanisms underlying their efficacy and selectivity remain unknown. The objectives of this proposal are to complete concise and convergent syntheses of the ocimyquines and gukulenins and evaluate their efficacy as radical cure anti-malarials and anti-proliferative agents. We have made significant progress toward the syntheses of both families of metabolites, having developed chemistry to access many of the key substructures of the targets. Our synthetic efforts have led to the development of new methods for the synthesis of tetrasubstituted aminocyclopropanes by a ring expansion-ring contraction strategy and 3,5,6-trisubsituted-a-tropolone rings by a novel reductive cleavage reaction. The collaborative nature of the proposal provides the infrastructure required to evaluate the antimalarial prophylactic and therapeutic activity of the ocimyquines and their synthetic derivatives and to elucidate their biological target. In addition, we will conduct structure-functin studies of the gukulenins, test the hypothesis that the natural products engage in reversible covalent bond formation with their target, and identify candidate binding proteins. These experiments will lead to the identification of new antimalarial and anticancer agents with improved potencies and activities, provide insights into the biological mechanisms underlying these activities, and lay the foundation for their preclinical evaluation as new treatments for malaria and colorectal cancer.