Chemical Synthesis of Complex Natural Products for Translational Science

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 DESCRIPTION (provided by applicant): The goals of the proposed MIRA (R35) research program are to continue chemical syntheses of bioactive molecules and expand our efforts and capabilities in translational science. The MIRA effort will allow flexibility and stability to enabe important new research directions that come up during the course of research. Our two NIGMS-funded RO1 grants (Biomimetic Synthesis of Complex Natural Products (GM-073855) and Chemical Synthesis of Bioactive Flavonoid and Xanthone-Derived Natural Products) have been highly productive and have led to 41 publications from 2015 - 2010. These include 19 collaborative manuscripts with clinical and biological investigators. As part of our studies, we have taken opportunities to address key questions and contemporary needs in organic chemistry including asymmetric catalysis of photocycloadditions, enantioselective dearomatization, and atropselective synthesis. Key accomplishments in the past five years include asymmetric photocycloadditions of 3-hydroxyflavones to access rocaglate antitumor agents, synthesis of derivatives of the tubulin inhibitor chamaecypanone C using copper-mediated enantioselective oxidative dearomatization, synthesis of the anticancer agents and antibiotics kibdelones A and C using Pt(IV)-mediated arylations of quinone monoketals, and synthesis of the antibiotic rugulotrosin A employing vinylogous addition of siloxyfurans to chromones and atropselective dimerization. As part of the proposed MIRA project, the Principal Investigator Professor John Porco and colleagues will continue development of novel synthetic methodologies for concise entry to bioactive classes of natural products including oxaphenalenones, meroterpenoids, polyprenylated acylphloroglucinols, tetrahydroxanthones, and dimeric chromones. The project will continue major emphasis on collaborations to study biological properties and mode of action (MoA) of target molecules for ultimate use as pharmacological therapies for human cancers as well as viral and bacterial illnesses. It is anticipated that the MIRA effort will allow us to continue development of innovative syntheses of complex natural products and derivatives and continue work to highly interface these studies with applications of compounds in clinical and translational research.