Synthetic Studies Of Biologically Active Molecules: Irl 2500, Bruceantin, And Biliatresone

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Doctor of Philosophy (PhD)
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Organic Chemistry
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Glass, Andrew David

Part 1: Carbon monoxide (CO) is a poisonous gas that binds to hemoglobin, preventing oxygen transport to the tissues. CO poisoning causes ~50,000 emergency room visits per year. Treatments for CO poisoning are extremely limited. IRL 2500 is a small molecule allosteric effector of hemoglobin that has been shown to decrease the half-life of CO-bound hemoglobin (COHb). Herein we describe the synthesis of a novel, structurally constrained derivative of IRL 2500 and its effect on COHb.Part 2: Bruceantin is a natural product that has long been studied for its anticancer activity. Inspired by the structure of bruceantin, we proposed to develop a homologous Pauson Khand reaction utilizing a strained bicyclic compound to generate bridged cyclohexenones via a [3+2+1] cycloaddition as a possible method to generate the bruceantin ring system. The synthesis of suitable bicyclic substrates for this reaction has been achieved, and their viability in a rhodium- catalyzed cycloaddition has been evaluated, with nitrogen-containing bicyclic compounds having been shown to undergo ring opening reactions. Progress towards the synthesis of substrates with stabilizing groups will also be discussed. Part 3: Biliary atresia is a rare disease that is the most common indication for liver transplant among the pediatric population. Biliatresone was discovered to be an environmental toxin that recapitulates the biliary atresia phenotype. Analogs of biliatresone the could be used to identify the cellular target of the toxin have been designed and synthesized for use in a photoaffinity pulldown experiment. The best analog has been shown to cause the biliary atresia phenotype in zebrafish and has been used in experiments aimed at determining the molecular target of biliatresone. Future study and determination of the molecular target will aid in our understanding of biliary atresia.

Jeffrey D. Winkler
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