Development of methodologies for the synthesis and diversification of bioactive molecules




Stephens, David E.

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By 2020, the IMS Institute for Healthcare Informatics predicts that total spending on pharmaceuticals will reach 1.4 trillion USD as drug therapies are being more ubiquitous in developing countries. In order to meet this need, presumably for increasing the quality of life of all people, pharmaceutical companies are constantly improving their drug profiles on new, drug-resistant, and under represented diseases. In the Larionov lab we are creating new methods for simple diversification of various heterocycles that have medicinal importance.

Heterocycles are common motifs found in naturally occurring compounds. These compounds, often isolated and tested for biological activity, are so called secondary metabolites due to their production being required for the plant or organism to fight off threat's in the organism's natural environment. Not only is this structure found in nature, but it has also been utilized in pharmaceuticals.

In order to take a drug to market, tens of thousands of compounds are made with small differences for screening purposes. In order to make such a large body of compounds, a general methodology for simple diversification of the core structure is utilized. Making such small changes can be difficult however, which is why we have investigated significant time and effort into simplifying the route to final product. My thesis deals with a number of methodologies that allow for the pharmaceutical chemist to be able to change a simple proton in a molecule to aryl's, perfluoro groups, alkanes, heterocycles, and more.

The methods employed utilize transition metal catalysts, stoichiometric reagents, low and high temperatures, asymmetric ligands, and commercial reagents. The compounds that have been transformed are novel to the field, with biological activity being observed in a number of these novel compounds. Collaborations have been made with Eli Lilly, national, and international career scientists to find activity in area's of diabetes, cholesterol, Leishmaniasis, Chagas disease, Alzheimer's, and more. While pertinent biological activity has not yet been reported, we hope to bring forward these exciting results to the field in the coming months and years.


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Azine, Heterocycle, N-oxide, Natural Product, oxazine, Pharmaceutical