Leveraging Natural Product Scaffolds for Drug Discovery and Development




Clanton, Nicholas Ashby

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Natural products have long served as a source for potent, selective drugs. While these compounds often exhibit powerful biological activity, clinical development is often hampered by a number of factors. First, limited compound supply from the natural source is often an issue, complicating the requisite in vivo studies for preclinical development. Second and related, the structures of many of these compounds are too complex to access enough material by direct synthesis. Third, the biological activity may need to be optimized, or the structure modified to improve the pharmacokinetic profile of these compounds. In the following dissertation, methods to overcome these issues and advance natural product scaffolds towards further development will be explored. First, a methodology was developed to synthetically modify the indole core, a highly prevalent structure in natural products. Second, a new synthetic route towards simplified analogs of the taccalonolides was investigated to identify a synthetically tractable compound that retained the biological activity of the natural product. Third, emerging from the taccalonolides chemistry, a new class of antiproliferative steroids was discovered. Last, a new, scalable synthesis of aretmisinic acid from the biosynthetic precursor 4,11-amorphadiene was developed to utilize this starting material as feedstock for the production of the antimalarial drug artemisinin.


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Artemisinin, Cancer, Drug Discovery, Microtubules, Natural Products