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Title: Steric Hindrance’s Effect on Metabolic Rate in Semi-Synthetic C-\(_{10}\) Artemisinin Ether Derivatives
Authors: Zhou, Sheng
Advisors: Reider, Paul J.
Department: Chemistry
Class Year: 2014
Abstract: Artemisinin and its derivatives are the most effective drugs against malaria, but are plagued by short half-lives, leading to complicated treatment regimens and poor patient compliance. This thesis presents the synthesis and stereochemical characterization of a series of cycloalkyl and alkyl artemisinin ether substituents with the potential to significantly increase half-life. Ether synthesis experimented with BF\(_{3}\), pTsOH, PTA, and CSA activating catalysts. Nmr characterization found BF\(_{3}\) to be optimal, favoring β-ether formation. These results were complemented with energy optimization calculations of the α and β epimers of ethers using the DFT-B\(_{3}\)LYP/6-\(_{31}\)G level. This level of theory confirmed the conformational stability of the β epimer and indicated the potential of branched alkyl ether substituents to sterically shield the metabolic active site. Furthermore, theoretical calculations showed total energy differences of α and β epimers to be unrelated to substituent size. Both experimental and theoretical results, thus, accentuate the multitude of factors impacting metabolism and necessitate future metabolic experiments.
Extent: 85 pages
Type of Material: Princeton University Senior Theses
Language: en_US
Appears in Collections:Chemistry, 1926-2017

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