Date of Award

Summer 2020

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

School

Mathematics and Natural Sciences

Committee Chair

Douglas Masterson

Committee Chair School

Mathematics and Natural Sciences

Committee Member 2

Julie Pigza

Committee Member 2 School

Mathematics and Natural Sciences

Committee Member 3

Vijay Rangachari

Committee Member 3 School

Mathematics and Natural Sciences

Committee Member 4

Faqing Huang

Committee Member 4 School

Mathematics and Natural Sciences

Committee Member 5

Robert Hondal

Committee Member 5 School

Mathematics and Natural Sciences

Abstract

Selenoproteins, such as glutathione peroxidase, have gained interest for their ability to act as antioxidants, and their potential to act as anti-cancer agents. Synthesizing and studying selenoproteins can be problematic, however, due to their propensity to degrade from over-oxidation. The degradation from over-oxidation can be avoided by the incorporation of the unnatural amino acid, alpha-methylselenocysteine. A synthesis utilizing methyl malonic esters was used to synthesize protected (R)-alpha-methylselenocysteine efficiently (46% over four steps) and in high enantio-purity (88% enantiomeric excess). Using similar procedures, the (S)-enantiomer was also synthesized as well as a beta-analogue.

The use of enzymes in a chemical laboratory is beneficial as they provide an efficient enantioselective method to synthesize chiral materials. Unless known substrates are used, the stereochemistry of the product cannot be known with certainty. The Mosher method employs NMR to analyze an MTPA-derivatized version of a chiral compound, however, use on congested chiral centers is limited. While sitting in the MTPA-plane differently than the model predicts, the Mosher method can be used to determine unknown configurations in alpha-methyl amino acids. By synthesizing two MTPA-based diastereomers from enantio-enriched alpha-methylselenocysteine, the absolute configuration of the stereocenter at the alpha-carbon was determined to be an (R)-stereocenter.

Within the glutathione catalytic cycle, glutathione reduces the oxidized selenium of glutathione peroxidase to a selenol, allowing the enzyme to function again, however glutathione is oxidized to glutathione disulfide. Glutathione disulfide, while oxidized, cannot operate normally and is needed to be reduced. The action of glutathione reductase reduces glutathione disulfide to two molar equivalents of glutathione. If both cysteines in glutathione disulfide are alpha-methyl amino acids, glutathione reductase is unable to perform the reduction. Work has been done to synthesize an asymmetric cystine and future work will be to elaborate to the asymmetric glutathione disulfide and study its inhibitory effects on glutathione reductase.

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