Serendipitous Synthesis of Sulfur and Selenium-Containing Macrocycles and Their Application as GPx Mimetics
Date
2022-11-01
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Abstract
Glutathione peroxidase, or GPx, is a selenocysteine based enzyme whose role is to prevent
oxidative stress in mammalian cells by catalytically reducing harmful hydrogen peroxide and
hydroperoxides, to water or their corresponding alcohols, respectively. This process
simultaneously results in the oxidation of glutathione, a naturally abundant thiol, to glutathione
disulfide. While GPx generally works well at preventing oxidative stress, there are certain
circumstances where GPx can become overwhelmed, such as during reperfusion after a heart
attack or stroke, that can result in excessive oxidative stress. Therefore, there is interest in the
development of small molecule selenium compounds that could act as mimetics of GPx and aid it
in the reduction of harmful peroxides. Spirodioxyselenuranes have been reported to be particularly effective GPx mimetics and analogues
that contain heteroatoms other than oxygen are also of interest. During attempts to prepare
spirodithiaselenuranes, which would be a novel class of compounds, a series of macrocyclic dimers
containing both selenide and disulfide moieties was obtained instead. Chapter two describes
attempts toward the synthesis of spirodithiaselenuranes and the characterization of the isolated
macrocyclic species. Based on these results, the remainder of chapter two describes the synthesis
of a range of these macrocyclic dimers. Chapter three focuses on the application of these dimers as GPx mimetics and the assays used to
measure their activity. During this study a surprising induction period in the catalysis was observed
which was determined to be due to autocatalysis by the oxidized macrocycle.
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Keywords
Selenium, Sulfur, GPx Mimetics, Antioxidants
Citation
McMillan, J. D. R. (2022). Serendipitous synthesis of sulfur and selenium-containing macrocycles and their application as GPx mimetics (Master's thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.