Design, Synthesis and Evaluation of Novel Organoselenium Antioxidants
Abstract
Glutathione peroxidase is an antioxidant selenoenzyme that protects against oxidative stress by reducing peroxides in the presence of glutathione, a tripeptide thiol. Under certain circumstances, such as ischemic reperfusion, this protective mechanism can be overwhelmed. There is a need for potential therapeutics that mimic the function of this selenoenzyme that could be administered during abnormal levels of oxidative stress. Organoselenium compounds can function as antioxidants by catalytically reducing peroxides in the presence of thiols. The design, synthesis and evaluation of novel organoselenium compounds as glutathione peroxidase mimetics is the main focus of the work presented in this thesis.
Of particular interest is the synthesis of water-soluble compounds. Two main strategies were investigated, the addition of hydroxymethyl groups or the PEGylation of known glutathione peroxidase mimetics. The addition of hydroxymethyl groups to cyclic seleninate esters and half aromatic half aliphatic selenides resulted in increased polarity of the compounds but only moderate catalytic activity. During the synthesis of these catalysts, an unexpected rearrangement was observed and the mechanism was thoroughly investigated. PEGylated compounds based on the half aromatic half aliphatic selenides were synthesized and demonstrated superior catalytic activity. With several novel organoselenium catalysts in hand, a water-based assay was desired for their evaluation. A D2O-based NMR assay was developed, validated and subsequently used to evaluate the novel organoselenium catalysts.
In addition to using organoselenium compounds as glutathione peroxidase mimetics, oxidation catalysis is also possible when hydrogen peroxide is used as a stoichiometric oxidant. The observation of unusual kinetics associated with several cyclic seleninate esters, suggested that these catalysts could not only oxidize thiols to disulfides but could further oxidize disulfides to thiolsulfinates. Based on this observation, a new methodology for the oxidation of disulfides to thiolsulfinates using cyclic seleninate esters and hydrogen peroxide as a stoichiometric oxidant was developed.
Finally, a spirodioxyselenurane was investigated using variable-temperature NMR and computational methods. This compound displayed unexpected proton NMR behaviour and a computational investigation into the effects of activated vibrational modes on chemical shift determined that the experimental observations were a result of temperature-dependent chemical shifts and not from dynamic exchange processes.
Description
Keywords
Chemistry--Organic
Citation
McNeil, N. M. (2016). Design, Synthesis and Evaluation of Novel Organoselenium Antioxidants (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca. doi:10.11575/PRISM/25593