Browsing by Author "Press, David James"

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    The Design and Properties of Organoselenium Compounds with Glutathione Peroxidase-Like Activity
    (2013-12-04) Press, David James; Back, Thomas George
    The selenoenzyme glutathione peroxidase protects against oxidative stress by reducing peroxides in the presence of glutathione, a tripeptide thiol. Under conditions of extreme oxidative stress, for example during ischemic reperfusion, this process can become overwhelmed. Glutathione peroxidase mimetics are organoselenium compounds which catalytically destroy peroxides and can be used to treat oxidative stress associated with ischemic reperfusion and related conditions. The majority of this Thesis describes the design of efficacious glutathione peroxidase mimetics. An investigation of substituent effects upon the glutathione peroxidase-like activity of aromatic cyclic seleninate esters and spirodioxyselenuranes was initiated. It was found that para-substitution with electron-donating groups resulted in the greatest increase in catalytic activity. Hammett analysis established that the rate-determining step in each compound’s catalytic cycle was the oxidation of Se(II) to Se(IV). Overall, para-methoxy substitution caused the greatest increase in thiol peroxidase activity, while dimethoxy and trimethoxy substitution did not ensure superior thiol peroxidase activity. Included in this study were 3-hydroxypropyl and 2,3-dihydroxypropyl (2-hydroxymethyl)phenyl selenides, which are new classes of glutathione peroxidase mimetics that displayed strong peroxide destroying activity. The former class of compounds includes the most active organoselenium glutathione peroxidase mimetic prepared in our group to date, while members of the latter class are sufficiently water soluble to allow for their activity to be monitored in aqueous environments. Additionally, naphthalene peri-diselenides were found to have significantly improved thiol peroxidase activity relative to acyclic diselenides. This was due to the severely reduced dihedral angle found in the naphthalene peri-diselenides, which leads to a destabilized ground state, lower ionization potential and an increased rate of reaction with peroxides. These diselenides also produced stable charge-transfer complexes with tetracyanoquinodimethane that are of potential interest as photovoltaic materials. Finally, configurational stability of the cyclic seleninate esters and spirodioxyselenuranes was investigated by variable-temperature NMR spectroscopy. These compounds were configurationally stable at high temperatures, while the spirodioxyselenuranes displayed unexpected proton NMR behaviour, caused by temperature-dependant chemical shifts.