Date of Award
Doctor of Philosophy (PhD)
Chemistry and Biochemistry
Craig A. Bayse
Selenium, a toxic element, is required in trace quantities for the proper functioning of biological systems. The experimental mechanistic study of the reactions of ebselen and selenious acid is difficult due to complexity of the reaction mixtures and the presence of short-lived intermediates. Computational modeling of the reactivity of these species can give us an insight into their mechanisms, but the process is complicated by proton exchanges associated with the mechanistic steps. In gas phase modeling, this may be corrected to a certain level using the solvent assisted proton exchange (SAPE) method. SAPE is a modeling technique that mimics solvent participation in proton transfer associated with chemical reactions. Within this microsolvation method, explicit water molecules allow relay of a proton between the protonation and deprotonation sites of the reactants and the products. In this dissertation, density functional theory (DFT) and solvent assisted proton exchange (SAPE) are used to explore proposed mechanisms for (a) the reactions of ebselen under normal cellular conditions and under oxidative stress, (b) the reactions of selenite with thiols, and (c) the reduction of a zinc finger model compound by ebselen. The activation barriers obtained by SAPE for the these mechanisms fall within the limits expected for a catalytic system at physiological temperatures, and are significantly lower than studies which force direct proton transfer. The results suggest that under normal cellular conditions, ebselen reacts with thiol to form the corresponding selenenyl sulfide, a terminal pathway in the antioxidant activity of the compound. Under oxidative stress, ebselen catalyzes the reduction of oxidants through a thioselenurane intermediate. In the thiol reduction of selenite to the selenotrisulfide, formation of a selenurane intermediate is predicted to be the rate determining step. The initial reduction of a zinc finger model complex with ebselen is shown to be a low-barrier reaction consistent with experimental rate constants.
"Computational Investigation of the Bioactive Selenium Compounds Ebselen and Selenious Acid"
(2011). Doctor of Philosophy (PhD), Dissertation, Chemistry and Biochemistry, Old Dominion University, DOI: 10.25777/z6fr-rn66