Doctor of Philosophy, Case Western Reserve University, 2010, Chemistry

Hydroperoxy endoperoxides, the singlet oxygen cycloadducts of hydroperoxy diene,are likely to be generated in the retina owing to the presence of photosensitizers that can generate singlet oxygen. We speculated that these endoperoxides would undergo fragmentation reactions to give toxic aldehydes, e.g., γ-hydroxyl alkenals. A simple model hydroperoxy endoperoxide and its linoleate derivatives were prepared and were found to undergo fragmentations. The reactions are catalyzed by metal ions and promoted by vitamin (Vit) E. Thus, the hydroperoxy endoperoxides readily give γ-hydroxy alkenals and their oxidation products, butenolides. Vit E converts metal ions to their reduced forms that react with hydroperoxy endoperoxides, causing fragmentation to aldehydes. We also examined the influence of a membrane environment on the fate of hydroperoxy endoperoxides. In the membrane, further oxidation of the initially formed γ-hydroxyalkenal to a butenolide is disfavored. A conformational preference for the γ-hydroxyalkenal, to protrude like a whisker from the membrane into the aqueous phase,may protect it from oxidation induced by lipid hydroperoxides that remain buried in the lipophilic membrane core. We prepared a simple model β-hydroxy hydroperoxide, through disproportionation of a hydroperoxy endoperoxide, and investigated mechanisms of its fragmentation. We found that antioxidants, e.g., Vit E and Vit C, in the presence of catalytic amounts of transition metal ions (Fe3+ or Cu2+), can strongly promote the fragmentation of β-hydroxy hydroperoxides to deliver toxic aldehyde products. These findings further demonstrated the potential for some “antioxidants” to exhibit pro-oxidant effects. The fragmentation mechanism for a linoleate-derived hydroperoxy epoxide (13-HP-Epo-Acid) was investigated. The pseudosymmetric formation of toxic aldehydes during the Fe2+-promoted fragmentation of 13-HP-Epo-Acid implies the existence of a pseudosymmetric diepoxycarbinyl radical intermediate. (open full item for complete abstract)

Committee: Robert Salomon (Advisor); Anthony Pearson (Committee Chair); Rajesh Viswanathan (Committee Member); Michael Zagoski (Committee Member); Paul Carey (Committee Member) Subjects: Chemistry

Doctor of Philosophy, Case Western Reserve University, 2010, Chemistry

Hydroperoxy endoperoxides, the singlet oxygen cycloadducts of hydroperoxy diene, are likely to be generated in the retina owing to the presence of photosensitizers that can generate singlet oxygen. We speculated that these endoperoxides would undergo fragmentation reactions to give toxic aldehydes, e.g., γ-hydroxyl alkenals. A simple model hydroperoxy endoperoxide and its linoleate derivatives were prepared and were found to undergo fragmentations. The reactions are catalyzed by metal ions and promoted by vitamin (Vit) E. Thus, the hydroperoxy endoperoxides readily give γ-hydroxy alkenals and their oxidation products, butenolides. Vit E converts metal ions to their reduced forms that react with hydroperoxy endoperoxides, causing fragmentation to aldehydes. We also examined the influence of a membrane environment on the fate of hydroperoxy endoperoxides. In the membrane, further oxidation of the initially formed γ- hydroxyalkenal to a butenolide is disfavored. A conformational preference for the γ- hydroxyalkenal, to protrude like a whisker from the membrane into the aqueous phase, may protect it from oxidation induced by lipid hydroperoxides that remain buried in the lipophilic membrane core. We prepared a simple model β-hydroxy hydroperoxide, through disproportionation of a hydroperoxy endoperoxide, and investigated mechanisms of its fragmentation. We found that antioxidants, e.g., Vit E and Vit C, in the presence of catalytic amounts of transition metal ions (Fe3+ or Cu2+), can strongly promote the fragmentation of β-hydroxy hydroperoxides to deliver toxic aldehyde products. These findings further demonstrated the potential for some “antioxidants” to exhibit pro-oxidant effects. The fragmentation mechanism for a linoleate-derived hydroperoxy epoxide (13-HP- Epo-Acid) was investigated. The pseudosymmetric formation of toxic aldehydes during the Fe2+-promoted fragmentation of 13-HP-Epo-Acid implies the existence of a pseudosymmetric diepoxycarbinyl radical interm (open full item for complete abstract)

Committee: Robert Salomon PhD (Advisor); Anthony Pearson PhD (Committee Chair); Paul Carey PhD (Committee Member); Rajesh Viswanathan PhD (Committee Member); Michael Zagorski PhD (Committee Member) Subjects: Chemistry