Oxidative lipid fragmentation; New mechanisms, synthesis and reactions of putative intermediates

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. We postulated that diepoxycabinyl radical intermediates would undergo C-O cleavage to give alkoxyl radicals which would undergo subsequent β-scission to deliver vinyl radical intermediates. To test this hypothesis, vinyl radical intermediates were generated photolytically from the corresponding vinyl bromides and shown to serve as precursors for the formation of γ-oxo-α,β-unsaturated aldehydes.