Some manganese complexes can catalyze both antioxidant and pro-oxidant reactions, whereby the disparate reactivity modes are determined by the catalyst environment and afford distinct therapeutic effects. We recently reported the reduction of radicals in buffered aqueous solution catalyzed by a ruthenium complex with biologically relevant non-tertiary alcohols as terminal reductants. Mechanistic evidence is presented, indicating that this catalytic radical reduction is achieved by a Ru-hydride intermediate formed by β-hydride elimination from a Ru-alkoxide species. A similar mechanism and Ru-hydride intermediate was previously reported to kill cancer cells with catalytic pro-oxidant effects. Therefore, our demonstration of catalytic antioxidant effects by the same type of intermediate reveals new potential therapeutic strategies and applications for catalytic systems that form Ru-hydride intermediates.

Reduced nicotinamide adenine dinucleotide (NADH) can generate a ruthenium-hydride intermediate that catalyzes the reduction of O to HO, which endows it with potent anticancer properties. A catalyst that could access a Ru-H intermediate using oxidized nicotinamide adenine dinucleotide (NAD) as the H source, however, could draw upon a supply of reducing equivalents 1000-fold more abundant than NADH, which would enable significantly greater HO production. Herein, it is demonstrated, using the reduction of ABTS to ABTS, that NAD can function as a reductant. Mechanistic evidence is presented that suggests a Ru-H intermediate is formed via β-hydride elimination from a ribose subunit in NAD. The insight gained from the heretofore unknown ability of NAD to function as a reductant and H donor may lead to undiscovered biological carbohydrate oxidation pathways and new chemotherapeutic strategies.

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