Aerobic Aqueous Redox Catalysis by a Ruthenium–Hydride Species and Evidence for the Reducing/Hydride Transfer Ability of Biological Oxidants
Abstract
Reactive oxygen species (ROS), such as superoxide and hydrogen peroxide, have been classically viewed as being monolithically harmful to biological systems, only leading to disease and dysfunction. This understanding has evolved recently in light of new findings; 1) ROS are essential in fighting infections and 2) antioxidant enzyme, catalase that removes ROS (antioxidant activity) can also generate ROS (pro-oxidant activity) depending on the identity of the corresponding oxidized products. We hypothesize that a complex that catalyzes oxidization of alcohols will be able to catalyze the reduction of radicals. We chose an organoruthenium catalyst (Ru1), air-stable and soluble in water-miscible solvents, as a catalyst for aerobic aqueous redox reaction and 2,2'-azino-bis(3-ethylbenzo-thiazoline-6-sulfonate) radical monoanion (ABTSâ—–) as a model for radical species due to its comparable oxidizing potential to ROS. Because radicals can be reduced using alcohols as terminal reductants, we chose biologically-relevant alcohols that can be recycled to their reduced states by our body. We have shown that Ru1 catalyzed the reduction of ABTSâ—– to its precursor ABTS2– in phosphate buffered saline (pH 7.4). In doing so, Ru1 used biologically-relevant alcohols containing CH–OH groups such as NAD+, amino acids, sugars, citric acid cycle metabolites as terminal reductants. Mechanistic evidence reveals that the catalytic radical reduction is achieved by a Ru-hydride intermediate formed by a β-hydride elimination from a ribose subunit in NAD+ and from a Ru-alkoxide species in citric acid cycles metabolites. These findings demonstrate the undiscovered reducing ability of biological oxidants. We have also revealed a new potential therapeutic strategy by Ru catalysts that use the same type of Ru-hydride intermediate by demonstrating the catalytic antioxidant effects. Collectively, these findings illustrate a central principle of redox therapeutics: it is not the identity of the redox catalyst itself that determines whether it produces pro- or antioxidant effects, but rather the identities and concentrations of the species being reduced (the terminal oxidant) and the species being oxidized (the terminal reductant).