An organometallic catalase mimic with exceptional activity, H₂O₂ stability, and catalase/peroxidase selectivity

Manganese-porphyrin and -salen redox therapeutics catalyze redox reactions involving O₂˙^-, H₂O₂, and other reactive oxygen species, thereby modulating cellular redox states. Many of these complexes perform catalase reactions via high-valent Mn-oxo or -hydroxo intermediates that oxidize H₂O₂ to O₂, but these intermediates can also oxidize other molecules (e.g., thiols), which is peroxidase reactivity. Whether catalase or peroxidase reactivity predominates depends on the metal-ligand set and the local environment, complicating predictions of what therapeutic effects (e.g., promoting vs. suppressing apoptosis) a complex might produce in a given disease. We recently reported an organoruthenium complex (Ru1) that catalyzes ABTS˙^- reduction to ABTS^2- with H₂O₂ as the terminal reductant. Given that H₂O₂ is thermodynamically a stronger oxidant than ABTS˙^-, we reasoned that the intermediate that reduced ABTS˙^- would also be able to reduce H₂O₂ to H₂O. Herein we demonstrate Ru1-catalyzed H₂O₂ disproportionation into O₂ and H₂O, exhibiting an 8,580-fold faster catalase TOF vs. peroxidase TOF, which is 89.2-fold greater than the highest value reported for a Mn-porphyin or -salen complex. Furthermore, Ru1 was 120-fold more stable to H₂O₂ than the best MnSOD mimic (TON = 4000 vs. 33.4) Mechanistic studies provide evidence that the mechanism for Ru1-catalyzed H₂O₂ disproportionation is conserved with the mechanism for ABTS˙^- reduction. Therapeutic effects of redox catalysts can be predicted with greater accuracy for catalysts that exhibit exclusively catalase activity, thereby facilitating the development of future redox therapeutic strategies for diseases.