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

Abstract

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 ABTS²⁻ 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.