Nickel superoxide dismutase (NiSOD) is an enzyme that protects cells against O2 · –. While the structure of its active site is known, the mechanism of the catalytic cycle is still not elucidated. Its active site displays a square planar NiII center with two thiolates, the terminal amine and an amidate. We report here a bioinspired NiII complex built on an ATCUN-like binding motif modulated with one cysteine, which demonstrates catalytic SOD activity in water (k cat = 8.4(2) × 105 M–1 s–1 at pH = 8.1). Its reactivity with O2 · – was also studied in acetonitrile allowing trapping two different short-lived species that were characterized by electron paramagnetic resonance or spectroelectrochemistry and a combination of density functional theory (DFT) and time-dependent DFT calculations. Based on these observations, we propose that O2 · – interacts first with the complex outer sphere through a H-bond with the peptide scaffold in a [NiIIO2 · –] species. This first species could then evolve into a NiIII hydroperoxo inner sphere species through a reaction driven by protonation that is thermodynamically highly favored according to DFT calculations.

The cellular level of reactive oxygen species (ROS) has to be controlled to avoid some pathologies, especially those linked to oxidative stress. One strategy for designing antioxidants consists of modeling natural enzymes involved in ROS degradation. Among them, nickel superoxide dismutase (NiSOD) catalyzes the dismutation of the superoxide radical anion, O 2•− , into O 2 and H 2 O 2 . We report here Ni complexes with tripeptides derived from the amino-terminal Cu II -and Ni II -binding (ATCUN) motif that mimics some structural features found in the active site of the NiSOD. A series of six mononuclear Ni II complexes were investigated in water at physiological pH with different first coordination spheres, from compounds with a N3S to N2S2 set, and also complexes that are in equilibrium between the N-coordination (N3S) and S-coordination (N2S2). They were fully characterized by a combination of spectroscopic techniques, including 1 H NMR, UV−vis, circular dichroism, and X-ray absorption spectroscopy, together with theoretical calculations and their redox properties studied by cyclic voltammetry. They all display SOD-like activity, with a k cat ranging between 0.5 and 2.0 × 10 6 M −1 s −1 . The complexes in which the two coordination modes are in equilibrium are the most efficient, suggesting a beneficial effect of a nearby proton relay.