Mononuclear Ni(II) Complexes with a S3O Coordination Sphere Based on a Tripodal Cysteine-Rich Ligand: pH Tuning of the Superoxide Dismutase Activity

The superoxide dismutase (SOD) activity of mononuclear NiII complexes, whose structures are inspired by the NiSOD, has been investigated. They have been designed with a sulfur-rich pseudopeptide ligand, derived from nitrilotriacetic acid (NTA), where the three acid functions are grafted with cysteines (L 3S ). Two mononuclear complexes, which exist in pH-dependent proportions, have been fully characterized by a combination of spectroscopic techniques including 1H NMR, UV–vis, circular dichroism, and X-ray absorption spectroscopy, together with theoretical calculations. They display similar square-planar S3O coordination, with the three thiolates of the three cysteine moieties from L 3S coordinated to the NiII ion, together with either a water molecule at physiological pH, as [NiL 3S (OH2)]−, or a hydroxo ion in more basic conditions, as [NiL 3S (OH)]2–. The 1H NMR study has revealed that contrary to the hydroxo ligand, the bound water molecule is labile. The cyclic voltammogram of both complexes displays an irreversible one-electron oxidation process assigned to the NiII/NiIII redox system with E pa = 0.48 and 0.31 V versus SCE for NiL 3S (OH2) and NiL 3S (OH), respectively. The SOD activity of both complexes has been tested. On the basis of the xanthine oxidase assay, an IC50 of about 1 μM has been measured at pH 7.4, where NiL 3S (OH2) is mainly present (93% of the NiII species), while the IC50 is larger than 100 μM at pH 9.6, where NiL 3S (OH) is the major species (92% of the NiII species). Interestingly, only NiL 3S (OH2) displays SOD activity, suggesting that the presence of a labile ligand is required. The SOD activity has been also evaluated under catalytic conditions at pH 7.75, where the ratio between NiL 3S (OH2)/ NiL 3S (OH) is about (86:14), and a rate constant, k cat = 1.8 × 105 M–1 s–1, has been measured. NiL 3S (OH2) is thus the first low-molecular weight, synthetic, bioinspired Ni complex that displays catalytic SOD activity in water at physiological pH, although it does not contain any N-donor ligand in its first coordination sphere, as in the NiSOD. Overall, the data show that a key structural feature is the presence of a labile ligand in the coordination sphere of the NiII ion.