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 Ni II 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 1 H 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 Ni II ion, together with either a water molecule at physiological pH, as [Ni L 3S (OH 2 )] - , or a hydroxo ion in more basic conditions, as [Ni L 3S (OH)] 2- . The 1 H 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 Ni II /Ni III redox system with E pa = 0.48 and 0.31 V versus SCE for Ni L 3S (OH 2 ) and Ni L 3S (OH), respectively. The SOD activity of both complexes has been tested. On the basis of the xanthine oxidase assay, an IC 50 of about 1 μM has been measured at pH 7.4, where Ni L 3S (OH 2 ) is mainly present (93% of the Ni II species), while the IC 50 is larger than 100 μM at pH 9.6, where Ni L 3S (OH) is the major species (92% of the Ni II species). Interestingly, only Ni L 3S (OH 2 ) 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 Ni L 3S (OH 2 )/ Ni L 3S (OH) is about (86:14), and a rate constant, k ca = 1.8 × 10 5 M -1 s -1 , has been measured. Ni L 3S (OH 2 ) 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 Ni II ion.