Dipeptide-Based Models of Nickel Superoxide Dismutase: Solvent Effects Highlight a Critical Role to Ni–S Bonding and Active Site Stabilization

Nickel superoxide dismutase (Ni–SOD) catalyzes the disproportionation of the superoxide radical to O2 and H2O2 utilizing the Ni(III/II) redox couple. The Ni center in Ni–SOD resides in an unusual coordination environment that is distinct from other SODs. In the reduced state (Ni–SODred), Ni(II) is ligated to a primary amine-N from His1, anionic carboxamido-N/thiolato-S from Cys2, and a second thiolato-S from Cys6 to complete a NiN2S2 square-planar coordination motif. Utilizing the dipeptide N2S2– ligand, H2N-Gly-l-Cys-OMe (GC-OMeH2), an accurate model of the structural and electronic contributions provided by His1 and Cys2 in Ni–SODred, we constructed the dinuclear sulfur-bridged metallosynthon, [Ni2(GC-OMe)2] (1). From 1 we prepared the following monomeric Ni(II)–N2S2 complexes: K[Ni(GC-OMe)(SC6H4-p-Cl)] (2), K[Ni(GC-OMe)(S t Bu)] (3), K[Ni(GC-OMe)(SC6H4-p-OMe)] (4), and K[Ni(GC-OMe)(SNAc)] (5). The design strategy in utilizing GC-OMe2– is analogous to one which we reported before (see Inorg. Chem. 2009, 48, 5620 and Inorg. Chem. 2010, 49, 7080) where Ni–SODred active site mimics can be assembled at will with electronically variant RS– ligands. Discussed herein is our initial account pertaining to the aqueous behavior of isolable, small-molecule Ni–SOD model complexes (non-maquette based). Spectroscopic (FTIR, UV–vis, ESI-MS, XAS) and electrochemical (CV) measurements suggest that 2–5 successfully simulate many of the electronic features of Ni–SODred. Furthermore, the aqueous studies reveal a dynamic behavior with regard to RS– lability and bridging interactions, suggesting a stabilizing role brought about by the protein architecture.