Literature Survey of NiSOD Analogues

According to the protein structure of NiSOD reported by literature, some researchers started to synthesize model compounds for investigating the spectroscopy and reactivity of NiSOD. The active site structure of NiSODred is a Ni(II) square planar geometry and NiSODox is a Ni(III) square pyramidal geometry. In synthetic chemistry, Ni(II) compounds could be stablized with four or six coordination environments, depending on its ligand donating ability. Several complexes with a Ni(III) center have been reported,^21-24 but structurally characterized Ni(III) complexes with a square pyramidal geometry are rare. Hence, the analogues of NiSODred were much more than that of NiSODox. Herein, we will introduce some literature survey about NiSOD analogues, including structural NiSODred mimics, structural NiSODox

mimics, and functional NiSODmodels.

1.3.1 Structural NiSODred Mimics

Because NiSODred demonstrates a N2S2 square planer coordination environment, most of structural NiSODred mimics were square planar Ni(II) complexes. Their structural and spectroscopic studies were investigated.

In 1987, Krüger and Holm reported several complexes as hydrogenase mimics (Fig. 1-7). The nickel center of these complexes was coordinated by two nitrogen atoms and two sulfur atoms with cis arrangement. With this structural similarity, these nickel compounds were used for the some further investigations of NiSODred. In addition, because of the electron rich ligand environments, the nickel center of compounds can be oxidized to higher oxidation state by the addition of oxidants.

Fig. 1-7 Ni(II)N2S2 complexes reported by Krüger and Holm.

Fig. 1-8 EPR spectra of the Ni(III)N2S2 complexes reported by Krüger and Holm.

Shearer and Hegg reported a structural NiSODred mimic with a similar N2S2

ligand skeleton in 2010 and provided insight into the consequences of the different coordination environments on the properties of the Ni ions. They systematically examined two square-planar Ni(II)N2S2 complexes and discussed the spectroscopy and DFT results by comparing with the active center of NiSODred.²⁵

Fig. 1-9 Structural NiSODred mimic by Sheare and Hegg and co-workers.

In 2008, Jensen and co-workers synthesized several pentadentate nickel(II) complexes, they prepared hydrotris(3-phenyl-5-methylpyrazoyl)- boratonickel(II) complexes with organoxanthate or dithiocarbamate coligands equilibrate between κ²- and κ³-chelation modes of the scorpionate ligand in solution, connecting N2S2 square-planar and N3S2 pyramidal ligand fields and a spin crossover. The complexes also exhibit quasi-reversible oxidations at low anodic potentials, thus modeling the structure, dynamics, and redox reactivity of the reduced NiSOD active site.²⁶

Fig. 1-10 Structural NiSODred mimics by Jesen and co-workers.

Moreover, Harrop reported several mimics, one of those mimics was synthesized by N3S2 ligand by modified from a N2S2 ligand, forming a square planar Ni(II) complex with an axial position pyrindinyl group. The structural and electoral property of this mimic is quite similar to that of NiSODred. However, oxidation of this complex provides a disulfide-linked dinuclear species, which is due to the formation of thiyl

radical during the redox process. The EPR spectrum revealed an isotropic signal at g

= 2.00 that likely originates from an S-based (thiyl) radical. Also an anisotropic signal with a large g spread (g = [2.26, 2.17, 2.00]) is observed, indicating a Ni(III) species.

Simulation of this data suggests that it is likely coincidental with the S-radical signal and the five coordinate Ni(III) intermediate can not be isolated.²⁷

Fig. 1-11 Structural NiSODred mimics by Harrop and co-workers.

1.3.2 Structural NiSODox Mimics

In 1998, Hanss and Krüger found a nearly axial signal in EPR by adding excess pyridine to [Ni(phmi)]^-, which is one of the series complexes published by Krüger and Holm in 1987. The splitting of the gz component due to super-hyperfine coupling of a

complex [Ni(emi)]^- was also been reported.

Fig. 1-12 EPR specrum of structural NiSODox mimics by adding excess pyridine.

In 2010, a square pyramidal [Ni^IIN2S2] complex was generated by electrochemical oxidation in the presence of imidazole by Duboc and co-workers, mimicking the redox structural changes of NiSOD. In addition, EPR measurements coupled to DFT calculations demonstrate that the metal character in the redox active orbital increases drastically upon imidazole binding, implicating that these geometrical modifications are crucial for the stabilization of the Ni(III) state.^23b

Fig. 1-13 Structural NiSODox mimic by Duboc and co-workers.

made it possible to oxidize the nickel center from Ni(II) to Ni(III), and the Ni(III) EPR signal was demonstrated. However, these salen-type or N2S2 nickel complexes could not execute the reactivity of superoxide disproportionation.

1.3.3 Functional Models of NiSOD

In functional models of NiSOD study, several model systems employed peptides maquettes, and some low-MW coordination complexes have been constructed. The first peptide analogue was synthesized by Shearer and co-workers, several derivatives were also constructed with electronically modification of the axial position histidine (Fig. 1-14).²⁸

Fig. 1-14 Structures of the NiSOD maquette models based on [Ni(SOD^M1)] [SOD^M1 = H′CDLPCGVYDPA, where H′ = H (1), Me (1^MeIm), 2,4-dinitrophenyl (1^DNP), and tosyl (1^Tos)].

On the other hand, the first low-MW NiSOD model complex that demonstrated reactivity toward superoxide radical was synthesized by Darensbourg and co-workers in 2009.²⁹ The superoxide reactivity of these complexes was investigated by the nitroblue tetrazolium assay. This qualitative test based on the reduction of NBT by

NiSOD provide O2− stability to the coordination unit, however, this complex could not stable with the addition of H2O2. Besides, The exact role of the nickel center in the SOD chemistry was not defined.

Fig. 1-15 Functional NiSOD_red model by Darensbourg and co-workers.

Fig. 1-16 Nitroblue tetrazolium (NBT) reaction with superoxide to produce formazan.

In 2010, Laurence and co-workers synthesized a model shown that the coordination sphere of Ni-SOD can be mimicked using the tripeptide asparagine- cysteine-cysteine (NCC).³¹ A standard SOD activity assay using xanthine oxidase was performed,³² showing that Ni-NCC does exhibit SOD activity, but it is slower than NiSOD. The IC50 for Ni-NCC (4.1 × 10^-5 M) is comparable to those values reported for other peptide mimics, particularly the maquette with bis-amide nitrogen coordination (3 × 10^-5 M).³³

Fig. 1-17 The proposed coordination in Ni-NCC.

The first five-coordinate analogue of NiSODox was described in 2012 by our group utilizing an N3O2 ligand. Because of the steric restrictions imposed by the ligand frame, the pyridine-N was forced to occupy the axial position upon coordination to the Ni center. Regardless of the oxidation state, a clever design strategy to impose a five-coordinate geometry, a Ni(II) complex, Ni(BDPP) was formed. Chemical oxidation of Ni(BDPP) cleanly yielded the Ni(III) complex [Ni(BDPP)](PF6) that was structurally characterized by X-ray crystallography.

Furthermore, [Ni(BDPP)](PF6) was employed to react with excess KO2, O2 and Ni(BDPP) in stoichiometric yields occured. Unfortunately, Ni(BDPP) did not react with KO2 to produce H2O2. It appears that careful construction of the ligand frame to house five-coordinate and low-spin Ni(II) could be an additional requirement for a functional NiSOD model.^22e

Fig. 1-18 Functional NiSODox model by Lee and co-workers.

(Left: Ni(BDPP), Right: [Ni(BDPP)](PF₆))

In this study, we design and synthesize several complexes based on Ni(BDPP) skeleton for the superoxide reactivity improvement and the ligand alterability. These complexes could provide us the opportunities to compare the differences of the coordination numbers and electronic environments of the nickel complexes with Ni(BDPP). Furthermore, we could oxidize these Ni(II) complexes to Ni(III) species and then investigate their reactivity towards superoxide, and gain insight into the role of structure and reactivity with the active center of NiSOD.

CHAPTER TWO: EXPERIMENTAL SECTION