Tuning cobalt(III) Schiff base complexes as activated protein inhibitors.

Cobalt(III) Schiff base complexes ([Co(acacen)(L)2](+), where L = NH3) inhibit histidine-containing proteins through dissociative exchange of the labile axial ligands (L). This work investigates axial ligand exchange dynamics of [Co(acacen)(L)2](+) complexes toward the development of protein inhibitors that are activated by external triggers such as light irradiation. We sought to investigate ligand exchange dynamics to design a Co(III) complex that is substitutionally inert under normal physiological conditions for selective activation. Fluorescent imidazoles (C3Im) were prepared as axial ligands in [Co(acacen)(L)2](+) to produce complexes (CoC3Im) that could report on ligand exchange and, thus, complex stability. These fluorescent imidazole reporters guided the design of a new dinuclear Co(III) Schiff base complex containing bridging diimidazole ligands, which exhibits enhanced stability to ligand exchange with competing imidazoles and to hydrolysis within a biologically relevant pH range. These studies inform the design of biocompatible Co(III) Schiff base complexes that can be selectively activated for protein inhibition with spatial and temporal specificity.

Modulation of amyloid-ß aggregation by histidine-coordinating Cobalt(III) Schiff base complexes.

Oligomers of the Aß42 peptide are significant neurotoxins linked to Alzheimer's disease (AD). Histidine (His) residues present at the N terminus of Aß42 are believed to influence toxicity by either serving as metal-ion binding sites (which promote oligomerization and oxidative damage) or facilitating synaptic binding. Transition metal complexes that bind to these residues and modulate Aß toxicity have emerged as therapeutic candidates. Cobalt(III) Schiff base complexes (Co-sb) were evaluated for their ability to interact with Aß peptides. HPLC-MS, NMR, fluorescence, and DFT studies demonstrated that Co-sb complexes could interact with the His residues in a truncated Aß16 peptide representing the Aß42 N terminus. Coordination of Co-sb complexes altered the structure of Aß42 peptides and promoted the formation of large soluble oligomers. Interestingly, this structural perturbation of Aß correlated to reduced synaptic binding to hippocampal neurons. These results demonstrate the promise of Co-sb complexes in anti-AD therapeutic approaches.