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.
Departments of Chemistry, Molecular Biosciences, Neurobiology, Biomedical Engineering, and Radiology, Northwestern University , Evanston, Illinois 60208-3113, United States.
Marie C
MC
Heffern
Departments of Chemistry, Molecular Biosciences, Neurobiology, Biomedical Engineering, and Radiology, Northwestern University , Evanston, Illinois 60208-3113, United States.
Viktorie
V
Reichova
Departments of Chemistry, Molecular Biosciences, Neurobiology, Biomedical Engineering, and Radiology, Northwestern University , Evanston, Illinois 60208-3113, United States.
Joseph L
JL
Coomes
Departments of Chemistry, Molecular Biosciences, Neurobiology, Biomedical Engineering, and Radiology, Northwestern University , Evanston, Illinois 60208-3113, United States.
Allison S
AS
Harney
Departments of Chemistry, Molecular Biosciences, Neurobiology, Biomedical Engineering, and Radiology, Northwestern University , Evanston, Illinois 60208-3113, United States.
Elizabeth A
EA
Bajema
Departments of Chemistry, Molecular Biosciences, Neurobiology, Biomedical Engineering, and Radiology, Northwestern University , Evanston, Illinois 60208-3113, United States.
Thomas J
TJ
Meade
D003035:Cobalt; D056831:Coordination Complexes / Q000138:chemical synthesis / Q000494:pharmacology*; D005456:Fluorescent Dyes / Q000138:chemical synthesis / Q000494:pharmacology*; D007093:Imidazoles / Q000138:chemical synthesis; D008024:Ligands; D009842:Oligopeptides / Q000037:antagonists & inhibitors*; D012545:Schiff Bases / Q000138:chemical synthesis / Q000494:pharmacology*
D056831:Coordination Complexes; D005456:Fluorescent Dyes; D007093:Imidazoles; D008024:Ligands; D009842:Oligopeptides; D012545:Schiff Bases; D003035:Cobalt