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 inhibi...

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Bibliographic Details
Published in:Inorganic chemistry 2015-09, Vol.54 (18), p.9066-9074
Main Authors: Heffern, Marie C, Reichova, Viktorie, Coomes, Joseph L, Harney, Allison S, Bajema, Elizabeth A, Meade, Thomas J
Format: Article
Language:English
Subjects:
Activated
Cobalt
Coordination Complexes - chemical synthesis
Coordination Complexes - pharmacology
Dynamic tests
Exchange
Fluorescence
Fluorescent Dyes - chemical synthesis
Fluorescent Dyes - pharmacology
Imidazole
Imidazoles - chemical synthesis
Ligands
Oligopeptides - antagonists & inhibitors
Proteins
Schiff bases
Schiff Bases - chemical synthesis
Schiff Bases - pharmacology
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Summary: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.
ISSN:0020-1669
1520-510X
DOI:10.1021/acs.inorgchem.5b01415