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.