Rational design of [Co(acacen)L2]+ inhibitors of protein function.

Cobalt(III) Schiff base complexes, such as [Co(acacen)L(2)](+), inhibit the function of Zn(II)-dependent proteins through dissociative exchange of the axial ligands with key histidine residues of the target protein. Consequently the efficacy of these compounds depends strongly on the lability of the axial ligands. A series of [Co(acacen)L(2)](+) complexes with various axial ligands was investigated using DFT to determine the kinetics and thermodynamics of ligand exchange and hydrolysis. Results showed excellent agreement with experimental data, indicating that axial ligand lability is determined by several factors: pK(a) of the axial ligand, the kinetic barrier to ligand dissociation, and the relative thermodynamic stability of the complexes before and after exchange. Hammett plots were constructed to determine if the kinetics and thermodynamics of exchange can be modulated by the addition of an electron-withdrawing group (EWG) to either the axial ligand itself or to the equatorial acacen ligand. Results predict that addition of an EWG to the axial ligand will shift the kinetics and thermodynamics so as to promote axial ligand exchange, while addition of an EWG to acacen will decrease axial ligand lability. These investigations will aid in the design of the next generation of [Co(acacen)L(2)](2+), allowing researchers to develop new, more effective inhibitors.