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

Lauren M. Matosziuk, Robert J. Holbrook, Lisa M. Manus, Marie C. Heffern, Mark A. Ratner, Thomas J. Meade

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Cobalt(iii) Schiff base complexes, such as [Co(acacen)L2]+, 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)L2]+ 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: pKa 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)L2]2+, allowing researchers to develop new, more effective inhibitors.

Original languageEnglish
Pages (from-to)4002-4012
Number of pages11
JournalJournal of the Chemical Society. Dalton Transactions
Volume42
Issue number11
DOIs
Publication statusPublished - Jan 22 2013

    Fingerprint

ASJC Scopus subject areas

  • Chemistry(all)

Cite this

Matosziuk, L. M., Holbrook, R. J., Manus, L. M., Heffern, M. C., Ratner, M. A., & Meade, T. J. (2013). Rational design of [Co(acacen)L2]+ inhibitors of protein function. Journal of the Chemical Society. Dalton Transactions, 42(11), 4002-4012. https://doi.org/10.1039/c2dt32565a