Axial Ligand Exchange of N-heterocyclic Cobalt(III) Schiff Base Complexes: Molecular Structure and NMR Solution Dynamics

Abstract

The kinetic and thermodynamic ligand exchange dynamics are important considerations in the rational design of metal-based therapeutics and therefore, require detailed investigation. Co(III) Schiff base complex derivatives of bis(acetylacetone) ethylenediimine [acacen] have been found to be potent enzyme and transcription factor inhibitors. These complexes undergo solution exchange of labile axial ligands. Upon dissociation, Co(III) irreversibly interacts with specific histidine residues of a protein, that alters structure and causes inhibition. In order to guide the rational design of next generation agents, understanding the mechanism and dynamics of the ligand exchange process is essential. To investigate the lability, pH stability, and axial ligand exchange of these complexes in the absence of proteins, the pD- and temperature-dependent axial ligand substitution dynamics of a series of N-heterocyclic [Co(acacen)(X)2]+ complexes [where X = 2-methylimidazole (2MeIm), 4-methylimidazole (4MeIm), ammine (NH3), N-methylimidazole (NMeIm), and pyridine (Py)] were prepared and characterized by NMR spectroscopy. The pD stability was shown to be closely related to the nature of the axial ligand with the following trend toward aquation: 2MeIm > NH3 >> 4MeIm > Py > Im > NMeIm. Reaction of each [Co(III)(acacen)(X)2]+ derivative with 4MeIm showed formation of a mixed ligand Co(III) intermediate via a dissociative ligand exchange mechanism. The stability of the mixed ligand adduct was directly correlated to the pD-dependent stability of the starting Co(III) Schiff base with respect to [Co(acacen)(4MeIm)2]+. Crystal structure analysis of the [Co(acacen)(X)2]+ derivatives confirmed the trends in stability observed by NMR spectroscopy. Bond distances between the Co(III) and the axial nitrogen atoms were longest in the 2MeIm derivative as a result of distortion in the planar tetradentate ligand, and this was directly correlated to axial ligand lability and propensity toward exchange.

Light-Activated Protein Inhibition through Photoinduced Electron Transfer of a Ruthenium(II)–Cobalt(III) Bimetallic Complex

“…Consequently, the reaction reaches equilibrium with a distribution of 50% Co-Im and 50% Co-4MeIm bonds. 24 Furthermore, PET from PbS QDs was previously observed to increase axial ligand substitution of adsorbed Co(acacen)(Im) 2 upon irradiation by 8-fold, relative to the dark control. 23 …”

Tuning Cobalt(III) Schiff Base Complexes as Activated Protein Inhibitors

“…15,16 Ligand exchange of CoC3Im was evaluated in the presence of competing imidazole ligands, 2-methylimidazole (2MeIm), 4MeIm, NMeIm, and Im, as well as pyridine (Py) and ammonia (NH 3 ) (see Figure 3A). Coumarin-derived fluorescence of the various solutions was monitored and correlated to the concentration of free C3Im by a linear standard curve (SI Figure 6).…”

“…These results are consistent with previous NMR studies attributing less favored coordination of 2MeIm to steric interference of the C4 methyl of the imidazole and the lability of the latter two to p K a of the free ligands. 15,16 Treatment of CoC3Im with 4MeIm, NMeIm, and Im at 37 °C for 1 h results in ligand substitution that increases with increasing molar equivalents of the competing ligand to the starting C3Im concentration, with ~50% of C3Im dissociating at 4 equiv of the competing ligand. These observations correlate well with previous NMR studies where the formation of mixed axial ligand species rather than complete substitution was observed.…”

“…15,16,30 In contrast, the 4-carbon linker of DiIm4 is expected to be too short to coordinate [Co(acacen)-(L) 2 ] + complexes in a similar manner without distortion of the octahedral geometry. 15,16 …”

“…18 Relative to CoNH 3 , CoIm exhibits higher stability to ligand exchange in the presence of a competing N-heterocycle and histidine mimic, 4MeIm. 15,16 Irradiation of the quantum dots reduced the Co(III) center to Co(II) by PET into the d z 2 orbital while weakening the axial ligand bond to facilitate ligand dissociation. Subsequent oxidation to Co(III) through charge recombination produced the protein inhibitor.…”