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Physical properties, ligand substitution reactions, and biological activity of Co(iii)-Schiff base complexes.

ABSTRACT: Four cobalt(iii) complexes of the general formula [Co(Schiff base)(L)2]+, where L is ammonia (NH3) or 3-fluorobenzylamine (3F-BnNH2), were synthesized. The complexes were characterized by NMR spectroscopy, mass spectrometry, and X-ray crystallography. Their electrochemical properties, ligand substitution mechanisms, and ligand exchange rates in aqueous buffer were investigated. These physical properties were correlated to the cellular uptake and anticancer activities of the complexes. The complexes undergo sequential, dissociative ligand substitution, with the exchange rates depending heavily on the axial ligands. Eyring analyses revealed that the relative ligand exchange rates were largely impacted by differences in the entropy, rather than enthalpy, of activation for the complexes. Performing the substitution reactions in the presence of ascorbate led to a change in the reaction profile and kinetics, but no change in the final product. The cytotoxic activity of the complexes correlates with both the ligand exchange rate and reduction potential, with the more easily reduced and rapidly substituted complexes showing higher toxicity. These relationships may be valuable for the rational design of Co(iii) complexes as anticancer or antiviral prodrugs.

SUBMITTER: King AP

PROVIDER: S-EPMC6504617 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Physical properties, ligand substitution reactions, and biological activity of Co(iii)-Schiff base complexes.

King A Paden AP Gellineau Hendryck A HA MacMillan Samantha N SN Wilson Justin J JJ

Dalton transactions (Cambridge, England : 2003) 20190501 18

Four cobalt(iii) complexes of the general formula [Co(Schiff base)(L)2]+, where L is ammonia (NH3) or 3-fluorobenzylamine (3F-BnNH2), were synthesized. The complexes were characterized by NMR spectroscopy, mass spectrometry, and X-ray crystallography. Their electrochemical properties, ligand substitution mechanisms, and ligand exchange rates in aqueous buffer were investigated. These physical properties were correlated to the cellular uptake and anticancer activities of the complexes. The comple ...[more]

PMID: 30672949

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Project description: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, and consequently alters structure and causes inhibition. 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 (NH(3)), N-methylimidazole (NMeIm), and pyridine (Py)] were 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 > NH(3) ? 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.

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Physical properties, ligand substitution reactions, and biological activity of Co(iii)-Schiff base complexes.

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Physical properties, ligand substitution reactions, and biological activity of Co(iii)-Schiff base complexes.

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