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Modulation of amyloid-? aggregation by histidine-coordinating Cobalt(III) Schiff base complexes.

ABSTRACT: Oligomers of the A?42 peptide are significant neurotoxins linked to Alzheimer's disease (AD). Histidine (His) residues present at the N terminus of A?42 are believed to influence toxicity by either serving as metal-ion binding sites (which promote oligomerization and oxidative damage) or facilitating synaptic binding. Transition metal complexes that bind to these residues and modulate A? toxicity have emerged as therapeutic candidates. Cobalt(III) Schiff base complexes (Co-sb) were evaluated for their ability to interact with A? peptides. HPLC-MS, NMR, fluorescence, and DFT studies demonstrated that Co-sb complexes could interact with the His residues in a truncated A?16 peptide representing the A?42 N terminus. Coordination of Co-sb complexes altered the structure of A?42 peptides and promoted the formation of large soluble oligomers. Interestingly, this structural perturbation of A? correlated to reduced synaptic binding to hippocampal neurons. These results demonstrate the promise of Co-sb complexes in anti-AD therapeutic approaches.

SUBMITTER: Heffern MC

PROVIDER: S-EPMC4166533 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Modulation of amyloid-β aggregation by histidine-coordinating Cobalt(III) Schiff base complexes.

Heffern Marie C MC Velasco Pauline T PT Matosziuk Lauren M LM Coomes Joseph L JL Karras Constantine C Ratner Mark A MA Klein William L WL Eckermann Amanda L AL Meade Thomas J TJ

Chembiochem : a European journal of chemical biology 20140624 11

Oligomers of the Aβ42 peptide are significant neurotoxins linked to Alzheimer's disease (AD). Histidine (His) residues present at the N terminus of Aβ42 are believed to influence toxicity by either serving as metal-ion binding sites (which promote oligomerization and oxidative damage) or facilitating synaptic binding. Transition metal complexes that bind to these residues and modulate Aβ toxicity have emerged as therapeutic candidates. Cobalt(III) Schiff base complexes (Co-sb) were evaluated for ...[more]

PMID: 24961930

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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.

Project description:The reaction of 2,6-diformyl-4-methylphenol (DFMF) with 1-amino-2-propanol (AP) and tris(hydroxymethyl)aminomethane (THMAM) was investigated in the presence of Cobalt(II) salts, (X = ClO4-, CH3CO2-, Cl-, NO3-), sodium azide (NaN3), and triethylamine (TEA). In one pot, the variation in Cobalt(II) salt results in the self-assembly of dinuclear, tetranuclear, and H-bonding-directed polynuclear coordination complexes of Cobalt(III), Cobalt(II), and mixed-valence CoIICoIII: [Co2III(H2L-1)2(AP-1)(N3)](ClO4)2 (1), [Co4(H2L-1)2(µ3-1,1,1-N3)2(µ-1,1-N3)2Cl2(CH3OH)2]·4CH3OH (2), [Co2IICo2III(HL-2)2(µ-CH3CO2)2(µ3-OH)2](NO3)2·2CH3CH2OH (3), and [Co2IICo2III (H2L12-)2(THMAM-1)2](NO3)4 (4). In 1, two cobalt(III) ions are connected via three single atom bridges; two from deprotonated ethanolic oxygen atoms in the side arms of the ligands and one from the1-amino-2-propanol moiety forming a dinuclear unit with a very short (2.5430(11) Å) Co-Co intermetallic separation with a coordination number of 7, a rare feature for cobalt(III). In 2, two cobalt(II) ions in a dinuclear unit are bridged through phenoxide O and μ3-1,1,1-N3 azido bridges, and the two dinuclear units are interconnected by two μ-1,1-N3 and two μ3-1,1,1-N3 azido bridges generating tetranuclear cationic [Co4(H2L-1)2(µ3-1,1,1-N3)2(µ-1,1-N3)2Cl2(CH3OH)2]2+ units with an incomplete double cubane core, which grow into polynuclear 1D-single chains along the a-axis through H-bonding. In 3, HL2- holds mixed-valent Co(II)/Co(III) ions in a dinuclear unit bridged via phenoxide O, μ-1,3-CH3CO2-, and μ3-OH- bridges, and the dinuclear units are interconnected through two deprotonated ethanolic O in the side arms of the ligands and two μ3-OH- bridges generating cationic tetranuclear [Co2IICo2III(HL-2)2(µ-CH3CO2)2(µ3-OH)2]2+ units with an incomplete double cubane core. In 4, H2L1-2 holds mixed-valent Co(II)/Co(III) ions in dinuclear units which dimerize through two ethanolic O (μ-RO-) in the side arms of the ligands and two ethanolic O (μ3-RO-) of THMAM bridges producing centrosymmetric cationic tetranuclear [Co2IICo2III (H2L1-2)2(THMAM-1)2]4+ units which grow into 2D-sheets along the bc-axis through a network of H-bonding. Bulk magnetization measurements on 2 demonstrate that the magnetic interactions are completely dominated by an overall ferromagnetic coupling occurring between Co(II) ions.

Dataset Information

Modulation of amyloid-? aggregation by histidine-coordinating Cobalt(III) Schiff base complexes.

Publications

Modulation of amyloid-β aggregation by histidine-coordinating Cobalt(III) Schiff base complexes.

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