Premium bonds: The pH‐dependent coordination of CuII to the Alzheimer′s disease amyloid‐β peptide has been studied by NMR spectroscopy. Several equivalent ligands are in equilibrium for CuII binding near pH 6.6 and 8.7. Fewer conformers are detected at high pH, in line with a reshuffling of the CuII binding site induced by deprotonation of the Asp1Ala2 peptide bond (see picture).

According to the amyloid cascade hypothesis, metal ions, mainly Cu and Zn ions, bound to the amyloid-β (Aβ) peptides are implicated in Alzheimer's disease (AD), a widespread neurodegenerative disease. They indeed impact the aggregation pathways of Aβ and are involved in the catalytic generation of reactive oxygen species (ROS) that participate in oxidative stress, while Aβ aggregation and oxidative stress are regarded as two key events in AD etiology. Cu ions due to their redox ability have been considered to be the main potential therapeutic targets in AD. A considerable number of ligands have been developed in order to modulate the toxicity associated with Cu in this context, via disruption of the Aβ− Cu interaction. Among them, small synthetic ligands and small peptide scaffolds have been designed and studied for their ability to remove Cu from Aβ. Some of those ligands are able to prevent Cu(Aβ)-induced ROS production and can modify the aggregation pathways of Aβ in vitro and in cellulo. Examples of such ligands are gathered in this Viewpoint, as a function of their structures and discussed with respect to their properties against Cu(Aβ) deleterious fallouts. Nevertheless, the beneficial activities of the most promising ligands detected in vitro and in cellulo have not been transposed to human yet. Some parameters that might explain this apparent contradiction and key concepts to consider for the design of "more" efficient ligands are thus reported and discussed. En passant, this Viewpoint sheds light on the difficulties in comparing the results from one study to another that hamper significant advances in the field.

The dinuclear phenolato-bridged complex [(mL)Mn(II)Mn(II)(mL)](ClO(4))(2) (1(ClO(4))(2)) has been obtained with the new [N(4)O] pentadentate ligand mL(-) (mLH=N,N'-bis-(2-pyridylmethyl)-N-(2-hydroxybenzyl)-N'-methyl-ethane-1,2-diamine) and has been characterised by X-ray crystallography. X- and Q-band EPR spectra were recorded and their variation with temperature was examined. All spectra exhibit features extending over 0-800 mT at the X band and over 100-1450 mT at the Q band, features that are usually observed for dinuclear Mn(II) complexes. Cyclic voltammetry of 1 exhibits two irreversible oxidation waves at E(1)(p)=0.89 V and E(2)(p)=1.02 V, accompanied on the reverse scan by an ill-defined cathodic wave at E(1')(p)=0.56 V (all measured versus the saturated calomel electrode (SCE)). Upon chemical oxidation with tBuOOH (10 equiv) at 20 degrees C, 1 is transformed into the mono-mu-oxo species [(mL)Mn(III)-(mu-O)-Mn(III)(mL)](2+) (2), which eventually partially evolves into the di-mu-oxo species [(mL)Mn(III)-(mu-O)(2)-Mn(IV)(mL)](n+) (3) in which one of the aromatic rings of the ligand is decoordinated. The UV/Vis spectrum of 2 displays a large absorption band at 507 nm, which is attributed to a phenolate-->Mn(III) charge-transfer transition. The cyclovoltammogram of 2 exhibits two reversible oxidation waves, at 0.65 and 1.16 V versus the SCE, corresponding to the Mn(III)Mn(III)/Mn(III)Mn(IV) and Mn(III)Mn(IV)/Mn(IV)Mn(IV) oxidation processes, respectively. The one-electron electrochemical oxidation of 2 leads to the mono-mu-oxo mixed-valent species [(mL)Mn(III)-(mu-O)-Mn(IV)(mL)](3+) (2 ox). The UV/Vis spectrum of 2 ox exhibits one large band at 643 nm, which is attributed to the phenolate-->Mn(IV) charge-transfer transition. 2 ox can also be obtained by the direct electrochemical oxidation of 1 in the presence of an external base. The 2 ox and 3 species exhibit a 16-line EPR signal with first peak to last trough widths of 125 and 111 mT, respectively. Both spectra have been simulated by using colinear rhombic Mn-hyperfine tensors. Mechanisms for the chemical formation of 2 and the electrochemical oxidation of 1 into 2 ox are proposed.