In vitro coordination of Fe-protoheme with amyloid ß is non-specific and exhibits multiple equilibria.

In addition to copper and zinc, heme is thought to play a role in Alzheimer's disease and its metabolism is strongly affected during the course of this disease. Amyloid ß, the peptide associated with Alzheimer's disease, was shown to bind heme in vitro with potential catalytic activity linked to oxidative stress. To date, there is no direct determination of the structure of this complex. In this work, we studied the binding mode of heme to amyloid ß in different conditions of pH and redox state by using isotopically labelled peptide in combination with advanced magnetic and vibrational spectroscopic methods. Our results show that the interaction between heme and amyloid ß leads to a variety of species in equilibrium. The formation of these species seems to depend on many factors suggesting that the binding site is neither very strong nor highly specific. In addition, our data do not support the currently accepted model where a water molecule is bound to the ferric heme as sixth ligand. They also exclude structural models mimicking a peroxidatic site in the amyloid ß-Fe-protoheme complexes.

The first water-soluble bowl complex: molecular recognition of acetate by the biomimetic tris(imidazole) Zn(II) system at pH 7.4.

A supramolecular approach for modeling active sites of metallo-enzymes relies on the association of a metal ion bound to a tris(imidazole) core under the control of a cavity. One step further is the water-solubilization of the cavity-complex. Here, we describe the synthesis of a water-soluble bowl-ligand that has been successively achieved through an 11-step strategy from resorcinol. First insights into its coordination properties in water show that it readily binds Zn(II) at physiological pH and acts as a molecular receptor for the hydrophilic acetate guest ligand.

Supramolecular control of a mononuclear biomimetic copper(II) center: bowl complexes vs funnel complexes.

Modeling the mononuclear site of copper enzymes is important for a better understanding of the factors controlling the reactivity of the metal center. A major difficulty stems from the difficult control of the nuclearity while maintaining free sites open to coordination of exogenous ligands. A supramolecular approach consists in associating a hydrophobic cavity to a tripodal ligand that will define the coordination spheres as well as access to the metal ion. Here, we describe the synthesis of a bowl Cu(II) complex based on the resorcinarene scaffold. This study supplements a previous work on Cu(I) coordination. It provides a complete picture of the cavity-copper system in its two oxidation states. The first XRD structure of such a bowl complex was obtained, evidencing a 5-coordinate Cu(II) ion with the three imidazole donors bound to the metal (two in the base of the pyramid, one in the apical position) and with an acetate anion, completing the base of the pyramid, and deeply included in the bowl. Solution studies conducted by EPR and UV-vis absorption spectroscopies as well as cyclic voltammetry highlighted interaction with coordinating solvents, various carboxylates that can sit either in the endo or in the exo position depending on their size as well as possible stabilization of hydroxo species in a mononuclear state. A comparison of the binding and redox properties of the bowl complex with funnel complexes based on the calix[6]arene core further highlights the importance of supramolecular features defining the first, second, and third coordination sphere for control of the metal ion.

Copper and heme-mediated Abeta toxicity: redox chemistry, Abeta oxidations and anti-ROS compounds.

Oxidative stress mediated by reactive oxygen or nitrogen species (ROS/RNS) seems to be implicated in several diseases including neurodegenerative ones. In one of them, namely Alzheimer's disease, there is a large body of evidence that the aggregation of the peptide amyloid-beta (Abeta) is implicated in the generation of the oxidative stress. Redox active metal ions play a key role in oxidative stress, either in the production of ROS/RNS by enzymes or loosely bound metals or in the protection against ROS, mostly as catalytic centers in enzymes. In Alzheimer's disease, it is thought that metals (mostly Cu, Fe and heme) can bind to amyloid-beta and that such systems are involved in the generation of oxidative stress. In the present article, we review the role of ROS/RNS produced by redox active Cu ions and heme compounds in the context of the amyloid cascade. We focus on (i) the coordination chemistry of Cu and heme to Abeta; (ii) the role of the corresponding Abeta adducts in the (catalytic) production of ROS/RNS; (iii) the subsequent degradation of Abeta by these reactive species and (iv) the use of antioxidants, in particular metal sequestering compounds and direct antioxidants like polyphenols as a therapeutic strategies.

First Zn(II) bowl-complexes modeling the tris(histidine) metallo-site of enzymes.

The bowl-shaped resorcin[4]arene-based ligand was prepared as a model of the trihistidine coordination core present in many mononuclear metalloenzymes. The -CH(2)-O-CH(2)- linkers connecting the imidazoles to the cavity allow three imidazoles to simultaneously bind a metal ion, and favor cis-coordination of two exchangeable ligands. The corresponding mononuclear Zn(II) complexes were shown to be capable of the selective guest binding and exchange at both endo and exo positions.