Preparation and Study of New Poly-8-Hydroxyquinoline Chelators for an anti-Alzheimer Strategy

• Published in: Chemistry : a European journal 2008-01, Vol.14 (2), p.682-696
• Main Authors: Deraeve, Céline, Boldron, Christophe, Maraval, Alexandrine, Mazarguil, Honoré, Gornitzka, Heinz, Vendier, Laure, Pitié, Marguerite, Meunier, Bernard
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - drug therapy; Amyloid beta-Peptides - chemistry; Amyloid beta-Peptides - drug effects; amyloids; chelates; Chelating Agents - chemical synthesis; Chelating Agents - chemistry; Chelating Agents - pharmacology; Chemical Sciences; copper; Copper - chemistry; Crystallography, X-Ray; Hydrogen Peroxide - antagonists & inhibitors; Hydrogen Peroxide - chemical synthesis; Hydrogen Peroxide - chemistry; Hydrophobic and Hydrophilic Interactions; Ligands; Models, Molecular; Molecular Structure; Nickel - chemistry; Organic chemistry; Organometallic Compounds - chemical synthesis; Organometallic Compounds - chemistry; Organometallic Compounds - pharmacology; Oxyquinoline - chemistry; Peptide Fragments - chemistry; Peptide Fragments - drug effects; peptides; Polymers - chemistry; zinc; Zinc - chemistry
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.200701024

Fourteen different ligands have been synthesized with two covalently linked 8‐hydroxyquinoline motifs that favor metal complexation. These bis‐chelators include different bridges at the C2 positions and different substituents to modulate their physicochemical properties. They can form metal complexes in a ratio of one ligand per metal ion with CuII and ZnII, two metal ions involved in the formation of amyloid aggregates of the toxic Aβ‐peptides in the Alzheimer disease. The apparent affinity of all bis‐8‐hydroxyquinoline ligands for CuII and ZnII are similar with logK Cu II ≈16 and logK Zn II ≈13 and are 10 000 times more efficient than for the corresponding 8‐hydroxyquinoline monomers. Their strong chelating capacities allow them to inhibit more efficiently than the corresponding monomers the precipitation of Aβ‐peptides induced by CuII and ZnII and also to inhibit the toxic formation of H2O2 due to copper complexes of Aβ. The best results were obtained with a one‐atom linker between the two quinoline units. X‐ray analyses of single‐crystals of CuII, ZnII or NiII complexes of 2,2′‐(2,2‐propanediyl)‐bis(8‐hydroxyquinoline), including a one‐atom linker, showed that all heteroatoms of the bis‐8‐hydroxyquinoline ligand chelate the same metal ion in a distorted square‐planar geometry. The CuII and ZnII complexes include a fifth axial ligand and are pentacoordinated. Fourteen ligands including a linkage between the C2 of 8‐hydroxyquinoline were synthesized. They favor metal complexes where two 8‐hydroxyquinolines chelate the same metal ion. The complexes inhibit the precipitation of Aβ‐peptide induced by CuII and ZnII but also the toxic formation of H2O2 due to a Aβ–Cu complex. The copper(II) and zinc(II) complexes of these ligands were also characterized.