Preparation and study of new poly-8-hydroxyquinoline chelators for an anti-Alzheimer strategy

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 Cu II and Zn II, two metal ions involved in the formation of amyloid aggregates of the toxic Abeta-peptides in the Alzheimer disease. The apparent affinity of all bis-8-hydroxyquinoline ligands for Cu II and Zn II are similar with logK Cu II approximately 16 and logK Zn II approximately 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 Abeta-peptides induced by Cu II and Zn II and also to inhibit the toxic formation of H2O2 due to copper complexes of Abeta. The best results were obtained with a one-atom linker between the two quinoline units. X-ray analyses of single-crystals of Cu II, Zn II or Ni II 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 Cu II and Zn II complexes include a fifth axial ligand and are pentacoordinated.