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 A beta-peptides in the Alzheimer disease. ne apparent affinity of all bis-8-hydroxyquinoline ligands for Cull and Zn-II are similar with logK(Cu)(II)approximate to 16and logK(Zn)(II) approximate to 13 and are 10000 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 A beta-peptides induced by Cu-II and Zn-II and also to inhibit the toxic formation of H2O2 due to copper complexes of A beta. 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.