Characterization of copper(II) specific pyridine containing ligands: Potential metallophores for Alzheimer's disease therapy

Abstract

Two amide group containing pyridine derivatives, N-(pyridin-2-ylmethyl)picolinamide (PMPA) and N-(pyridin-2-ylmethyl)-2-((pyridin-2-ylmethyl)amino)acetamide (DPMGA), have been investigated as potential metallo-phores in the therapy of Alzheimer's disease. Their complex formation with Cu(II) and Zn(II) were characterized in details. Unexpectedly not only the Cu(II) but also the Zn(II) was able to induce deprotonation of the amide-NH, however, it occurred only at higher pH or at higher metal ion concentrations than the biological conditions. At μM concentration level mono complexes (MLH−1) dominate with both ligands. Direct fluorescence and reactive oxygen species (ROS) producing measurements prove that both ligands are able to remove Cu(II) from its amyloid-β complexes (CuAβ). Correlation was also established between the conditional stability constant of the Cu(II) complexes with different ligands and their ability of inhibition of ROS production by CuAβ.