N₄ -Tetradentate Chelators Efficiently Regulate Copper Homeostasis and Prevent ROS Production Induced by...

The disruption of copper homeostasis and the oxidative stress induced by Cu-amyloids are crucial features of Alzheimer's disease pathology. The copper specific N₄ -tetradendate ligands TDMQ20 and 1 are able to fully inhibit in vitro the aerobic oxidation of ascorbate induced by Cu-Aβ_1-16 , even in the presence of 100 molar equivalents of Zn^II with respect to Cu^II , whereas other ligands with N₂ O₂ or N₃ O₂ coordination spheres failed to do so. This essential result indicates that, in addition to metal selectivity, the coordination sphere of copper chelators should exhibit a N₄ -tetradendate motif to be able to reduce an oxidative stress in the zinc-rich physiological environment of brain. The N₄ -scaffolds of these two aminoquinoline-based ligands, TDMQ20 or 1, suitable for a square-planar coordination of copper(II), allowed them to enhance both the selectivity for copper and the ability to reduce the oxidative stress induced by copper-amyloid in a zinc-rich environment.