N 4 ‐Tetradentate Chelators Efficiently Regulate Copper Homeostasis and Prevent ROS Production Induced by Copper‐Amyloid‐β 1–16

The disruption of copper homeostasis and the oxidative stress induced by Cu‐amyloids are crucial features of Alzheimer's disease pathology. The copper specific N 4 ‐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 N 2 O 2 or N 3 O 2 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 N 4 ‐tetradendate motif to be able to reduce an oxidative stress in the zinc‐rich physiological environment of brain. The N 4 ‐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.