Why Is Tetradentate Coordination Essential for Potential Copper Homeostasis Regulators in Alzheimer's Disease?

International audienceResearch of effective drugs against Alzheimer's disease (AD) is currently one of the most challenging topics in medicinal chemistry. Despite the documented detrimental effect of the disruption of copper ion homeostasis in AD, this potential pharmacological target has been weakly explored. The design of chelators as drug candidates for copper regulation in AD brain should meet critical coordination chemistry requirements, in addition to requested biological parameters (membrane crossing, activity, …). Among the various possibilities offered by the diversity of metal ligands, we found that N4-tetradentate 8-aminoquinoline ligands able to generate stricly square planar Cu(II) complexes, are the most suitable for the transfer of copper from metal-amyloids to metal-carrier proteins, and are able to inhibit the catalytic reduction of dioxygen produced by copper-loaded amyloids exposed to a biological reductant. In vivo, such tetradentate ligands are able to inhibit the loss of episodic memory in non-transgenic amyloid-impaired mice