Structures of the Copper and Zinc Complexes of PBT2, a Chelating Agent Evaluated as Potential Drug for Neurodegenerative Diseases

Abstract

Clioquinol and PBT2, based on a 8-hydroxyquinoline scaffold, have been proposed as drugs able to treat the disruption of metal homeostasis in neurodegenerative diseases, especially Alzheimer's disease (AD). They are believed to reduce metal-amyloid (A ) interactions and regulate redox homeostasis in AD brains. Therefore, the understanding of the molecular aspects of metal chelation by 8-hydroxyquinolines is clearly important for the development of future metal chelators as putative drugs. Despite this, literature data on these aspects are rather limited. We report herein the stoichiometries and structures of the copper(II) and zinc(II) complexes of PBT2. The reported data indicate that the coordination chemistry of PBT2 is [a]

Preparation of Tetradentate Copper Chelators as Potential Anti‐Alzheimer Agents

“…Substitution of the quinoline ring by one or several electronwithdrawing substituent(s) resulted in al ower affinity forC u II : log K app [Cu II -L] = 9.7 to 10.8 for TDMQ5, 8, 9, 10, 11,1 2, 13, 16, and 18, whose quinoline was substituted by 5,7-Cl 2 ,5 -F,6 -F, 5,6-Cl 2 ,5 -Cl, 6-Cl, 7-Cl, 6-CF 3 ,a nd 4-Cl, respectively.M ore importantly,t he affinity for Cu II was drastically modulated by the side chain. The values of log K app were 9.8, 10.2, and 16.5 for TDMQ5 (n = 1, m = 2), TDMQ19( n = 1, m = 3), and TDMQ20 (n = 2, m = 2), respectively.T his indicates that increasing the length of the proximal part of the sidec hain (TDMQ20 compared to 19), but not the distal part (TDMQ19 compared to TDMQ5), resultedi ni ncreasing the affinity for Cu II by about six orders of magnitude. In addition, TDMQ20, having such an aliphatic diamines ide chain (equal distal and proximal chains with two methylene residues each) seems to be an optimal feature:afurtheri ncrease in the distal chain resulted in ad rastically lower log K app (Cu II -TDMQ21 = 8.1, n = 2, m = 3).…”

“…To restore metal homeostasis in AD brain tissue, mild chelators should be able to extract copper ions from sinks (amyloids being the major one) and transfer them to copper‐carrier proteins. Bidentate ligands such as clioquinol (CQ) and PBT2 form ternary complexes with copper amyloids, and for this reason, are unable to extract copper from these amyloids . Tetradendate ligands of the PA1637 series efficiently regulate copper homeostasis and consequently inhibit ROS production induced by Cu‐Aβ .…”

“…Bidentate ligands such as clioquinol (CQ) and PBT2 form ternary complexes with coppera myloids,a nd for this reason, are unable to extract copperf rom these amyloids. [15][16][17][18][19] Tetradendatel igandso ft he PA1637 series efficientlyr egulate copperh omeostasisa nd consequently inhibitR OS production induced by Cu-Ab. [15][16][17][18][19] However,t od ecrease the size and molecular weighto ft hese bis-aminoquinoline ligandsf or facilitating their passage through the blood-brain barrier (BBB), we designed new tetradentate copperl igands based on am onoquinoline motif.…”

“…[15][16][17][18][19] Tetradendatel igandso ft he PA1637 series efficientlyr egulate copperh omeostasisa nd consequently inhibitR OS production induced by Cu-Ab. [15][16][17][18][19] However,t od ecrease the size and molecular weighto ft hese bis-aminoquinoline ligandsf or facilitating their passage through the blood-brain barrier (BBB), we designed new tetradentate copperl igands based on am onoquinoline motif. These ligands, termed TDMQ for TetraDentate MonoQuinolines (Figure 1), [20] are based on an 8-aminoquinoline skeleton substituted at C2 by a bis-chelatings ide chain (the distal substituent R 1 containing at least one coordinatinga tom).…”

N4‐Tetradentate Chelators Efficiently Regulate Copper Homeostasis and Prevent ROS Production Induced by Copper‐Amyloid‐β1–16

“…PBT2, whose copper complex has a N 3 O 2 coordination sphere, and a metal/ligand stoichiometry = 1/2,16 failed to inhibit oxygen reduction either in the presence or in the absence of zinc.…”