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Type: Journal article
Title: Copper(II) binding to PBT2 differs from that of other 8-hydroxyquinoline chelators: implications for the treatment of neurodegenerative protein misfolding diseases
Author: Summers, K.L.
Roseman, G.P.
Sopasis, G.J.
Millhauser, G.L.
Harris, H.H.
Pickering, I.J.
George, G.N.
Citation: Inorganic Chemistry: including bioinorganic chemistry, 2020; 59(23):17519-17534
Publisher: American Chemical Society
Issue Date: 2020
ISSN: 0020-1669
Statement of
Kelly L. Summers, Graham P. Roseman, George J. Sopasis, Glenn L. Millhauser, Hugh H. Harris, Ingrid J. Pickering and Graham N. George
Abstract: PBT2 (5,7-dichloro-2-[(dimethylamino)methyl]-8-hydroxyquinoline) is a small Cu(II)-binding drug that has been investigated in the treatment of neurodegenerative diseases, namely, Alzheimer's disease (AD). PBT2 is thought to be highly effective at crossing the blood-brain barrier and has been proposed to exert anti-Alzheimer's effects through the modulation of metal ion concentrations in the brain, specifically the sequestration of Cu(II) from amyloid plaques. However, despite promising initial results in animal models and in clinical trials where PBT2 was shown to improve cognitive function, larger-scale clinical trials did not find PBT2 to have a significant effect on the amyloid plaque burden compared with controls. We propose that the results of these clinical trials likely point to a more complex mechanism of action for PBT2 other than simple Cu(II) sequestration. To this end, herein we have investigated the solution chemistry of Cu(II) coordination by PBT2 primarily using X-ray absorption spectroscopy (XAS), high-energy-resolution fluorescence-detected XAS, and electron paramagnetic resonance. We propose that a novel bis-PBT2 Cu(II) complex with asymmetric coordination may coexist in solution with a symmetric four-coordinate Cu(II)-bis-PBT2 complex distorted from coplanarity. Additionally, PBT2 is a more flexible ligand than other 8HQs because it can act as both a bidentate and a tridentate ligand as well as coordinate Cu(II) in both 1:1 and 2:1 PBT2/Cu(II) complexes.
Keywords: Animals
Alzheimer Disease
Neuroprotective Agents
Chelating Agents
Molecular Structure
Coordination Complexes
X-Ray Absorption Spectroscopy
Proteostasis Deficiencies
Density Functional Theory
Rights: © 2020 American Chemical Society.
DOI: 10.1021/acs.inorgchem.0c02754
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