Molecular and Environmental Sciences Group, Department of Geological Sciences, University of Saskatchewan, 114 Science Place, Saskatoon, Saskatchewan S7N 5E2, Canada.
Department of Chemistry, University of Saskatchewan, 110 Science Place, Saskatoon, Saskatchewan S7N 5C9, Canada.
Inorg Chem. 2020 Dec 7;59(23):17519-17534. doi: 10.1021/acs.inorgchem.0c02754. Epub 2020 Nov 23.
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 -PBT2 Cu(II) complex with asymmetric coordination may coexist in solution with a symmetric four-coordinate Cu(II)--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.
PBT2（5,7-二氯-2-[(二甲氨基)甲基]-8-羟基喹啉）是一种可与 Cu(II)结合的小分子药物，用于治疗神经退行性疾病，包括阿尔茨海默病（AD）。PBT2 被认为具有高效穿透血脑屏障的能力，并通过调节大脑中金属离子浓度，特别是从淀粉样斑块中螯合 Cu(II)，从而发挥抗 AD 作用。然而，尽管在动物模型和临床试验中取得了有希望的初步结果，显示 PBT2 可改善认知功能，但更大规模的临床试验并未发现 PBT2 与对照组相比对淀粉样斑块负担有显著影响。我们认为，这些临床试验的结果可能表明 PBT2 的作用机制比单纯的 Cu(II)螯合更为复杂。为此，我们主要使用 X 射线吸收光谱（XAS）、高能分辨荧光探测 XAS 和电子顺磁共振研究了 PBT2 与 Cu(II)的配位溶液化学。我们提出，一种新的 PBT2-Cu(II)配合物可能与对称的四配位 Cu(II)-PBT2 配合物一起存在于溶液中，后者从共面发生扭曲。此外，PBT2 是一种比其他 8HQ 更具柔性的配体，因为它可以作为双齿和三齿配体，并以 1:1 和 2:1 的 PBT2/Cu(II)配合物形式配位 Cu(II)。
