Gomes Luiza M F, Vieira Rafael P, Jones Michael R, Wang Michael C P, Dyrager Christine, Souza-Fagundes Elaine M, Da Silva Jeferson G, Storr Tim, Beraldo Heloisa
Departamento de Química, Universidade Federal de Minas Gerais, 31270-901 Belo Horizonte, MG, Brazil; Department of Chemistry, Simon Fraser University, V5A-1S6 Burnaby, BC, Canada.
Department of Chemistry, Simon Fraser University, V5A-1S6 Burnaby, BC, Canada.
J Inorg Biochem. 2014 Oct;139:106-16. doi: 10.1016/j.jinorgbio.2014.04.011. Epub 2014 Apr 28.
One of the hallmarks of Alzheimer's disease (AD) in the brain are amyloid-β (Aβ) plaques, and metal ions such as copper(II) and zinc(II) have been shown to play a role in the aggregation and toxicity of the Aβ peptide, the major constituent of these extracellular aggregates. Metal binding agents can promote the disaggregation of Aβ plaques, and have shown promise as AD therapeutics. Herein, we describe the syntheses and characterization of an acetohydrazone (8-H2QH), a thiosemicarbazone (8-H2QT), and a semicarbazone (8-H2QS) derived from 8-hydroxyquinoline. The three compounds are shown to be neutral at pH7.4, and are potent antioxidants as measured by a Trolox Equivalent Antioxidant Capacity (TEAC) assay. The ligands form complexes with Cu(II), 8-H2QT in a 1:1 metal:ligand ratio, and 8-H2QH and 8-H2QS in a 1:2 metal:ligand ratio. A preliminary aggregation inhibition assay using the Aβ1-40 peptide showed that 8-H2QS and 8-H2QH inhibit peptide aggregation in the presence of Cu(II). Native gel electrophoresis/Western blot and TEM images were obtained to give a more detailed picture of the extent and pathways of Aβ aggregation using the more neurotoxic Aβ1-42 in the presence and absence of Cu(II), 8-H2QH, 8-H2QS and the drug candidate PBT2. An increase in the formation of oligomeric species is evident in the presence of Cu(II). However, in the presence of ligands and Cu(II), the results match those for the peptide alone, suggesting that the ligands function by sequestering Cu(II) and limiting oligomer formation in this assay.
大脑中阿尔茨海默病（AD）的标志性特征之一是β-淀粉样蛋白（Aβ）斑块，已证明铜（II）和锌（II）等金属离子在这些细胞外聚集体的主要成分Aβ肽的聚集和毒性中起作用。金属结合剂可促进Aβ斑块的解聚，并已显示出作为AD治疗药物的前景。在此，我们描述了源自8-羟基喹啉的乙酰腙（8-H2QH）、硫代半卡巴腙（8-H2QT）和半卡巴腙（8-H2QS）的合成与表征。这三种化合物在pH7.4时呈中性，通过Trolox等效抗氧化能力（TEAC）测定显示它们是有效的抗氧化剂。这些配体与Cu（II）形成配合物，8-H2QT的金属：配体比例为1:1，8-H2QH和8-H2QS的金属：配体比例为1:2。使用Aβ1-40肽进行的初步聚集抑制试验表明，8-H2QS和8-H2QH在Cu（II）存在下抑制肽聚集。获得了天然凝胶电泳/蛋白质印迹和透射电镜图像，以更详细地了解在有和没有Cu（II）、8-H2QH、8-H2QS和候选药物PBT2的情况下，使用神经毒性更强的Aβ1-42时Aβ聚集的程度和途径。在Cu（II）存在下，寡聚体物种的形成明显增加。然而，在配体和Cu（II）存在下，结果与单独肽的结果相符，表明在该试验中配体通过螯合Cu（II）和限制寡聚体形成发挥作用。
