帕金森病体外细胞模型中新型 1-羟基吡嗪-2(1H)-one 铁螯合剂的合成、理化表征和神经保护评价,Dalton Transactions

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帕金森病体外细胞模型中新型 1-羟基吡嗪-2(1H)-one 铁螯合剂的合成、理化表征和神经保护评价
Dalton Transactions ( IF 3.5 ) Pub Date : 2022-02-11 , DOI: 10.1039/d1dt02604f
Frank W Lewis ₁ , Kathleen Bird ₁ , Jean-Philippe Navarro ₁ , Rawa El Fallah ₂ , Jeremy Brandel ₂ , Véronique Hubscher-Bruder ₂ , Andrew Tsatsanis _{3,

4} , James A Duce _{3,

4} , David Tétard ₁ , Samuel Bourne ₅ , Mahmoud Maina ₅ , Ilse S Pienaar _{5,

6}

Affiliation

铁失调、多巴胺耗竭、细胞氧化应激和 α-突触核蛋白错误折叠是帕金森病进展中的关键神经元病理特征。长期以来，人们一直建议赋予一种或多种治疗作用模式的铁螯合剂作为其治疗的疾病修饰疗法。本研究合成了新型 1-羟基吡嗪-2( 1H )-one 铁螯合剂，并在帕金森病细胞培养模型中评估了它们的理化性质、铁螯合能力、抗氧化能力和神经保护作用。理化性质（log β , log D _7.4 , pL _0.5) 表明这些配体穿透细胞膜和形成较弱铁络合物的能力比密切相关的 1-hydroxypyridin-2(1 H )-ones 更差。尽管如此，我们表明这些配体在体外对儿茶酚胺能神经毒素 6-羟基多巴胺提供的神经保护水平与之前使用 1-羟基吡啶-2（1 H)-ones 和临床使用的铁螯合剂 Deferiprone，与对照相比，其中两种配体可将细胞活力恢复至 ≥89%。两个配体被赋予了额外的苯酚部分，以试图衍生出具有双重铁螯合/抗氧化活性的多功能螯合剂。然而，这些配体的神经保护水平不高于缺乏该部分的配体，这表明这些配体的神经保护特性主要是由于细胞内不稳定铁的螯合和钝化，防止产生自由基和活性氧，否则会导致在帕金森病中看到的神经元细胞死亡。

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Synthesis, physicochemical characterization and neuroprotective evaluation of novel 1-hydroxypyrazin-2(1H)-one iron chelators in an in vitro cell model of Parkinson's disease

Iron dysregulation, dopamine depletion, cellular oxidative stress and α-synuclein protein mis-folding are key neuronal pathological features seen in the progression of Parkinson's disease. Iron chelators endowed with one or more therapeutic modes of action have long been suggested as disease modifying therapies for its treatment. In this study, novel 1-hydroxypyrazin-2(1H)-one iron chelators were synthesized and their physicochemical properties, iron chelation abilities, antioxidant capacities and neuroprotective effects in a cell culture model of Parkinson's disease were evaluated. Physicochemical properties (log β, log D_7.4, pL_0.5) suggest that these ligands have a poorer ability to penetrate cell membranes and form weaker iron complexes than the closely related 1-hydroxypyridin-2(1H)-ones. Despite this, we show that levels of neuroprotection provided by these ligands against the catecholaminergic neurotoxin 6-hydroxydopamine in vitro were comparable to those seen previously with the 1-hydroxypyridin-2(1H)-ones and the clinically used iron chelator Deferiprone, with two of the ligands restoring cell viability to ≥89% compared to controls. Two of the ligands were endowed with additional phenol moieties in an attempt to derive multifunctional chelators with dual iron chelation/antioxidant activity. However, levels of neuroprotection with these ligands were no greater than ligands lacking this moiety, suggesting the neuroprotective properties of these ligands are due primarily to chelation and passivation of intracellular labile iron, preventing the generation of free radicals and reactive oxygen species that otherwise lead to the neuronal cell death seen in Parkinson's disease.

更新日期：2022-02-11

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