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

Lewis, Frank, Bird, Kathleen, Navarro, Jean-Philippe, El Fallah, Rawa, Brandel, Jeremy, Hubscher-Bruder, Veronique, Tsatsanis, Andrew, Duce, James A., Tetard, David, Bourne, Samuel, Maina, Mahmoud and Pienaar, Ilse S. (2022) 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. Dalton Transactions, 51 (9). pp. 3590-3603. ISSN 1477-9226

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Official URL: https://doi.org/10.1039/d1dt02604f

Abstract

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 D7.4, pL0.5) 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.

Item Type: Article
Additional Information: Funding information: Work carried out in Leeds was supported by Parkinson’s UK, Alzheimer’s Research UK and the European Research Council. Experimental work performed at Sussex was funded by grants awarded to I. S. P from the Alzheimer’s Society and the Royal Society. We gratefully acknowledge the Royal Society of Chemistry (RSC) for awarding a Researcher Mobility Grant to F. W. L. We thank the EPSRC UK National Mass Spectrometry Facility at Swansea University for recording high-resolution mass spectra. We also thank Northumbria University for the award of an Anniversary Research Fellowship to F. W. L.
Subjects: B900 Others in Subjects allied to Medicine
C100 Biology
F100 Chemistry
Department: Faculties > Health and Life Sciences > Applied Sciences
Depositing User: John Coen
Date Deposited: 21 Jan 2022 11:51
Last Modified: 20 Apr 2022 13:15
URI: http://nrl.northumbria.ac.uk/id/eprint/48222

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