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

Frank Lewis, Kathleen Bird, Jean-Philippe Navarro, Rawa El Fallah, Jeremy Brandel, Véronique Hubscher-Bruder, Andrew Tsatsanis, James Duce, David Tetard, Samuel Bourne, Mahmoud Maina, Ilse Pienaar

Research output: Contribution to journalArticlepeer-review

5 Downloads (Pure)

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.
Original languageEnglish
JournalDalton Transactions
Early online date11 Feb 2022
DOIs
Publication statusE-pub ahead of print - 11 Feb 2022

Keywords

  • 1,2-HOPOs1,2s
  • Iron chelators
  • Neurodegeneration
  • Parkinson's disease
  • Reactive Oxygen Species

ASJC Scopus subject areas

  • Pharmacology, Toxicology and Pharmaceutics(all)

Fingerprint

Dive into the research topics of 'Synthesis, physicochemical characterization and neuroprotective evaluation of novel 1-hydroxypyrazin-2(1 H)-one iron chelators in an in vitro cell model of Parkinson's disease.'. Together they form a unique fingerprint.

Cite this