Abstract
BackgroundParkinson’s disease is a neurodegenerative disorder associated with oxidative stress and glutathione depletion. The induction of cellular glutathione levels by exogenous molecules is a promising neuroprotective approach to limit the oxidative damage that characterizes Parkinson’s disease pathophysiology. Dithiolethiones, a class of sulfur-containing heterocyclic molecules, are known to increase cellular levels of glutathione; however, limited information is available regarding the influence of dithiolethione structure on activity. Herein, we report the design, synthesis, and pharmacological evaluation of a further series of dithiolethiones in the SH-SY5Y neuroblastoma cell line.ResultsOur structure–activity relationships data show that dithiolethione electronic properties, given as Hammett σp constants, influence glutathione induction activity and compound toxicity. The most active glutathione inducer identified, 6a, dose-dependently protected cells from 6-hydroxydopamine toxicity. Furthermore, the protective effects of 6a were abrogated by the inhibitor of glutathione synthesis, buthionine sulfoximine, confirming the importance of glutathione in the protective activities of 6a.ConclusionsThe results of this study further delineate the relationship between dithiolethione chemical structure and glutathione induction. The neuroprotective properties of analog 6a suggest a role for dithiolethiones as potential antiparkinsonian agents.
Highlights
Parkinson’s disease is a neurodegenerative disorder associated with oxidative stress and glutathione depletion
Compounds 5b, 5c, and 5d, each containing electron-withdrawing aromatic groups, induced a lesser amount of GSH (94, 114 and 130 %, respectively). These results are consistent with our previous findings that alkyl groups at this position are superior to aromatic groups
Our results showed that the extent of GSH induction is related to the electronic properties of DTTs
Summary
Parkinson’s disease is a neurodegenerative disorder associated with oxidative stress and glutathione depletion. The induction of cellular glutathione levels by exogenous molecules is a promising neuroprotective approach to limit the oxidative damage that characterizes Parkinson’s disease pathophysiology. Dithiolethiones, a class of sulfur-containing heterocyclic molecules, are known to increase cellular levels of glutathione; limited information is available regarding the influence of dithiolethione structure on activity. Parkinson’s disease (PD), the second most common neurodegenerative disease, is a movement disorder characterized by the gradual disintegration of the nigrostriatal dopaminergic pathway. Analyses of the brains of PD patients have demonstrated extensive cellular damage caused by oxidative stress [1]. Dopaminergic neurons experience an additional oxidative burden due to the autoxidation and metabolism of DA.
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