Background: Parkinsonââ?¬â?¢s disease is a neurodegenerative disorder associated with oxidative stress and glutathione\ndepletion. The induction of cellular glutathione levels by exogenous molecules is a promising neuroprotective\napproach to limit the oxidative damage that characterizes Parkinsonââ?¬â?¢s disease pathophysiology. Dithiolethiones, a\nclass of sulfur-containing heterocyclic molecules, are known to increase cellular levels of glutathione; however, limited\ninformation is available regarding the influence of dithiolethione structure on activity. Herein, we report the design,\nsynthesis, and pharmacological evaluation of a further series of dithiolethiones in the SH-SY5Y neuroblastoma cell\nline.\nResults: Our structureââ?¬â??activity relationships data show that dithiolethione electronic properties, given as Hammett\nÃÆ?p constants, influence glutathione induction activity and compound toxicity. The most active glutathione inducer\nidentified, 6a, dose-dependently protected cells from 6-hydroxydopamine toxicity. Furthermore, the protective\neffects of 6a were abrogated by the inhibitor of glutathione synthesis, buthionine sulfoximine, confirming the importance\nof glutathione in the protective activities of 6a.\nConclusions: The results of this study further delineate the relationship between dithiolethione chemical structure\nand glutathione induction. The neuroprotective properties of analog 6a suggest a role for dithiolethiones as potential\nantiparkinsonian agents.
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