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- Title
Further structure-activity relationships study of substituted dithiolethiones as glutathione-inducing neuroprotective agents.
- Authors
Brown, Dennis A.; Betharia, Swati; Jui-Hung Yen; Ping-Chang Kuo; Mistry, Hitesh
- Abstract
Background: 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; 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. Results: Our structure-activity relationships data show that dithiolethione electronic properties, given as Hammett sp 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. Conclusions: The 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.
- Subjects
THIONES; DITHIOLE; NEUROPROTECTIVE agents; PARKINSON'S disease treatment; GLUTATHIONE
- Publication
Chemistry Central Journal, 2016, Vol 10, p1
- ISSN
1752-153X
- Publication type
Article
- DOI
10.1186/s13065-016-0210-z