Further structure-activity relationships study of substituted dithiolethiones as glutathione-inducing neuroprotective agents.
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 σpconstants, 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 of6awere abrogated by the inhibitor of glutathione synthesis, buthionine sulfoximine, confirming the importance of glutathione in the protective activities of6a.


CONCLUSIONS
The results of this study further delineate the relationship between dithiolethione chemical structure and glutathione induction. The neuroprotective properties of analog6asuggest a role for dithiolethiones as potential antiparkinsonian agents.
Department of Pharmaceutical Sciences, Manchester University College of Pharmacy, 10627 Diebold Rd, Fort Wayne, IN 46845 USA.
Dennis A
0000-0002-7503-3750
DA
Brown
Department of Pharmaceutical Sciences, Manchester University College of Pharmacy, 10627 Diebold Rd, Fort Wayne, IN 46845 USA.
Swati
S
Betharia
Department of Microbiology and Immunology, Indiana University School of Medicine, 2101 E. Coliseum Blvd, Fort Wayne, IN 46805 USA.
Jui-Hung
JH
Yen
Department of Microbiology and Immunology, Indiana University School of Medicine, 2101 E. Coliseum Blvd, Fort Wayne, IN 46805 USA.
Ping-Chang
PC
Kuo
Department of Pharmaceutical Sciences, Manchester University College of Pharmacy, 10627 Diebold Rd, Fort Wayne, IN 46845 USA.
Hitesh
H
Mistry
Dithiolethiones; Glutathione; Neuroprotection; Parkinson’s disease