title: Synthesis and structure-activity relationships study of dithiolethiones as inducers of glutathione in the SH-SY5Y neuroblastoma cell line.
abstract: Parkinson's disease is a neurodegenerative disorder that involves the degeneration of nigrostriatal dopaminergic neurons. Elevated levels of reactive oxygen species have been shown to deplete cellular levels of the ubiquitous antioxidant glutathione, leading to oxidative stress and eventual neuronal cell death. Dithiolethiones, a class of sulfur-containing heterocyclic molecules, have been shown to induce cellular production of glutathione in a variety of tissues, but have not been extensively evaluated in neurons. Herein, we report the synthesis and preliminary structure-activity relationships study of several substituted dithiolethiones. Three molecules were identified (D3T, CPDT, and 2d) that potently induced cellular glutathione in the SH-SY5Y neuroblastoma cell line. Furthermore, these compounds were found to provide neuroprotection in the 6-hydroxydopamine model of neurotoxicity. This study suggests that dithiolethione-mediated neuroprotection may have potential as a disease-modifying antiparkinsonian therapy.
authors.affiliation: Department of Pharmaceutical Sciences, Manchester University College of Pharmacy, 10627 Diebold Rd, Fort Wayne, IN 46845, United States. Electronic address: dabrown@manchester.edu.
authors.forename: Dennis A
authors.initials: DA
authors.lastname: Brown
authors.affiliation: Department of Pharmaceutical Sciences, Manchester University College of Pharmacy, 10627 Diebold Rd, Fort Wayne, IN 46845, United States.
authors.forename: Swati
authors.initials: S
authors.lastname: Betharia
authors.affiliation: Department of Microbiology and Immunology, Indiana University School of Medicine, 2101 Coliseum Blvd, Fort Wayne, IN 46805, United States.
authors.forename: Jui-Hung
authors.initials: JH
authors.lastname: Yen
authors.affiliation: Department of Pharmaceutical Sciences, Manchester University College of Pharmacy, 10627 Diebold Rd, Fort Wayne, IN 46845, United States.
authors.forename: Quang
authors.initials: Q
authors.lastname: Tran
authors.affiliation: Department of Pharmaceutical Sciences, Manchester University College of Pharmacy, 10627 Diebold Rd, Fort Wayne, IN 46845, United States.
authors.forename: Hitesh
authors.initials: H
authors.lastname: Mistry
authors.affiliation: Department of Pharmaceutical Sciences, Manchester University College of Pharmacy, 10627 Diebold Rd, Fort Wayne, IN 46845, United States.
authors.forename: Kari
authors.initials: K
authors.lastname: Smith
mesh_terms: D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism*; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D009447:Neuroblastoma / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016627:Oxidopamine / Q000633:toxicity; D013329:Structure-Activity Relationship; D013455:Sulfur / Q000737:chemistry
chemical_list: D006571:Heterocyclic Compounds; D018696:Neuroprotective Agents; D013455:Sulfur; D016627:Oxidopamine; D005978:Glutathione
keywords: Dithiolethione; Glutathione; Neuroprotection