Synthesis and structure-activity relationships study of dithiolethiones as inducers of glutathione in the SH-SY5Y neuroblastoma cell line

被引:24
作者
Brown, Dennis A. [1 ]
Betharia, Swati [1 ]
Yen, Jui-Hung [2 ]
Tran, Quang [1 ]
Mistry, Hitesh [1 ]
Smith, Kari [1 ]
机构
[1] Univ Manchester, Coll Pharm, Dept Pharmaceut Sci, Ft Wayne, IN 46845 USA
[2] Indiana Univ Sch Med, Dept Microbiol & Immunol, Ft Wayne, IN 46805 USA
关键词
Dithiolethione; Neuroprotection; Glutathione; PHASE-2; ENZYME-INDUCTION; PARKINSONS-DISEASE; OXIDATIVE STRESS; INDUCED CYTOTOXICITY; HYDROGEN-PEROXIDE; MAJOR METABOLITE; 3H-1,2-DITHIOLE-3-THIONE; OLTIPRAZ; MITOCHONDRIA; DOPAMINE;
D O I
10.1016/j.bmcl.2014.10.005
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
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. (C) 2014 Elsevier Ltd. All rights reserved.
引用
收藏
页码:5829 / 5831
页数:3
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