Nitro‑, Azo‑, and Amino Derivatives of Ebselen: Synthesis, Structure, and Cytoprotective Effects

• Published in: Journal of organic chemistry 2017-01, Vol.82 (1), p.313-321
• Main Authors: Singh, Vijay P, Poon, Jia-fei, Yan, Jiajie, Lu, Xi, Ott, Marjam Karlsson, Butcher, Ray J, Gates, Paul J, Engman, Lars
• Format: Article
• Language: English
• Subjects: Animals; Azoles - chemical synthesis; Azoles - chemistry; Azoles - pharmacology; Cell Line; Cell Proliferation - drug effects; Cell Survival - drug effects; Crystallography, X-Ray; Cytoprotection - drug effects; Mice; Models, Molecular; Molecular Structure; Organoselenium Compounds - chemical synthesis; Organoselenium Compounds - chemistry; Organoselenium Compounds - pharmacology; Quantum Theory; Reactive Oxygen Species - antagonists & inhibitors; Reactive Oxygen Species - metabolism
• ISSN: 0022-3263; 1520-6904; 1520-6904
• DOI: 10.1021/acs.joc.6b02418

Novel azo-bis-ebselen compounds 7 were prepared by reduction of 7-nitro-2-aryl-1,2-benziso­selenazol-3­(2H)-ones 3 and 6 with sodium benzene­tellurolate, NaTeC6H5, and by reaction of 2-bromo-3-nitro­benzamides with Na2Se2. The X-ray structure of 7b showed that the molecule, due to strong intramolecular secondary Se···N interactions, is completely planar. Azo-compounds 7 upon further reaction with NaTeC6H5 were reductively cleaved to provide 2 equiv of the corresponding aromatic amine. The weak Se–N bond was not stable enough to survive the reaction conditions, and diselenides 8 were isolated after workup. Whereas azo-bis-ebselens 7 were poor mimics of the glutathione peroxidase (GPx)-enzymes, nitroebselens 3, 6, and 11b and diselenides 8 were 3–6-fold more active than ebselen. Based on 77Se NMR spectroscopy, a catalytic cycle for diselenide 8b, involving aminoebselen 14, was proposed. As assessed by chemiluminescence measurements, the good GPx-mimics could reduce production of reactive oxygen species (ROS) in stimulated human mononuclear cells more efficiently than Trolox. No toxic effects of the compounds were seen in MC3T3-cells at 25 μM.