title: Effect of a Bromo Substituent on the Glutathione Peroxidase Activity of a Pyridoxine-like Diselenide.
abstract: In search for better mimics of the glutathione peroxidase enzymes, pyridoxine-like diselenides 6 and 11, carrying a 6-bromo substituent, were prepared. Reaction of 2,6-dibromo-3-pyridinol 5 with sodium diselenide provided 6 via aromatic nucleophilic substitution of the 2-bromo substituent. LiAlH4 caused reduction of all four ester groups and returned 11 after acidic workup. The X-ray structure of 6 showed that the dipyridyl diselenide moiety was kept in an almost planar, transoid conformation. According to NBO-analysis, this was due to weak intramolecular Se···O (1.1 kcal/mol) and Se···N-interactions (2.5 kcal/mol). That the 6-bromo substituent increased the positive charge on selenium was confirmed by NPA-analysis and seen in calculated and observed (77)Se NMR-shifts. Diselenide 6 showed a more than 3-fold higher reactivity than the corresponding des-bromo compound 3a and ebselen when evaluated in the coupled reductase assay. Experiments followed for longer time (2 h) confirmed that diselenide 6 is a better GPx-catalyst than 11. On the basis of (77)Se-NMR experiments, a catalytic mechanism for diselenide 6 was proposed involving selenol, selenosulfide and seleninic acid intermediates. At low concentration (10 μM) where it showed only minimal toxicity, it could scavenge ROS produced by MNC- and PMNC-cells more efficiently than Trolox.
authors.affiliation: †Department of Chemistry-BMC, Uppsala University, Box 576, SE-751 23 Uppsala, Sweden.
authors.forename: Vijay P
authors.initials: VP
authors.lastname: Singh
authors.affiliation: †Department of Chemistry-BMC, Uppsala University, Box 576, SE-751 23 Uppsala, Sweden.
authors.forename: Jia-Fei
authors.initials: JF
authors.lastname: Poon
authors.affiliation: ‡Department of Chemistry, Howard University, Washington, D.C. 20059, United States.
authors.forename: Ray J
authors.initials: RJ
authors.lastname: Butcher
authors.affiliation: §Division of Applied Materials Science, Department of Engineering Sciences, Uppsala University, SE-751 23 Uppsala, Sweden.
authors.forename: Xi
authors.initials: X
authors.lastname: Lu
authors.affiliation: §Division of Applied Materials Science, Department of Engineering Sciences, Uppsala University, SE-751 23 Uppsala, Sweden.
authors.forename: Gemma
authors.initials: G
authors.lastname: Mestres
authors.affiliation: §Division of Applied Materials Science, Department of Engineering Sciences, Uppsala University, SE-751 23 Uppsala, Sweden.
authors.forename: Marjam Karlsson
authors.initials: MK
authors.lastname: Ott
authors.affiliation: †Department of Chemistry-BMC, Uppsala University, Box 576, SE-751 23 Uppsala, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Engman
mesh_terms: D001393:Azoles / Q000737:chemistry*; D001966:Bromine / Q000737:chemistry*; D018360:Crystallography, X-Ray; D005979:Glutathione Peroxidase / Q000737:chemistry*; D054833:Isoindoles; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D016566:Organoselenium Compounds / Q000737:chemistry*; D010084:Oxidation-Reduction; D011736:Pyridoxine / Q000737:chemistry*; D012643:Selenium / Q000737:chemistry*
chemical_list: D001393:Azoles; D054833:Isoindoles; D016566:Organoselenium Compounds; C042986:ebselen; D005979:Glutathione Peroxidase; D012643:Selenium; D011736:Pyridoxine; D001966:Bromine