Effect of a Bromo Substituent on the Glutathione Peroxidase Activity of a Pyridoxine-like Diselenide

• Published in: Journal of organic chemistry 2015-08, Vol.80 (15), p.7385-7395
• Main Authors: Singh, Vijay P, Poon, Jia-fei, Butcher, Ray J, Lu, Xi, Mestres, Gemma, Ott, Marjam Karlsson, Engman, Lars
• Format: Article
• Language: English
• Subjects: Azoles - chemistry; Bromine - chemistry; Crystallography, X-Ray; Glutathione Peroxidase - chemistry; Magnetic Resonance Spectroscopy; Molecular Conformation; Organoselenium Compounds - chemistry; Oxidation-Reduction; Pyridoxine - chemistry; Selenium - chemistry
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/acs.joc.5b00797

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 77Se 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 77Se-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.