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

In search for better mimics of the glutathione peroxidase enzymes, pyridoxine-like diselenides <b>6</b> and <b>11</b>, carrying a 6-bromo substituent, were prepared. Reaction of 2,6-dibromo-3-pyridinol <b>5</b> with sodium diselenide provided <b>6</b> via aromatic nucleophilic substitution of the 2-bromo substituent. LiAlH₄ caused reduction of all four ester groups and returned <b>11</b> after acidic workup. The X-ray structure of <b>6</b> 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 <b>6</b> showed a more than 3-fold higher reactivity than the corresponding des-bromo compound <b>3a</b> and ebselen when evaluated in the coupled reductase assay. Experiments followed for longer time (2 h) confirmed that diselenide <b>6</b> is a better GPx-catalyst than <b>11</b>. On the basis of ⁷⁷Se-NMR experiments, a catalytic mechanism for diselenide <b>6</b> 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