10.1021/acs.joc.5b00797.s001 Vijay P. Singh Vijay P. Singh Jia-fei Poon Jia-fei Poon Ray J. Butcher Ray J. Butcher Xi Lu Xi Lu Gemma Mestres Gemma Mestres Marjam Karlsson Ott Marjam Karlsson Ott Lars Engman Lars Engman Effect of a Bromo Substituent on the Glutathione Peroxidase Activity of a Pyridoxine-like Diselenide American Chemical Society 2015 Glutathione Peroxidase Activity substituent ROS kcal seleninic acid intermediates glutathione peroxidase enzymes diselenide 6 MNC Se dipyridyl diselenide moiety bromo 2015-08-07 00:00:00 Dataset https://acs.figshare.com/articles/dataset/Effect_of_a_Bromo_Substituent_on_the_Glutathione_Peroxidase_Activity_of_a_Pyridoxine_like_Diselenide/2142754 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. LiAlH<sub>4</sub> 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 <sup>77</sup>Se 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 <sup>77</sup>Se-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.