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 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.

为寻求更佳的谷胱甘肽过氧化物酶模拟物，制备了携带6-溴取代基的吡哆醇类二硒化物6和11。通过2,6-二溴-3-吡啶醇5与硒化钠的反应，经芳香亲核取代2-溴取代基得到6。LiAlH4引起所有四个酯基的还原，并在酸性处理后又得到11。6的X射线结构表明，二吡啶基二硒化物基团保持在一个几乎平面的反式构象中。根据NBO分析，这归因于较弱的分子内硒···氧（1.1 kcal/mol）和硒···氮（2.5 kcal/mol）相互作用。NPA分析证实了6-溴取代基增加了硒的正电荷，这在计算和观察到的77Se NMR位移中均有体现。在联合还原酶测定中，二硒化物6比相应的去溴化合物3a和ebselen显示出超过3倍的反应活性。在长达2小时的长时间实验中，证实了二硒化物6比11更优秀的GPx催化剂。基于77Se-NMR实验，提出了二硒化物6的催化机制，涉及硒醇、硒硫烷和硒酸中间体。在低浓度（10 μM）下，它表现出极低的毒性，能够比Trolox更有效地清除MNC和PMNC细胞产生的活性氧。