Department of Chemistry, University of Calgary, 2500 University Drive NW, Calgary, AB T2N 1N4, Canada.
Molecules. 2023 Apr 26;28(9):3732. doi: 10.3390/molecules28093732.
The antioxidant drug ebselen has been widely studied in both laboratories and in clinical trials. The catalytic mechanism by which it destroys hydrogen peroxide via reduction with glutathione or other thiols is complex and has been the subject of considerable debate. During reinvestigations of several key steps, we found that the seleninamide that comprises the first oxidation product of ebselen underwent facile reversible methanolysis to an unstable seleninate ester and two dimeric products. In its reaction with benzyl alcohol, the seleninamide produced a benzyl ester that reacted readily by selenoxide elimination, with formation of benzaldehyde. Oxidation of ebselen seleninic acid did not afford a selenonium seleninate salt as previously observed with benzene seleninic acid, but instead generated a mixture of the seleninic and selenonic acids. Thiolysis of ebselen with benzyl thiol was faster than oxidation by ca. an order of magnitude and produced a stable selenenyl sulfide. When glutathione was employed, the product rapidly disproportionated to glutathione disulfide and ebselen diselenide. Oxidation of the S-benzyl selenenyl sulfide, or thiolysis of the seleninamide with benzyl thiol, afforded a transient thiolseleninate that also readily underwent selenoxide elimination. The S-benzyl derivative disproportionated readily when catalyzed by the simultaneous presence of both the thiol and triethylamine. The phenylthio analogue disproportionated when exposed to ambient or UV (360 nm) light by a proposed radical mechanism. These observations provide additional insight into several reactions and intermediates related to ebselen.
抗氧化药物依布硒啉在实验室和临床试验中都得到了广泛的研究。它通过与谷胱甘肽或其他硫醇还原破坏过氧化氢的催化机制很复杂，一直是相当多争论的主题。在对几个关键步骤的重新研究中，我们发现构成依布硒啉最初氧化产物的硒酰胺很容易通过甲醇可逆水解生成不稳定的硒酸酯和两个二聚产物。在与苄醇的反应中，硒酰胺生成苄酯，很容易通过硒氧化物消除反应进行反应，生成苯甲醛。依布硒啉硒酸的氧化没有生成以前观察到的苯硒酸那样的硒翁盐，而是生成了硒酸和硒酸混合物。用苄硫醇对依布硒啉进行硫醇解的速度比氧化快约一个数量级，并生成稳定的硒烯基硫醚。当使用谷胱甘肽时，产物迅速歧化为谷胱甘肽二硫化物和依布硒啉二硒化物。S-苄基硒烯基硫醚的氧化，或硒酰胺与苄硫醇的硫醇解，得到一种瞬态的硫代硒酸盐，也很容易进行硒氧化物消除。当同时存在巯基和三乙胺时，S-苄基衍生物很容易发生歧化。当苯硫基类似物暴露在环境或 UV（360nm）光下时，通过自由基机制发生歧化。这些观察结果为与依布硒啉相关的几个反应和中间体提供了更多的了解。
