Chemistry Related to the Catalytic Cycle of the Antioxidant Ebselen.

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.

Unexpected Formation and Potent Antioxidant Activity of Macrocyclic Dimers Containing Disulfide and Selenide Groups.

During attempts to prepare spirodithiaselenuranes as GPx mimetics, a series of unexpected dimeric macrocycles was obtained, each containing two selenide and two disulfide moieties in rings ranging from 18- to 26-membered. The products showed potent GPx-like activity in an NMR assay based on their ability to catalyze the reduction of hydrogen peroxide with benzyl thiol. The high catalytic activity was attributed to transannular effects during selenide to selenoxide oxidation. This redox process was also characterized by an induction period that indicated autocatalysis in the formation of an intermediate selenoxide from the oxidation of the corresponding selenide.

One-Pot Synthesis of Aryl Selenonic Acids and Some Unexpected Byproducts.

The synthesis of aryl selenonic acids was achieved from diverse aryl bromides via a one-pot method involving metalation, selenation, and oxidation with hydrogen peroxide followed by ion exchange to afford the pure products in 77-90% yield. An o-hydroxymethyl derivative was found to dehydrate readily, affording the first example of a cyclic selenonic ester, while two minor byproducts were isolated and shown by X-ray crystallography to be mixed salts of aryl selenonic acids with either the corresponding aryl seleninic or selenious acid.

The Unexpected Role of SeVI Species in Epoxidations with Benzeneseleninic Acid and Hydrogen Peroxide.

Benzeneperoxyseleninic acid has been proposed as the key intermediate in the widely used epoxidation of alkenes with benzeneseleninic acid and hydrogen peroxide. However, it reacts sluggishly with cyclooctene and instead rapidly decomposes in solution to a mixed selenonium-selenonate salt that was identified by X-ray absorption and 77 Se NMR spectroscopy, as well as by single crystal X-ray diffraction. This process includes a selenoxide elimination of the peroxyseleninic acid with liberation of oxygen and additional redox steps. The salt is relatively stable in the solid state, but generates the corresponding selenonic acid in the presence of hydrogen peroxide. The selenonic acid is inert towards cyclooctene on its own; however, rapid epoxidation occurs when hydrogen peroxide is added. This shows that the selenonic acid must first be activated through further oxidation, presumably to the heretofore unknown benzeneperoxyselenonic acid. The latter is the principal oxidant in this epoxidation.

Cyclic Seleninate Esters, Spirodioxyselenuranes and Related Compounds: New Classes of Biological Antioxidants That Emulate Glutathione Peroxidase.

Selenium compounds play an important role in redox homeostasis in living organisms. One of their major functions is to suppress the harmful effects of hydrogen peroxide, hydroperoxides and downstream reactive oxygen species that lead to oxidative stress, which has in turn been implicated in many diseases and degenerative conditions. The glutathione peroxidase (GPx) family of selenoenzymes plays a key protective role by catalyzing the reduction of peroxides with glutathione. Considerable effort has been expended toward the discovery of small-molecule selenium compounds that mimic GPx. To date, ebselen has been the most widely studied such compound, including in several clinical trials. However, despite its proven lack of significant toxicity, it displays only moderate catalytic activity and very poor aqueous solubility. The cyclic seleninate esters and spirodioxyselenuranes have recently been investigated as potential next generation GPx mimetics, along with structurally related selenenate esters, diazaselenuranes and pincer selenuranes. Their catalytic activities, redox mechanisms and structure-activity relationships are described in this Review, along with a description and discussion of the relative merits of assays for measuring their activities.