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.

Comparison of free-radical inhibiting antioxidant properties of carvedilol and its phenolic metabolites.

Carvedilol is a widely prescribed drug for the treatment of heart failure and the prevention of associated ventricular arrhythmias. It has also been reported to function as a biological antioxidant via hydrogen atom transfer from its carbazole N-H moiety to chain-propagating radicals. Metabolites of the drug include phenolic derivatives, such as 3-hydroxy-, 4'-hydroxy- and 5'-hydroxycarvedilol, which are also potential antioxidants. A comparison of the radical-inhibiting activities of the parent drug and the three metabolites was carried out in two separate assays. In the first, hydrogen atom transfer from these four compounds to the stable radical DPPH was measured by the decrease in the UV-visible absorption at 515 nm of the latter. The known radical inhibitors BHT, 4-hydroxycarbazole and α-tocopherol were employed as benchmarks in parallel experiments. In the second assay, inhibition of the photoinduced free-radical 1,2-addition of Se-phenyl p-tolueneselenosulfonate to cyclopropylacetylene, along with competing ring-opening of the cyclopropane ring, was monitored by 1H NMR spectroscopy in the presence of the carvedilol-based and benchmark antioxidants. In both assays, carvedilol displayed negligible antioxidant activity, while the three metabolites all proved superior radical inhibitors to BHT, with radical-quenching abilities in the order 3-hydroxy- > 5'-hydroxy > 4'-hydroxycarvedilol. Among the metabolites, 3-hydroxycarvedilol displayed even stronger activity in both assays than α-tocopherol, the best of the benchmark antioxidants. These results suggest that the radical-inhibiting antioxidant properties that have been attributed to carvedilol are largely or exclusively due to its metabolites and not to the parent drug itself.