Antioxidant Activity of the Anti‐Inflammatory Compound Ebselen: A Reversible Cyclization Pathway via Selenenic and Seleninic Acid Intermediates

Abstract

A revised mechanism that accounts for the glutathione peroxidase (GPx)-like catalytic activity of the organoselenium compound ebselen is described. It is shown that the reaction of ebselen with H(2)O(2) yields seleninic acid as the only oxidized product. The X-ray crystal structure of the seleninic acid shows that the selenium atom is involved in a noncovalent interaction with the carbonyl oxygen atom. In the presence of excess thiol, the Se--N bond in ebselen is readily cleaved by the thiol to produce the corresponding selenenyl sulfide. The selenenyl sulfide thus produced undergoes a disproportionation in the presence of H(2)O(2) to produce the diselenide, which upon reaction with H(2)O(2), produces a mixture of selenenic and seleninic acids. The addition of thiol to the mixture containing selenenic and seleninic acids leads to the formation of the selenenyl sulfide. When the concentration of the thiol is relatively low in the reaction mixture, the selenenic acid undergoes a rapid cyclization to produce ebselen. The seleninic acid, on the other hand, reacts with the diselenide to produce ebselen as the final product. DFT calculations show that the cyclization of selenenic acids to the corresponding selenenyl amides is more favored than that of sulfenic acids to the corresponding sulfenyl amides. This indicates that the regeneration of ebselen under a variety of conditions protects the selenium moiety from irreversible inactivation, which may be responsible for the biological activities of ebselen.

Inhibition of Anthracycline Alcohol Metabolite Formation in Human Heart Cytosol: A Potential Role for Several Promising Drugs

“…Ebselen is a synthetic organo-selenium compound (see the structure in Fig. 1) that exhibits antioxidant, antiinflammatory, and cytoprotective properties in a variety of animal models (Sakurai et al, 2006;Sarma and Mugesh, 2008). Moreover, unlike other selenium compounds, ebselen displays very low toxicity due to its great structural stability that does not allow the selenium moiety to be released during drug transformation and does not impair selenium metabolism (Sies and Masumoto, 1997;Zhao and Holmgren, 2002).…”

“…The chemistry of ebselen is considered complex and still controversial (see the viewpoints presented in Sakurai et al, 2006;Sarma and Mugesh, 2008). In fact, although, most of the biologic activities of ebselen seem to be related to its ability to quickly react with protein and nonprotein thiol groups, GSH included (Sakurai et al, 2006;Sarma and Mugesh, 2008), the details of these reactions remain obscure, mainly because of the lack of undisputed identification of the reaction intermediates.…”

“…In fact, although, most of the biologic activities of ebselen seem to be related to its ability to quickly react with protein and nonprotein thiol groups, GSH included (Sakurai et al, 2006;Sarma and Mugesh, 2008), the details of these reactions remain obscure, mainly because of the lack of undisputed identification of the reaction intermediates. According to the revised catalytic mechanism, ebselen rapidly reacts with GSH to produce the corresponding selenenyl sulfide derivative that undergoes a disproportionation reaction to produce ebselen diselenide, which is now considered the storage form of ebselen in the cells (Sarma and Mugesh, 2008). Therefore, we investigated the effect of ebselen diselenide on anthracycline alcohol metabolite formation by human heart cytosolic fractions.…”

Basic Principles and Emerging Concepts in the Redox Control of Transcription Factors

“…Similarly, in the DSP Cdc25 phosphatase B, a second cysteine resides in the active site, which in the oxidized form is disulfide-linked to the nucleophilic cysteine of the signature motif (51). In contrast, in PTP1B, the cysteine in the active site motif [I/V]HCxxGxxR[S/T] forms a cyclic sulfenyl-amide (419,495) in analogy to the redox cycle of the GPx mimic ebselen (423) (Fig. 3E).…”

Water-dependent synthesis of biologically active diaryl diselenides

“…25,26 It is assumed that the most-studied GPx mimic ebselen (Nphenylbenzisoselenazo-3(2H)-one, 1), through the reaction with thiols, can be transformed to the corresponding diaryl diselenide with amido function 2 and in this form act as a bio-active intermediate that eliminates peroxides. [27][28][29] It has been proven that Se-N bond is not necessary to observe an enhanced GPx-like activity. Non-bonding selenium-heteroatom interactions can increase the antioxidant capacity what was established in the case of several diaryl diselenides possessing an additional heteroatom.…”