[47] Ebselen: A glutathione peroxidase mimic

doi:10.1016/0076-6879(94)34118-4

Methods in Enzymology

Volume 234, 1994, Pages 476-482

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This chapter discusses the activity of glutathione peroxidase. Ebselen, 2-phenyl-1,2-benzisoselenazol-3(2H)-one, exhibits activity as an enzyme mimic. The reaction catalyzed is that of a glutathione (GSH) peroxidase, namely, the reduction of a hydroperoxide at the expense of thiol. The specificity for substrates ranges from hydrogen peroxide and smaller organic hydroperoxides to membrane-bound phospholipid and cholesterol hydroperoxides. In addition to glutathione, the thiol reductant cosubstrate can be dithioerythritol, N-acetylcysteine, or dihydrolipoate, or other suitable thiol compounds. Ebselen also has properties of a free radical and singlet oxygen quencher. Model experiments in vitro with liposomes, microsomes, isolated cells, and organs show that the protection against oxidative challenge afforded by ebselen can be explained largely by the activity as GSH peroxidase mimic. It is important to note that no unchanged ebselen was detectable in urine, plasma, and bile. The facile ring opening of the isoselenazonone ring to form a selenosulfide is a probable basis for this. The current concept of transport of ebselen in the organism is that it is bound to proteins and that there is an interchange with low molecular weight thiols within cells and tissues.

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Oxidative stress (OS) and disturbed intracellular redox balance have been predominantly observed in different types of cancer, including hepatocellular carcinoma (HCC). Agents which can stop OS multi-stressor events and modulate the intracellular redox state are becoming a major focus in HCC prevention. Among them, compounds with glutathione peroxidase (GPx)-like activity are of particularly concern. We herein report the synthesis of novel series of organoselenocyanates and symmetrical diselenide antioxidants, inspired by the natural redox enzyme, GPx and the synthetic organoselenium ebselen antioxidants. Their cytotoxic activity was evaluated against Hep G2 cells and their antimicrobial activities were evaluated against Candida albicans (C. albicans) fungus as well as against Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus), gram-negative and gram-positive bacteria, respectively. These compounds were also tested for their antioxidant activities using 2,2-diphenyl-1-picrylhydrazyl (DPPH), GPx-like activity and bleomycin dependent DNA damage assays and a basic structure–activity relationship was subsequently established. The physicochemical parameters and drug-likeness were computed employing the Molinspiration online property calculation toolkit and MolSoft software. Interestingly, some compounds proved to be more cytotoxic than ebselen and the known anticancer drug 5-Fu and in the same time they showed similar, sometime even more, antifungal activity than the reference antifungal drugs. Among these compounds, compound 16 was considered to be the most interesting with free radical-scavenging activity comparable to ascorbic acid and a GPx-like activity similar to ebselen. As most of these compounds comply with Lipinski's Rule of Five, they promise good bioavailability, which needs to be studied as part of future investigations.
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This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy.
This article has been retracted at the request of the Editor-in-Chief and certain co-authors.
In attempting to verify the experimental findings presented in the paper, the co-authors we were able to contact were unable to reproduce key results. While they were indeed able to detect and sequence dimedone-labeled glutathione peroxidase by MS/MS, it was not possible to trap it at the conditions reported in the paper. Other results reported in the paper appear irreproducible as well. The retraction request comes from the authors Jun Liu and Sharon Rozovsky. The first author, Fei Li, is no longer at the University of Delaware and it has not been possible to contact her. The remaining two authors ask that the paper be retracted immediately and apologize for any inconvenience this publication might have caused to readers.
The early research and development of ebselen
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Ebselen (2-phenyl-1,2-benzisoselenazol-3(2H)-one; PZ-51, DR-3305), is an organoselenium compound with glutathione peroxidase (GPx)-like, thiol-dependent, hydroperoxide reducing activity. As an enzyme mimic for activity of the selenoenzyme GPx, this compound has proved to be highly useful in research on mechanisms in redox biology. Furthermore, the reactivity of ebselen with protein thiols has helped to identify novel, selective targets for inhibitory actions on several enzymes of importance in pharmacology and toxicology. Importantly, the selenium in ebselen is not released and thus is not bioavailable, ebselen metabolites being excreted in bile and urine. As a consequence, initial concerns about selenium toxicity, fortunately, were unfounded. Potential applications in medical settings have been explored, notably in brain ischemia and stroke. More recently, there has been a surge in interest as new medical applications have been taken into consideration. The first publication on the biochemical effects of ebselen appeared 30 years ago (Müller et al. [4]), which prompted the authors to retrace the early development from their perspective. It is a fascinating example of fruitful interaction between research-oriented industry and academia
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Citation Excerpt :
Ebselen, 2-phenyl-1,2-benzisoselenazol-3(2 H)one (Fig. 1B), catalyzes thiol-dependent reduction of peroxides by a non-radical mechanism [12,13]. Although earlier literature suggested that ebselen has properties such as free radical quenching [12], this activity was subsequently shown to have little effect [14]. Sequential reduction of ebselen by glutathione produces a selenol which is the direct reductant for the peroxides [13].
Oxidative stress occurs through free radical- and non-radical-mediated oxidative mechanisms, but these are poorly discriminated by most assays. A convenient assay for oxidants in human serum is based upon the Fe²⁺-dependent decomposition of peroxides to oxidize N,N′-diethyl-1,4-phenylenediamine (DEPPD) to a stable radical cation which can be measured spectrophotometrically.
We investigated modification of the DEPPD oxidation assay to discriminate color formation due to non-radical oxidants, including hydroperoxides and endoperoxides, which are sensitive to ebselen.
Use of serum, which has been pretreated with ebselen as a reference, provides a quantitative assay for non-radical, reactive oxidant species in serum, including hydroperoxides, endoperoxides and epoxides. In a set of 35 human serum samples, non-radical oxidants largely accounted for DEPPD oxidation in 86% of the samples while the remaining 14% had considerable contribution from other redox-active chemicals.
The simple modification in which ebselen-pretreated sample is used as a reference provides means to quantify non-radical oxidants in human serum. Application of this approach could enhance understanding of the contribution of different types of oxidative stress to disease.

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[47] Ebselen: A glutathione peroxidase mimic

Publisher Summary

Biochem. Pharmacol.

Biochem. Pharmacol.

Free Radical Biol. Med.

Arch. Biochem. Biophys.

Prog. Drug Res.

Chem. Ber.

Bull. Soc. Chim. Fr.

Bull Soc. Chim. Belg.

J. Labelled Compd. Radiopharm.

Bull. Soc. Chim. Belg.

J. Org. Chem.

J. Am. Chem. Soc.

Chem.-Biol. Interact.

Biochemistry

Arch. Biochem. Biophys.

Biochem. Biophys. Res. Commun.

J. Mol. Biol.

Eur. J. Biochem.

Mol. Pharmacol.