Glutathione Peroxidase (GPx)-like Antioxidant Activity of the Organoselenium Drug Ebselen:  Unexpected Complications with Thiol Exchange Reactions

Sarma, Bani Kanta; Mugesh, Govindasamy

doi:10.1021/ja052794t

Cited by 268 publications

(244 citation statements)

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“…Selenic acid is unstable and reacts with GSH, forming a selenenyl sulfide adduct (glutathionylated selenenyl). A second molecule of GSH reduces this selenenyl sulfide bond to selenol and generates GSSG (37). These reactions occur in the catalytic center of GSH peroxidases and may require a more hydrophobic environment.…”

Section: Can Selenium Substitute For Sulfur?mentioning

confidence: 99%

Causes and Consequences of Cysteine S-Glutathionylation

Grek¹,

Zhang²,

Manevich³

et al. 2013

Journal of Biological Chemistry

279

275

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Post-translational S-glutathionylation occurs through the reversible addition of a proximal donor of glutathione to thiolate anions of cysteines in target proteins, where the modification alters molecular mass, charge, and structure/function and/or prevents degradation from sulfhydryl overoxidation or proteolysis. Catalysis of both the forward (glutathione S-transferase P) and reverse (glutaredoxin) reactions creates a functional cycle that can also regulate certain protein functional clusters, including those involved in redox-dependent cell signaling events. For translational application, S-glutathionylated serum proteins may be useful as biomarkers in individuals (who may also have polymorphic expression of glutathione S-transferase P) exposed to agents that cause oxidative or nitrosative stress.S-Glutathionylation targets cysteines in a basic environment (low pK a ) perhaps in close three-dimensional proximity to Arg, His, or Lys residues. Reports of reversible S-glutathionylation emerged as early as 1985 (1), but in concert with understanding the importance of reactive oxygen/nitrogen species (ROS/ RNS) 2 as second messengers, publications have increased substantially over the past 10 years. ROS/RNS signaling operates through a set of post-translational protein modifications that are discrete, site-specific, and reversible. Certain proteins undergo reversible chemical changes in response to altered localized redox potential. Among the most susceptible redoxsensitive targets are thiol (-SH) groups on cysteines. Signaling events are facilitated through redox-active proteins when one or more cysteines can exist as reactive thiolate anions. These cysteines are more nucleophilic and become susceptible to attack by GSH.Oxygen-based metabolism is arguably the most efficient and evolved method for producing energy from nutrients, but ROS

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Section: Can Selenium Substitute For Sulfur?mentioning

confidence: 99%

Causes and Consequences of Cysteine S-Glutathionylation

Grek¹,

Zhang²,

Manevich³

et al. 2013

Journal of Biological Chemistry

279

275

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“…This is due to the presence of a strong Se···O interaction in compound 6 a, which enhances a thiol exchange reaction at selenium. [18] Therefore, the rate of disproportionation depends on the nature of thiols and strength of the Se···O interactions. When GSH was employed instead of PhSH, the disproportionation selenenyl sulfide that led to the formation of diselenide 6 was significantly faster than that of 6 a.…”

Section: Wwwchemeurjorgmentioning

confidence: 99%

Synthesis and Antioxidant Activity of Peptide‐Based Ebselen Analogues

Satheeshkumar

Mugesh

2011

Chemistry A European J

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A series of di- and tripeptide-based ebselen analogues has been synthesized. The compounds were characterized by (1)H, (13)C, and (77)Se NMR spectroscopy and mass spectral techniques. The glutathione peroxidase (GPx)-like antioxidant activity has been studied by using H(2)O(2) , tert-butyl hydroperoxide (tBuOOH), and cumene hydroperoxide (Cum-OOH) as substrates, and glutathione (GSH) as a cosubstrate. Although all the peptide-based compounds have a selenazole ring similar to that of ebselen, the GPx activity of these compounds highly depends on the nature of the peptide moiety attached to the nitrogen atom of the selenazole ring. It was observed that the introduction of a phenylalanine (Phe) amino acid residue in the N-terminal reduces the activity in all three peroxide systems. On the other hand, the introduction of aliphatic amino acid residues such as valine (Val) significantly enhances the GPx activity of the ebselen analogues. The difference in the catalytic activity of dipeptide-based ebselen derivatives can be ascribed mainly to the change in the reactivity of these compounds toward GSH and peroxide. Although the presence of the Val-Ala-CO(2) Me moiety facilitates the formation of a catalytically active selenol species, the reaction of ebselen analogues that has a Phe-Ile-CO(2) Me residue with GSH does not generate the corresponding selenol. To understand the antioxidant activity of the peptide-based ebselen analogues in the absence of GSH, these compounds were studied for their ability to inhibit peroxynitrite (PN)-mediated nitration of bovine serum albumin (BSA) and oxidation of dihydrorhodamine 123. In contrast to the GPx activity, the PN-scavenging activity of the Phe-based peptide analogues was found to be comparable to that of the Val-based compounds. However, the introduction of an additional Phe residue to the ebselen analogue that had a Val-Ala dipeptide significantly reduced the potency of the parent compound in PN-mediated nitration.

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“…[13] Although ebselen exhibits interesting therapeutic properties, including anti-inflammatory activity, [7] it is a relatively inefficient catalyst for the in vitro reduction of hydroperoxides with aryl and benzylic thiols (such as PhSH and BnSH) as cosubstrates. [12,15] The relatively poor GPx-like antioxidant activity has been ascribed to undesired thiol exchange reactions that take place at the selenium center in the selenenyl sulfide intermediate. [15] However, ebselen has been shown to be a good antioxidant in vivo, as it exhibits significant GPx activity in the presence of natural thiols such as GSH.…”

Section: Introductionmentioning

confidence: 99%

“…[12,15] The relatively poor GPx-like antioxidant activity has been ascribed to undesired thiol exchange reactions that take place at the selenium center in the selenenyl sulfide intermediate. [15] However, ebselen has been shown to be a good antioxidant in vivo, as it exhibits significant GPx activity in the presence of natural thiols such as GSH. It has been recently shown that ebselen can act either beneficially as a peroxidase mimic, or detrimentally through the depletion of GSH.…”

Section: Introductionmentioning

confidence: 99%

Synthesis, Characterization, and Antioxidant Activity of Some Ebselen Analogues

Bhabak¹,

Mugesh²

2007

Chemistry A European J

189

110

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Simple synthetic routes for several analogues of the anti-inflammatory organoselenium drug, ebselen, are described. The compounds are characterized by (1)H, (13)C, and (77)Se NMR spectroscopy and mass spectral techniques and, in some cases, by single-crystal X-ray diffraction studies. The glutathione peroxidase (GPx)-like antioxidant activity has been studied by using H(2)O(2), tBuOOH, and Cum-OOH as substrates, and thiophenol (PhSH, 4-Me-C(6)H(4)SH) and glutathione (GSH) as cosubstrates. Density functional theory (DFT) calculations have been performed on these systems to understand the effects of various substituents on the (77)Se NMR chemical shifts; these results have been compared with the experimental data. The experimental and theoretical results suggest that the presence of a phenyl substituent on the nitrogen atom is important for the antioxidant activity of ebselen. While ebselen and its analogues are poor catalysts in aromatic thiol assays, these compounds exhibit high GPx activity when GSH is used as the cosubstrate. The poor catalytic activity of ebselen analogues in the presence of aromatic thiols such as PhSH and 4-Me-C(6)H(4)SH can be ascribed to the undesired thiol exchange reaction that takes place at the selenium center due to SeO nonbonding interactions. To understand the effects of different peroxides on the catalytic activities, we have determined the initial rates at various concentrations of GSH and peroxides. These data suggest that the nature of peroxide has little effect on the catalytic efficiencies, although the initial reaction rates observed with hydrogen peroxide were found to be higher than that with tBuOOH and Cum-OOH. In contrast to the effect of peroxides, the nature of thiols appears to have a dramatic effect on the catalytic activity of ebselen and its related derivatives.

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Glutathione Peroxidase (GPx)-like Antioxidant Activity of the Organoselenium Drug Ebselen: Unexpected Complications with Thiol Exchange Reactions

Cited by 268 publications

References 50 publications

Causes and Consequences of Cysteine S-Glutathionylation

Causes and Consequences of Cysteine S-Glutathionylation

Synthesis and Antioxidant Activity of Peptide‐Based Ebselen Analogues

Synthesis, Characterization, and Antioxidant Activity of Some Ebselen Analogues

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