Glutathione Peroxidase-like Activity Research Articles

In Search of Catalytic Antioxidants—(Alkyltelluro)phenols, (Alkyltelluro)resorcinols, and Bis(alkyltelluro)phenols

The quenching of peroxyl radicals by ortho-(alkyltelluro)phenols occurs by a more complex mechanism than formal H-atom transfer. In an effort to improve on this concept, we have prepared (alkyltelluro)resorcinols and bis(alkyltelluro)phenols and evaluated their catalytic chain-breaking and preventive antioxidative properties. The in situ formed trianion produced from 2-bromophenol and 3 equiv of tert-butyllithium was allowed to react with dialkyl ditellurides to provide ortho-(alkyltelluro)phenols in low yields. 2-Bromoresorcinols after treatment with 4 equiv of tert-butyllithium similarly afforded 2-(alkyltelluro)resorcinols. Bis(alkyltelluro)phenols were accessed by allowing the trianion produced from the reaction of 2,6-dibromophenol with 5 equiv of tert-butyllithium to react with dialkyl ditellurides. The novel phenolic compounds were found to inhibit azo-initiated peroxidation of linoleic acid much more efficiently than α-tocopherol in a two-phase peroxidation system containing excess N-acetylcysteine as a stoichiometric thiol reducing agent in the aqueous phase. Whereas most of the (alkyltelluro)phenols and resorcinols could inhibit peroxidation for only 89-228 min, some of the bis(alkyltelluro)phenols were more regenerable and offered protection for >410 min. The novel (alkyltelluro)phenols were also evaluated for their capacity to catalyze reduction of hydrogen peroxide in the presence of thiophenol (glutathione peroxidase-like activity). (Alkyltelluro)resorcinols 7a-c were the most efficient catalysts with activities circa 65 times higher than those recorded for diphenyl diselenide.

Synthesis and antioxidant activity of O-alkyl selenocarbamates, selenoureas and selenohydantoins

The preparation of three different families of lipophilic organoselenium compounds (aryl- and sugar-derived selenoureas, O-alkyl selenocarbamates and selenohydantoins) has been carried out in order to evaluate their in vitro antioxidant profile, analyzing the influence of the selenium-containing functional group, and the substituents on the activity. Title compounds have therefore been studied for the first time as free radical, hydrogen peroxide, alkyl peroxides and nitric oxide scavengers using colorimetric methods; furthermore, their glutathione peroxidase-like activity has also been analyzed by NMR spectroscopy. Free radical scavenging activity has been evaluated using the DPPH method; the strongest free radical scavengers were found to be both, aryl- and sugar-derived selenoureas, with EC50 values ranging 19–46μM. Concerning anti-H2O2 activity, measured by the horseradish peroxidase-mediated oxidation of phenol red, the best results were achieved for aryl selenohydantoins, showing a 61–76% inhibition at 0.5mM concentration. Organoselenium compounds were also found to be capable of inhibiting the chain reaction involving lipid peroxidation (ferric thiocyanate method); thus, when tested at 0.74mM, sugar selenocarbamates exhibited 49–71% inhibition of alkyl peroxides-mediated degradation of linoleic acid. Nitric oxide scavenging was studied by transforming sodium nitroprusside into nitrite ion, which in turn was transformed into an easily UV-detectable azocompound; aryl selenocarbamates exhibited 64–80% inhibition at 0.71mM concentration. It has also been demonstrated that selenoxo compounds can behave as excellent glutathione peroxidase mimics; thus a 0.05 molar equiv. of the title compounds catalyzed efficiently the H2O2-mediated oxidation of dithiothreitol into the corresponding cyclic disulfide, mimicking removal of H2O2 exerted by glutathione peroxidase; t1/2 values were found to be quite low for aryl- and sugar-derived selenoureas (2.0–12.7min).

Selenium/Tellurium-Containing Hyperbranched Polymers: Effect of Molecular Weight and Degree of Branching on Glutathione Peroxidase-Like Activity

A series of novel hyperbranched polyselenides and polytellurides with multiple catalytic sites at the branching units has been synthesized via the polycondensation of A2 + B3 monomers. The GPx-like activities of these polymer mimics were assessed and it was found that the polytellurides showed higher GPx-like activities than the corresponding polyselenides. Interestingly, the polymers with higher molecular weights and degree of branching (DB) showed higher GPx-like activities than the analogous lower molecular weight polymer. The enhancement in the catalytical activity of the hyperbranched polymers with increasing molecular weight affirmed the importance of the incorporation of multiple catalytic groups in the macromolecule which increases the local concentration of catalytic sites.

Synthesis and Glutathione Peroxidase-like activity of N-heterocyclic carbene derived cationic diselenides

Water soluble cationic diselenide derivatives of benzimidazolin-2-selenones and imidazolin-2-selenones have been synthesized. The Glutathione Peroxidase-like (GPx-like) activities of cationic diselenides have been investigated for the first time. The GPx-like activities are found to be quite low as compared to the neutral imidazole based diselenide and intramolecularly coordinated diselenides. A mechanism for GPx-like activity has been proposed. The oxidation reactions of N-heterocyclic carbene derived selenones with hydrogen peroxide have been studied.

Antioxidant activity of β-selenoamines and their capacity to mimic different enzymes

The antioxidant properties of organoselenium compounds have been extensively investigated because oxidative stress is a hallmark of a variety of chronic human diseases. Here, we reported the influence of substituent groups in the antioxidant activity of β-selenoamines. We have investigated whether they exhibited glutathione peroxidase-like (GPx-like) activity and whether they could be substrate of thioredoxin reductase (TrxR). In the DPPH assay, the β-selenium amines did not exhibit antioxidant activity. However, the β-selenium amines with p-methoxy and tosyl groups prevented the lipid peroxidation. The β-selenium amine compound with p-methoxy substituent group exhibited thiol-peroxidase-like activity (GPx-like activity) and was reduced by the hepatic TrxR. These results contribute to understand the influence of structural alteration of non-conventional selenium compounds as synthetic mimetic of antioxidant enzymes of mammalian organisms.

Effect of diphenyl diselenide on the development of experimental autoimmune encephalomyelitis

Experimental autoimmune encephalomyelitis (EAE) is a T cell-mediated inflammatory and demyelinating disease of the central nervous system with clinical and pathological similarities with multiple sclerosis. The oxidative stress is one of the major mediators of demyelination and axonal damage in both, multiple sclerosis and EAE. Therefore, several studies are being performed to assess whether treatment with antioxidants prevents the progression of these diseases. Some organic forms of selenium that exhibit glutathione peroxidase-like activity have become good candidates for disease prevention and therapy since they catalytically remove oxidative stressors. Particularly, diphenyl diselenide ((PhSe)2) exerts antioxidant activity and has neuroprotective effects in several systems. The aim of the present study was to prove the therapeutic activity of (PhSe)2 on the development of EAE. Intraperitoneally administered (PhSe)2 (1–25μmoles/kg body weight/day) reduced the incidence of the disease but was also deleterious for the animals. Conversely, (PhSe)2 given orally (80μmoles/kg body weight/day) produced a significant inhibition of EAE without any toxic effect. In addition, there was a reduction of the characteristic histological alterations and a diminished in vivo and in vitro T-cell response against the encephalitogenic myelin basic protein. These results show an effective suppression of the autoimmune response that could be the base for future developments of successful antioxidants therapies in EAE as well as in multiple sclerosis.

A superoxide anion-scavenger, 1,3-selenazolidin-4-one suppresses serum deprivation-induced apoptosis in PC12 cells by activating MAP kinase

Synthetic organic selenium compounds, such as ebselen, may show glutathione peroxidase-like antioxidant activity and have a neurotrophic effect. We synthesized 1,3-selenazolidin-4-ones, new types of synthetic organic selenium compounds (five-member ring compounds), to study their possible applications as antioxidants or neurotrophic-like molecules. Their superoxide radical scavenging effects were assessed using the quantitative, highly sensitive method of real-time kinetic chemiluminescence. At 166μM, the O2− scavenging activity of 1,3-selenazolidin-4-ones ranged from 0 to 66.2%. 2-[3-(4-Methoxyphenyl)-4-oxo-1,3-selenazolidin-2-ylidene]malononitrile (compound b) showed the strongest superoxide anion-scavenging activity among the 6 kinds of 2-methylene-1,3-selenazolidin-4-ones examined. Compound b had a 50% inhibitory concentration (IC50) at 92.4μM and acted as an effective and potentially useful O2− scavenger in vitro. The effect of compound b on rat pheochromocytome cell line PC12 cells was compared with that of ebselen or nerve growth factor (NGF) by use of the MTT [3-(4, 5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide] assay. When ebselen was added at 100μM or more, toxicity toward PC12 cells was evident. On the contrary, compound b suppressed serum deprivation-induced apoptosis in PC12 cells more effectively at a concentration of 100μM. The activity of compound b to phosphorylate mitogen-activated protein kinase/extracellular signal-regulated protein kinase (ERK) 1/2 (MAP kinase) in PC12 cells was higher than that of ebselen, and the former at 100μM induced the phosphorylation of MAP kinase to a degree similar to that induced by NGF. From these results, we conclude that this superoxide anion-scavenger, compound b, suppressed serum deprivation-induced apoptosis by promoting the phosphorylation of MAP kinase.

Diphenyl diselenide and analogs are substrates of cerebral rat thioredoxin reductase: A pathway for their neuroprotective effects

Thioredoxin reductase (TrxR) isoforms play important roles in cell physiology, protecting cells against oxidative processes. In addition to its endogenous substrates (Trx isoforms), hepatic TrxR can reduce organic selenium compounds such as ebselen and diphenyl diselenide to their selenol intermediates, which can be involved in their hepatoprotective properties. Taking this into account, the aim of the present study was to evaluate the hypothesis that ebselen, diphenyl diselenide and its analogs (4,4′-bistrifluoromethyldiphenyl diselenide, 4,4′-bismethoxydiphenyl diselenide, 4.4′-biscarboxy-diphenyl diselenide, 4,4′-bischlorodiphenyl diselenide, 2,4,6,2′,4′,6′-hexamethyldiphenyl diselenide) could be substrates of rat brain TrxR. In the presence of partially purified rat brain TrxR, diphenyl diselenide, bismethoxydiphenyl diselenide and bischlorodiphenyl diselenide (at 10, 15 and 20μM) stimulated NADPH oxidation, indicating that they are substrates of brain TrxR. In contrast, ebselen and bistrifluoromethyldiphenyl diselenide, that have been previously demonstrated to be substrate of hepatic TrxR, were not reduced by rat brain TrxR. The results presented here suggest that diphenyl diselenide can exert neuroprotective effects by mimicking glutathione peroxidase activity and also via its reduction by TrxR. However, ebselen was not reduced by brain TrxR, indicating that the neuroprotective properties of this compound is possibly mediate by its glutathione peroxidase-like activity.

Susceptibility of mice to bacterial and fungal infections after intragastric administration of ebselen.

The seleno-organic compound ebselen (2-phenyl-1,2-benzisoselenazol-3(2H)-one) has anti-inflammatory activity and exhibits glutathione peroxidase-like activity in-vitro. Ebselen inhibited candidacidal activity over the same range of concentrations as it inhibited the production of microbicidal H2O2 by human neutrophils and macrophage-like cells. Therefore, the long-term administration of ebselen might be expected to induce an immunocompromised state in the host. To examine such a possibility, mice (5-weeks-old ddY, male) were given daily intragastric doses of 0, 10 or 100 mg/kg-1 ebselen for 21 days and then infected intraperitoneally with Candida albicans (10(8) cells/mouse), Pseudomonas aeruginosa (1.5 x 10(7) cells/mouse) or methicillin-resistant Staphylococcus aureus (5 x 10(8) cells/mouse). Ebselen at none of the tested doses affected the increase in body weight of mice during administration of the drug. No evidence was obtained that mice became more susceptible to the various microorganisms after the administration of ebselen at any tested dose.

Synthesis of Cyclic Selenenate/Seleninate Esters Stabilized byortho‐Nitro Coordination: Their Glutathione Peroxidase‐Like Activities

The syntheses of selenenate/seleninate esters and related derivatives by aromatic nucleophilic substitution (S(N)Ar) reactions of 2-bromo-3-nitrobenzylalcohol (13) and 2-bromo-3-nitrobenzaldehyde (17) with Na(2)Se(2)/nBuSeNa are described. The reaction of 13 with Na(2)Se(2) at room temperature afforded 7-nitro-1,2-benzisoselenole(3H) (15) instead of the desired diaryl diselenide 14. Oxidation of selenenate ester 15 with hydrogen peroxide afforded the corresponding selenium(IV) derivative, 7-nitro-1,2-benzisoselenole(3H) selenium oxide (18). 2-(Butylselanyl)-3-nitrobenzaldehyde (19) was synthesized by treating compound 17 with in situ generated nBuSeNa. The bromination reaction of selenide 19 did not afford the expected arylselenenyl bromide 20, instead, it resulted in the formation of the unexpected 7-nitro-1,2-benzisoselenol(3H)-3-ol (21) and 3,3'-oxybis(7-nitro-1,2-benzisoselenole(3H)) (22), respectively. The facile formation of heterocycles 21 and 22 is rationalized in terms of the aromatic ring strain in selenenyl bromide 20. The presence of intramolecular secondary Se···O interactions in esters 15, 18, 21, 22, and selenenic anhydride 29 has been confirmed by single-crystal X-ray diffraction studies as well as computational studies. The presence of an intramolecular Se···O interaction in esters 4b, 8, 15, 18, 21, and 22 has been further proved by natural bond orbital (NBO) and atoms in molecules (AIM) calculations. Glutathione peroxidase-like (GPx) antioxidant activities of 15, 18, 21, 22, and related heterocycles such as 7-nitro-1,2-benzisoselenol(2H)-3-one selenium oxide (4b), 7-nitro-1,2-benzisoselenol(2H)-3-one (8), and 29 have been determined by the coupled reductase assay.

Specific effects of reactive thiol drugs on mitochondrial bioenergetics

In this minireview, the more recent findings about the effects of peculiar reactive thiol drugs on mitochondria are presented. These include the following compounds: metallo meso-tetrakis porphyrins, palladacycles, telluranes and phenothiazines. Metallo meso-tetrakis porphyrins can exhibit both beneficial and deleterious effects on mitochodria that are modulated by the central metal, cell location, and availability of axial ligands. Therefore, these compounds have the versatility to be used for cell and mitochondria protection and death. The antioxidant activity of manganese porphyrins is related to a glutathione peroxidase-like activity. By attacking exclusively the membrane protein thiol groups without glutathione depletion, palladacycles are able to induce mitochondrial permeability transition (MPT) and cytochrome c release in the absence of oxidative stress. In hepatoma cells, the mitochondrial action of palladacycles was able to induce apoptotic death. As opposed to palladacycles, telluranes and phenothiazines are able to conjugate the capacity to promote the MPT in a dose-dependent manner in association with efficient antioxidant activity toward lipids. These studies demonstrated that the action of drugs on mitochondrial bioenergetics can be modulated by peculiar reactivity with thiol groups. Therefore, they contribute to studies of toxicity as well as the design of new drugs.

Protective effects of selenocystine against γ-radiation-induced genotoxicity in Swiss albino mice

Selenocystine (CysSeSeCys), a diselenide aminoacid exhibiting glutathione peroxidase-like activity and selective antitumor effects, was examined for in vivo antigenotoxic and antioxidant activity in Swiss albino mice after exposure to a sublethal dose (5Gy) of γ-radiation. For this, CysSeSeCys was administered intraperitoneally (i.p.) to mice at a dosage of 0.5mg/kg body weight for 5 consecutive days prior to whole-body γ-irradiation. When examined in the hepatic tissue, CysSeSeCys administration reduced the DNA damage at 30min after radiation exposure by increasing the rate of DNA repair. Since antigenotoxic agents could alter the expression of genes involved in cell cycle arrest and DNA repair, the transcriptional changes in p53, p21 and GADD45α were monitored in the hepatic tissue by real-time PCR. The results show that CysSeSeCys alone causes moderate induction of these three genes. However, CysSeSeCys pretreatment resulted in a suppression of radiation-induced enhancement of p21 and GADD45α expression, but did not affect p53 expression. Further analysis of radiation-induced oxidative stress markers in the same tissue indicated that CysSeSeCys significantly inhibits lipid peroxidation and prevents the depletion of antioxidant enzymes and glutathione (GSH) levels. Additionally, it also prevents radiation-induced DNA damage in other radiation sensitive cellular systems like peripheral leukocytes and bone marrow, which was evident by a decrease in comet parameters and micronucleated polychromatic erythrocytes (mn-PCEs) frequency, respectively. Based on these observations, it is concluded that CysSeSeCys exhibits antigenotoxic effects, reduces radiation-induced oxidative stress, and is a promising candidate for future exploration as a radioprotector.

Diphenyl diselenide induces apoptotic cell death and modulates ERK1/2 phosphorylation in human neuroblastoma SH-SY5Y cells

Diphenyl diselenide (PhSe)(2) is a synthetic organoselenium compound displaying glutathione peroxidase-like activity. Protective and antioxidant potential of (PhSe)(2) have been extensively investigated in in vivo and in vitro studies. In spite of this, there is a lack of studies addressed to the investigation of potential cytotoxic effect and signaling pathways modulated by this compound. Herein, we aimed to analyze the effects of 24-h treatment with (PhSe)(2) on cell viability and a possible modulation of signaling pathways in human neuroblastoma cell line SH-SY5Y. For this purpose, cells were incubated with (PhSe)(2) (0.3-30μM) for 24h and cell viability, apoptotic cell death and modulation of MAPKs (ERK1/2 and p38(MAPK)), and PKC substrates phosphorylation was determined. (PhSe)(2) treatment significantly decreased cell viability and increased the number of apoptotic cells with induction of PARP cleavage. An increase in ERK1/2 phosphorylation was observed at (PhSe)(2) 3μM. In contrast, higher concentrations of the chalcogenide inhibited ERK1/2, p38(MAPK) and PKC substrate phosphorylation. Pre-treatment with ERK1/2 inhibitor, U0126, increased cell susceptibility to (PhSe)(2). Together, these data indicate a cytotoxic potential of (PhSe)(2) in a neuronal cell line, which appears to be mediated by the ERK1/2 pathway.

Aromatic Ring Strain in Arylselenenyl Bromides: Role in Facile Synthesis of Selenenate Esters via Intramolecular Cyclization

The synthesis and reactivity of 2,6-disubstituted arylselenium compounds derived from 2-bromo-5-tert-butylisophthalic acid (43) are described. The syntheses of bis(5-tert-butylisophthalic acid dimethyl ester)diselenide (46) and bis(5-tert-butylisophthalic acid diisopropyl ester)diselenide (47) have been achieved by the reaction of the corresponding ester precursors with disodium diselenide. Reduction of diselenide 46 with lithium aluminum hydride affords 2,2'-bis(5-tert-butylbenzene-1,3-dimethanol)diselenide (53). Diselenides 46 and 47 exhibit intramolecular Se...O interaction. Compound 53 does not show any intramolecular Se...O interaction. The anomalous Se...O nonbonded coordination observed in the single-crystal X-ray structures of compounds 46, 47 and 53 is compared and contrasted. The corresponding selenenyl bromides 54 and 55, derived from the reaction of diselenides 46 and 47 with bromine, are quite stable in the solid state. However, they undergo hydrolysis and subsequent intramolecular cyclization upon heating or after having been kept in solution over a period of time to give the corresponding selenenate esters 56 and 57. The X-ray crystallographic study and density functional theory calculations on 54 at the B3LYP/6-31G(d) level of theory indicate a significant distortion in planarity of the aromatic ring. Glutathione peroxidase-like activities of diselenides 46 and 47 and their selenenate esters 56 and 57 have been studied both by thiophenol and bioassay methods. The very low glutathione peroxidase-like activity of the diselenides (46 and 47) and their selenenate esters (56 and 57) in the thiophenol assay is attributed to the presence of the relatively strong Se...O intramolecular interaction in the selenenyl sulfide intermediates. The interaction retards the catalytic activity through both thiol exchange and an intramolecular cyclization reaction.

ChemInform Abstract: Novel Water-Soluble Diorganyl Tellurides with Thiol Peroxidase and Antioxidant Activity.

Novel water-soluble diaryl tellurides, alkyl aryl tellurides, and dialkyl tellurides carrying sulfopropyl groups were prepared and found to possess potent peroxide decomposing and chain-breaking antioxidative capacity. The dilithium, disodium, dipotassium, and bis-tetramethylammonium salts of bis(4-hydroxyphenyl) telluride (4) were treated with 2.3 equiv of 1,3-propanesultone in aqueous tert-butyl alcohol to give the corresponding salts 5 of bis-O-sulfopropylated diaryl telluride. A variety of diaryl ditellurides were reduced with sodium borohydride in ethanol. Upon addition of propanesultone to the resulting sodium arenetellurolates, the corresponding 3-aryltellurenylpropanesulfonic acid sodium salts 8 were precipitated. Diphenyl diselenide and dibutyl ditelluride reacted similarly to afford the sodium salts of 3-benzeneselenenylpropanesulfonic acid (9) and 4-telluraoctanesulfonic acid (10), respectively. The glutathione peroxidase-like activity of the water-soluble compounds was assessed at pH = 7.4 by ...

Synthesis of a New Seleninic Acid Anhydride and Mechanistic Studies into Its Glutathione Peroxidase Activity

Starting from low toxic salicyloylglycine, a new seleninic acid anhydride 7 that lacks SeN or SeO non-bonded interactions was synthesized. This compound exhibits a fourfold higher glutathione peroxidase-like (GPx-like) activity than ebselen and inhibits plant and mammalian 12/15-lipoxygenases at lower micromolar concentrations. Because of these pharmacological properties, 7 may constitute a new lead compound for the development of anti-inflammatory low-molecular-weight seleno-organic compounds. Analyzing the redox products of 7 with glutathione (GSH) and tBuOOH, we identified three potential catalytic cycles (A, B, C) of GPx-like activity that are interconnected by key metabolites. To study the relative contribution of these cycles to the catalytic activity, we prepared selected reaction intermediates and found that the activity of seleninic acid anhydride 7 and of the corresponding diselenide 11 and selenol 14 compounds were in the same range. In contrast, the GPx-like activity of monoselenide 9 was more than one order of magnitude lower. These data suggested that cycles A and B may constitute the major routes of GPx-like activity of 7, whereas cycle C may not significantly contribute to catalysis.

Superoxide radical‐scavenging effects from polymorphonuclear leukocytes and toxicity in human cell lines of newly synthesized organic selenium compounds

Synthetic organic selenium compounds such as 2-phenyl-1,2-benzisoselenazol-3(2H)-one may show glutathione peroxidase-like antioxidant activity. Recently, we synthesized new organic selenium compounds that are thought to be effective antioxidants. To study their possible applications as antioxidants, we evaluated two selenoureas, N,N-dimethylselenourea and 1-selenocarbamoylpyrrolidine, and two tertiary selenoamides, N-(phenylselenocarbonyl)-piperidine and N,N-diethyl-4-chloroselenobenzamide, for their superoxide radical (O2-)-scavenging effects and toxicity. We measured (O2-)-scavenging effects in polymorphonuclear leukocytes (PMNs) with a specific, sensitive and real-time kinetic chemiluminescence method. Furthermore, the toxicity of these compounds was measured in some human cell lines and PMNs using the tetrazolium method. Hydrogen peroxide was measured by a scopoletin method. Finally, translocation of an NADPH oxidase component, p47 phagocyte oxidase, to the cell membrane was investigated by confocal laser scanning microscopy. N,N-Dimethylselenourea and 1-selenocarbamoylpyrrolidine effectively scavenged (O2-) released from 4beta-phorbol 12-myristate 13-acetate-stimulated PMNs, and the 50% inhibitory concentrations were 6.8 +/- 2.2 and 6.5 +/- 2.5 microm, respectively. N-(Phenylselenocarbonyl)-piperidine and N,N-diethyl-4-chloroselenobenzamide also effectively scavenged (O2-) from PMNs, and the 50% inhibitory concentrations were 11.3 +/- 4.8 and 20.3 +/- 6.4 microm, respectively. Selenoureas showed very low toxicity in human cell lines and PMNs, even at high concentrations, whereas tertiary selenoamides were cytotoxic. These compounds did not produce significant amounts of hydrogen peroxide from 4beta-phorbol 12-myristate 13-acetate-stimulated PMNs. None of the compounds significantly affected the translocation of p47 phagocyte oxidase. Selenoureas acted as effective antioxidants and showed low toxicity in some human cells. Thus, these compounds might be new candidates as antioxidative substances.

Synthesis of 4 H-benzo[ e]-1,2-selanazin-4-one derivatives: a new heterocyclic ring system

The synthesis of novel 1,2-benzoselenazin-4-ones which are six-membered homologues of ebselen, is described in order to evaluate their glutathione peroxidase-like activity.

DFT Study of the Glutathione Peroxidase-Like Activity of Phenylselenol Incorporating Solvent-Assisted Proton Exchange

Modeling of the glutathione peroxidase-like activity of phenylselenol has been accomplished using density-functional theory and solvent-assisted proton exchange (SAPE). SAPE is a modeling technique intended to mimic solvent participation in proton transfer associated with chemical reaction. Within this method, explicit water molecules incorporated into the gas-phase model allow relay of a proton through the water molecules from the site of protonation in the reactant to that in the product. The activation barriers obtained by SAPE for the three steps of the GPx-like mechanism of PhSeH fall within the limits expected for a catalytic system at physiological temperatures (DeltaG(1)++ = 19.1 kcal/mol; DeltaG(2)++= 6.6 kcal/mol; G(3)++ = 21.7 kcal/mol) and are significantly lower than studies which require direct proton transfer. The size of the SAPE network is also considered for the model of the reduction of the selenenic acid, step 2 of the GPx-like cycle. Use of a four-water network better accommodates the reaction pathway and reduces the activation barrier by 5 kcal/mol over the two-water model.

Formation of a spirodiazaselenurane and its corresponding azaselenonium derivatives from the oxidation of 2,2′-selenobis(benzamide). Structure, properties and glutathione peroxidase activity

The oxidation of 2,2'-selenobis(benzamide) with N-chlorosuccinimide or hydrogen peroxide afforded the corresponding stable azaselenonium chloride and hydroxide, respectively. Both structures were characterized by spectroscopic and X-ray crystallographic methods. Each contains a covalent N-Se bond, as well as a noncovalent interaction between the selenium atom and the carbonyl oxygen atom of the other amide moiety. The treatment of the azaselenonium chloride with an excess of potassium hydride in DMSO-d(6) afforded the corresponding spirodiazaselenurane species, which proved hydrolytically unstable, but was characterized by NMR spectroscopy. The azaselenonium chloride displayed significant glutathione peroxidase-like catalytic activity in an assay with benzyl thiol and either hydrogen peroxide or tert-butyl hydroperoxide.