Lars Engman

α-(Phenylselenenyl)acetophenone derivatives with glutathione peroxidase-like activity: A comparison with ebselen

Here we describe a new class of organoselenium compounds possessing glutathione peroxidase-like activity. The parent compound, alpha-(phenylselenenyl)acetophenone (PSAP), increased the rate of reaction of glutathione with H2O2, tert-butylhydroperoxide, cumene hydroperoxide, linoleic acid hydroperoxide and dilinoleyl lecithin hydroperoxide by 7.0, 25.1, 34.1, 19.1 and 8.4-fold, respectively, as assessed by the oxidized glutathione (GSSG) reductase enzyme assay. Direct assay of the removal of hydrogen peroxide and glutathione from reaction mixtures confirmed the peroxidase-like activities of these selenoorganic compounds, but indicate that the conventional coupled GSSG reductase assay may be unsuitable for the assessment of the catalytic capacity of PSAP and Ebselen. One possible mechanism of catalysis by PSAP involves an initial oxidation at selenium. Thiol may then react with the selenoxide to yield a selenium (II) compound, H2O and a disulfide. Compounds derived from PSAP may provide potential selenium-based anti-inflammatory agents.

Characterisation and quantitation of a selenol intermediate in the reaction of ebselen with thiols

The reaction of ebselen (2-phenyl-1,2-benzisoselenazol-3(2H)-one) with thiols was investigated with particular attention to the formation of an ebselen selenol intermediate. The selenol intermediate could be trapped in a mixture of ebselen and thiols with 1-chloro-2,4-dinitrobenzene and the resulting product displayed unique spectral characteristics. The reaction of authentic, synthesised ebselen selenol with 1-chloro-2,4-dinitrobenzene (CDNB) was shown to give rise to the same compound (2,4-dinitrophenyl (N-phenyl-2-carboxamido phenyl) selenide as characterized by light spectroscopy, NMR, IR and elemental analysis. The determination of the absorbtion coefficient at 400 nm (E = 7.5 mM-1 cm-1) and the initial rate constant of the reaction (1.4 +/- 0.3 mM-1 min-1) allows for the convenient quantification of ebselen selenol concentrations by initial rate measurements after addition of CDNB. The choice of 400 nm to monitor the reaction excludes the interference of other intermediates in the reaction of ebselen with thiols as well as the reaction of the thiols with CDNB. When the assay is applied to typical incubation conditions used for investigating the glutathione peroxidase-like activity of ebselen it was shown that as much as 10-20% of ebselen is in the selenol form. If a stronger reductant (dithiothreitol) is used 60% is in the selenol form. These data could also be confirmed by the direct determination of ebselen selenol by UV spectroscopy, due to its peak absorption at 370 nm (E = 2 mM-1 cm-1). In conclusion, this investigation demonstrates, for the first time, the identity and quantity of ebselen selenol in the reaction of ebselen with thiols and also describes a convenient assay for its quantification. These observations allow further possibilities for investigation of the molecular species responsible for the antioxidant and peroxidase activities of ebselen.

Glutathione peroxidase-like activity of diaryl tellurides.

Abstract 4,4′-Disubstituted dirayl tellurides showed glutathione peroxidase-like catalysis of the reduction of hydroperoxides by glutathione. The most potent compound, bis(4-aminophenyl) telluride, demonstrated 348%, 530%, 995% and 900% of the catalytic efficacy of Ebselen for the glutathione dependent reduction of H 2 O 2 , t-butyl hydroperoxide, cumene hydroperoxide and linoleic acid hydroperoxide, respectively.

Determination of the relative contributions of the diselenide and selenol forms of ebselen in the mechanism of its glutathione peroxidase-like activity

The molecular basis of the glutathione peroxidase activity of ebselen (2-phenyl-1,2-benzisoselenazol-3(2H)-one) was investigated by the use of synthesised, authentic intermediates identical to those formed by the reaction of ebselen with glutathione. The second order rate constants for the reaction of ebselen (0.29 mM-1 min-1), ebselen-glutathione selenosulfide (less than or equal to 0.01 mM-1 min-1), ebselen selenol (2.8 mM-1 min-1) and ebselen diselenide (0.32 mM-1 min-1) with hydrogen peroxide reveal that the selenol is particularly active in this respect. The determination of the relative amounts of ebselen selenol and diselenide under typical peroxidase assay conditions implies that the selenol is the predominant molecular species responsible for the glutathione--(70%)--and dithiothreitol--(96%)--dependent peroxidase activity of ebselen.

Diaryl Tellurides as Inhibitors of Lipid Peroxidation in Biological and Chemical Systems

Diaryl tellurides carrying electron-donating substituents in the para positions were found to efficiently inhibit peroxidation of rat hepatocytes, rat liver microsomes and a chlorobenzene solution of phosphatidylcholine. The most active compound in the microsomal assay, bis(4-dimethylaminophenyl) telluride, showed an IC50-value of 30 nM. This compound also caused a dose-dependent delay of the onset of the linear phase of microsomal peroxidation stimulated by iron/ADP/ascorbate. The peak oxidation potentials of the diaryl tellurides (0.50-1.14 V in MeCN) correlated linearly with the IC50-values in this assay, with a point of inflection around 0.85 V. In the hepatocyte system, all compounds showed similar protective activity. It is proposed that diaryl tellurides exert an antioxidative effect by deactivating both peroxides and peroxyl radicals under the formation of telluroxides. These oxides may regenerate the active divalent organotellurides upon exposure to a suitable reducing agent.

Improved preparation of diaryl ditellurides

Abstract Diaryl ditellurides have been synthesized from aryl bromides via lithiation, tellurium insertion, and ferricyanide oxidation of the resulting lithium arenetellurolates.

Catalytic debromination of vicinal dibromides

Abstract A number of vicinal dibromides were debrominated using sodium borohydride and a catalytic amount of bis(2-thienyl)ditelluride.

Tellurium in organic synthesis : V. X-ray structure of 8-ethoxy-4-cyclooctenyltellurium trichloride and its relevance to the TeO2-oxidation of alkenes

Abstract The molecular structure of 8-ethoxy-4-cyclooctenyltellurium trichloride has been determined from three-dimensional X-ray diffraction data. The crystal belongs to the monoclinic system, space group P 2 1 / n , with four formula units in a cell of dimensions: a 7.712(1), b 13.406(3), c 13.820(2) A and β 95.18(1)°. The structure was solved by the conventional heavy atom method, and refined by the least-squares procedure to R = 0.025 for 2199 reflections. The compound is formed from the corresponding β-chloroalkyltellurium tri-chloride, obtained from TeCl 4 and cis , cis -1,5-cyclooctadiene, by an unusually mild solvolytic substitution reaction in ethanol. Similar β-chloroalkyltellurium compounds are postulated as intermediates in the TeO 2 oxidation of alkenes to alkanediol diacetates and alkanediol monoacetates in HOAc containing a lithium halide, LiX. Oxidation of cis -2-butene and trans -2-butene with TeO 2 /HOAc/LiBr gave a high preference for cis -stereochemistry in the products while 1-decene showed no stereospecificity.

A general procedure for the synthesis of methylthio-, methylseleno- and methyltelluro-substituted aromatic compounds

Abstract A one-pot procedure is described which allows the facile introduction of one or two methylchalcogeno groups into a variety of monobromo or dibromo aromatics. The bromo compounds were converted to their corresponding lithio derivatives by treatment with t-butyllithium in tetrahydrofuran at −78°C, and these derivatives were then treated, at ambient temperature with elemental sulfur, selenium, or tellurium. The resulting lithium thiolates, selenolates and tellurolates were finally methylated with methyl iodide to afford good yields (typically 50–80%) of the various methylchalcogeno-substituted aromatic compounds. The procedure could not be used for the synthesis of ortho -disubstituted compounds, or for the simultaneous introduction of three methylchalcogeno groups.

Tellurium in organic synthesis : IV. Carbonylation of some aromatic tellurium compounds in the presence of Ni(CO)4

Abstract The reaction of ArTeCl3 and Ar2TeCl2 with Ni(CO)4 in dimethylformamide followed by aqueous work-up readily gives the corresponding carboxylic acids. A mechanism is suggested in which the aromatic telluride adds oxidatively to nickel, and this is followed by insertion of a CO-unit yielding an ArCONi complex.