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  • 1. Amorati, Riccardo
    et al.
    Pedulli, Gian Franco
    Valgimigli, Luca
    Johansson, Henrik
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi.
    Engman, Lars
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi.
    Organochalcogen Substituents in Phenolic Antioxidants2010Inngår i: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052, Vol. 12, nr 10, s. 2326-2329Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Little is known about the ED/EW character of organochalcogen substituents and their contribution to the O-H bond dissociation enthalpy (BDE) in phenolic compounds. A series of ortho- and para-(S,Se,Te)R-substituted phenols were prepared and investigated by EPR, IR, and computational methods. Substituents lowered the O-H BDE by >3 kcal/mol in the para position, while the ortho-effect was modest due to hydrogen bonding ( approximately 3 kcal/mol) to the O-H group.

  • 2. Amorati, Riccardo
    et al.
    Valgimigli, Luca
    Dinér, Peter
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC.
    Bakhtiari, Khadijeh
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC.
    Saeedi, Mina
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC.
    Engman, Lars
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC.
    Multi-faceted reactivity of alkyltellurophenols towards peroxyl radicals: Catalytic antioxidant versus thiol-depletion effect2013Inngår i: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 19, nr 23, s. 7510-7522Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Hydroxyaryl alkyl tellurides are effective antioxidants both in organic solution and aqueous biphasic systems. They react by an unconventional mechanism with ROO. radicals with rate constants as high as 107M1s1 at 303K, outperforming common phenols. The reactions proceed by oxygen atom transfer to tellurium followed by hydrogen atom transfer to the resulting RO. radical from the phenolic OH. The reaction rates do not reflect the electronic properties of the ring substituents and, because the reactions occur in a solvent cage, quenching is more efficient when the OH and TeR groups have an ortho arrangement. In the presence of thiols, hydroxyaryl alkyl tellurides act as catalytic antioxidants towards both hydroperoxides (mimicking the glutathione peroxidases) and peroxyl radicals. The high efficiency of the quenching of the peroxyl radicals and hydroperoxides could be advantageous under normal cellular conditions, but pro-oxidative (thiol depletion) when thiol concentrations are low.

  • 3.
    Co, Michelle
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för fysikalisk och analytisk kemi, Analytisk kemi.
    Fagerlund, Amelie
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi.
    Engman, Lars
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC.
    Sunnerheim, Kerstin
    Department of Natural Sciences, Engineering and Mathematics, Mid Sweden University.
    Sjöberg, Per J. R
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för fysikalisk och analytisk kemi, Analytisk kemi.
    Turner, Charlotta
    Dept of Organic Chemistry, Lund University.
    Extraction of Antioxidants from Spruce (Picea abies) Bark using Eco-Friendly Solvents2012Inngår i: Phytochemical Analysis, ISSN 0958-0344, E-ISSN 1099-1565, Vol. 23, nr 1, s. 1-11Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Introduction-Antioxidants are known to avert oxidation processes and they are found in trees and other plant materials. Tree bark is a major waste product from paper pulp industries; hence it is worthwhile to develop an extraction technique to extract the antioxidants.

    Objective- To develop a fast and environmentally sustainable extraction technique for the extraction of antioxidants from bark of spruce (Picea abies) and also to identify the extracted antioxidants that are abundant in spruce bark.

    Methodology- A screening experiment that involved three different techniques, was conducted to determine the best technique to extract antioxidants.The antioxidant capacity of the extracts was determined with DPPH (2,2-diphenyl-2’-picrylhydrazyl) assay. Pressurised fluid extraction (PFE) turned out to be the best technique and a response surface design was therefore utilised to optimise PFE. Furthermore, NMR and HPLC-DAD-MS/MS were applied to identify the extracted antioxidants.

    Results- PFE using water and ethanol as solvent at 160 and 180°C, respectively, gave extracts of the highest antioxidant capacity. Stilbene glucosides such as isorhapontin, piceid and astringin were identified in the extracts.

    Conclusion-The study has shown that PFE is a fast and environmentally sustainable technique, using water and ethanol as solvent for the extraction of antioxidants from spruce bark.

  • 4.
    Engman, Lars
    Institutionen för Biokemi och Organisk Kemi.
    Compositions and Methods2008Patent (Annet (populærvitenskap, debatt, mm))
  • 5.
    Engman, Lars
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi, Organisk kemi I.
    Compositions and Methods.2009Patent (Annet (populærvitenskap, debatt, mm))
  • 6.
    Engman, Lars
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Kemiska institutionen, Avdelningen för organisk kemi.
    Al-Maharik, Nawaf
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Kemiska institutionen, Avdelningen för organisk kemi.
    McNaughton, Michael
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Kemiska institutionen, Avdelningen för organisk kemi.
    Birmingham, A
    Uppsala universitet.
    Powis, G.
    Uppsala universitet.
    Thioredoxin Reductase and Cancer Cell Growth Inhibition by Organotellurium Compounds that could be Selectively Incorporated into Tumor Cells2003Inngår i: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 11, nr 23, s. 5091-5100Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The thioredoxins are small ubiquitous redox proteins with the conserved redox catalytic sequence-Trp-Cys-Gly-Pro-Cys-Lys, where the Cys residues undergo reversible NADPH dependent reduction by selenocysteine containing flavoprotein thioredoxin reductases. Thioredoxin expression is increased in several human primary cancers including lung, colon, cervix, liver, pancreatic, colorectal and squamous cell cancer. The thioredoxin/thioredoxin reductase pathway therefore provides an attractive target for cancer drug development. Organotellurium steroid, lipid, amino acid, nucleic base, and polyamine inhibitors were synthesized on the basis that they might be selectively or differentially incorporated into tumor cells. Some of the newly prepared classes of tellurium-based inhibitors (lipid-like compounds 3b and 3e, amino acid derivative 5b, nucleic base derivative 8b, and polyamine derivatives 14a and 14b) inhibited TrxR/Trx and cancer cell growth in culture with IC(50) values in the low micromolar range.

  • 7.
    Engman, Lars
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi, Organisk kemi I.
    Holmgren, Arne
    Vlamis-Gardikas, A.
    Zhao, R.
    Kandasamy, K.
    Hoffner, S.
    Bacterial Thioredoxin Reductase Inhibitors and Methods for Use Thereof2009Patent (Annet (populærvitenskap, debatt, mm))
    Abstract [en]

    The mechanism of action of Ebselen differentiates between bacterial and mammalian thioredoxin reductase (TrxR). It displays fast oxidation of mammalian Trx and via the NADPH-TrxR catalyzed turnover of ebselen selenol with hydrogen peroxide, and therefore are mammalian antioxidants. Ebselen, and its diselenide, are strong competitive inhibitors of E. coli TrxR with K.sub.i of 0.14 .mu.M and 0.46 .mu.M, respectively. E. coli mutants lacking glutathione reductase or glutathione were much more sensitive to inhibition by ebselen. Since either glutaredoxin or thioredoxin systems are electron donors to ribonucleotide reductase, ebselen targets primarily glutathione and glutaredoxin-negative bacteria, a class which includes major pathogens. Ebselen, and similar compounds are therefore useful as antibacterial agents, even for multiresistant strains. Two major pathogenic bacteria, which previously had not been known to be sensitive to ebselen, Mycobacterium tuberculosis (tuberculosis) and Helicobacter pylori (stomach ulcer and cancer), were shown to be excellent targets. Helicobacter pylori was also sensitive to ebsulfur.

  • 8.
    Engman, Lars
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi, Organisk kemi I.
    Johansson, Henrik
    Antioxidants for use in therapy. 2009Patent (Annet (populærvitenskap, debatt, mm))
  • 9.
    Engman, Lars
    et al.
    Institutionen för Biokemi och Organisk Kemmi.
    McMillan, P
    Patzewitz, E. M.
    Young, S.E.
    Westrop, G. D.
    Coombs, G. H.
    Muller, S.
    Differential inhibition of high and low Mr thioredoxin reductases of parasites by organotelluriums supports the concept that low Mr thioredoxin reductases are good drug targets2009Inngår i: Parasitology, ISSN 0031-1820, E-ISSN 1469-8161, ISSN 0031-1820, Vol. 136, s. 27-33Artikkel i tidsskrift (Fagfellevurdert)
  • 10.
    Ericsson, Cecilia
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Kemiska institutionen. Institutionen för biokemi och organisk kemi, Organisk kemi I. Organisk kemi.
    Engman, Lars
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Kemiska institutionen. Institutionen för biokemi och organisk kemi, Organisk kemi I.
    Microwave-Assisted Group-Transfer Cyclization of Organotellurium Compounds2004Inngår i: The Journal of Organic Chemistry, Vol. 69, nr 15, s. 5143-5146Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Primary- and secondary-alkyl aryl tellurides, prepared by arenetellurolate ring-opening of epoxides/O-allylation, were, found to undergo rapid (3-10 min) group-transfer cyclization to afford tetrahydrofuran derivatives in 60-74% yield when heated in a microwave cavity at 250C in ethylene glycol or at 180C in water. To go to completion, similar transformations had previously required extended photolysis in refluxing benzene containing a substantial amount of hexabutylditin. The only drawback of the microwave-assisted process was the loss in diastereoselectivity wich is a consequence of the higher reaction temperature. Substitution in the Te-aryl moiety of the secondary-alkyl aryl tellurides (4-OMe, 4-H, 4-CF3) did not affect the outcome of the group-transfer reaction in ethylene glycol. However, at lower temperature, using water as a solvent, the CF3 derivative failed to react. The microwave-assisted grouptransfer cyclization was extended to benzylic but not to primary- and secondary-alkyl phenyl selenides.

  • 11. Eriksson, Per
    et al.
    Engman, Lars
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Kemiska institutionen. Institutionen för biokemi och organisk kemi, Organisk kemi I. Organisk kemi.
    Lind, Johan
    Merényi, Gabor
    Aqueous Phase One-Electron Reduction of Sulfonium, Selenonium and Telluronium Salts2005Inngår i: Eur. J. Org. Chem., s. 701-705Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Triorganylsulfonium, -selenonium and -telluronium salts were reduced by carbon dioxide radical anions/solvated electrons produced in aqueous solution by radiolysis. The radical expulsion accompanying reduction occurred with the expected leaving group propensities (benzyl > secondary alkyl> primary alkyl> methy> phenyl), although greater than expected loss of the phenyl group was often observed. Diorganyl chalcogenides formed in the reductions were conveniently isolated by extraction with an organic solvent. Product yields based on the amount of reducing radicals obtained from the y-source were often higher than stoichiometric (up to 1800%) in the reduction of selenonium an dtelluronium compounds; it is likely that this result can be accounted for in terms of a chain reaction with carbon-centred radicals/formate serving as the chain transfer agent. The product distribution was essentially independent of the reducing species for diphenyl alkyl telluronium salts, whereas significant variations were seen for some of the corresponding selenonium salts. This would suggest the intermediacy of telluranyl radicals in the one-electron reduction of telluronium salts. However, pulse radiolysis experiments indicated that the lifetimes of such a species (the triphenyltelluranyl radical) would have to be less than 1 us.

  • 12.
    Fagerlund, Amelie
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Kemiska institutionen.
    Shanks, David
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Kemiska institutionen.
    Sunnerheim, Kerstin
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Kemiska institutionen.
    Engman, Lars
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Kemiska institutionen.
    Frisell, Håkan
    Protective Effects of Synthetic and Naturally Occurring Antioxidants in Pulp Products2003Inngår i: Nordic Pulp & Paper Research Journal, ISSN 0283-2631, E-ISSN 2000-0669, Vol. 18, nr 2, s. 176-181Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Various types of natural and synthetic antioxidants when added to handsheets of pulp in low concentrations (0.2% weight%) could significantly reduce the emission of hexanal. The most efficient compounds caused a 90% reduction after eight weeks. Their capacity to inhibit brightness reversion was limited.

  • 13.
    Gustafsson, Tomas
    et al.
    Karolinska Inst, Div Biochem, Dept Med Biochem & Biophys, Scheeles Vag 2, SE-17177 Stockholm, Sweden.; Umea Univ, Sunderby Res Unit, Dept Clin Microbiol, Clin Bacteriol, Umea, Sweden.
    Osman, Harer
    Karolinska Inst, Div Biochem, Dept Med Biochem & Biophys, Scheeles Vag 2, SE-17177 Stockholm, Sweden.
    Werngren, Jim
    Publ Hlth Agcy Sweden, Dept Microbiol, Solna, Sweden.
    Hoffner, Sven
    Publ Hlth Agcy Sweden, Dept Microbiol, Solna, Sweden.
    Engman, Lars
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Syntetisk organisk kemi.
    Holmgren, Arne
    Karolinska Inst, Div Biochem, Dept Med Biochem & Biophys, Scheeles Vag 2, SE-17177 Stockholm, Sweden.
    Ebselen and analogs as inhibitors of Bacillus anthracis thioredoxin reductase and bactericidal antibacterials targeting Bacillus species, Staphylococcus aureus and Mycobacterium tuberculosis2016Inngår i: Biochimica et Biophysica Acta - General Subjects, ISSN 0304-4165, E-ISSN 1872-8006, Vol. 1860, nr 6, s. 1265-1271Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Bacillus anthracis is the causative agent of anthrax, a disease associated with a very high mortality rate in its invasive forms.

    Methods: We studied a number of ebselen analogs as inhibitors of B. anthracis thioredoxin reductase and their antibacterial activity on Bacillus subtilis, Staphylococcus aureus, Bacillus cereus and Mycobacterium tuberculosis.

    Results: The most potent compounds in the series gave IC50 values down to 70 nM for the pure enzyme and minimal inhibitory concentrations (MICs) down to 0.4 mu M (0.12 mu g/ml) for B. subtilis,1.5 mu M (0.64 mu g/ml) for S. aureus, 2 mu M (0.86 mu g/ml) for B. cereus and 10 mu g/ml for M. tuberculosis. Minimal bactericidal concentrations (MBCs) were found at 1-1.5 times the MIC, indicating a general, class-dependent, bactericidal mode of action. The combined bacteriological and enzymological data were used to construct a preliminary structure-activity-relationship for the benzoisoselenazol class of compounds. When S. aureus and B. subtilis were exposed to ebselen, we were unable to isolate resistant mutants on both solid and in liquid medium suggesting a high resistance barrier.

    Conclusions: These results suggest that ebselen and analogs thereof could be developed into a novel antibiotic class, useful for the treatment of infections caused by B. anthracis, S. aureus, M. tuberculosis and other clinically important bacteria. Furthermore, the high barrier against resistance development is encouraging for further drug development.

    General significance: We have characterized the thioredoxin system from B. anthracis as a novel drug target and ebselen and analogs thereof as a potential new class of antibiotics targeting several important human pathogens.

  • 14. Holmgren, Arne
    et al.
    Lu, Jun
    Vlamis-Gardikas, Alexios
    Zhao, Rong
    Kandasamy, Karuppasamy
    Engman, Lars
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi, Organisk kemi I.
    Hoffner, Sven
    Bacterial Thioredoxin Reductase Inhibitors and Methods for Use Thereof2007Patent (Annet (populærvitenskap, debatt, mm))
  • 15.
    Johansson, Henrik
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi.
    Shanks, David
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi.
    Engman, Lars
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi.
    Amorati, Riccardo
    Pedulli, Gian Franco
    Valgimigli, Luca
    Long-lasting Antioxidant Protection: A Regenerable BHA-Analogue2010Inngår i: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 75, nr 22, s. 7535-7541Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Introduction of an octyltelluro group ortho to the phenolic moiety in 3-tert-butyl-4-hydroxyanisole (BHA) was found to significantly improve the antioxidant characteristics of the material. In contrast to BHA and the corresponding ortho-substituted octylthio- (9c) and octylseleno (9b) derivatives, the organotellurium 9a was regenerable when assayed for its capacity to inhibit azo-initiated peroxidation of linoleic acid in a chlorobenzene/water two-phase system containing N-acetylcysteine as a stoichiometric reducing agent, and peroxyl radicals were quenched more efficiently than with α-tocopherol. In the homogeneous phase, inhibition of styrene autoxidation occurred with a rate constant kinh as large as 1 × 107 M-1 s-1 but with a low (n = 0.4) stoichiometric factor. Evans-Polanij plots of log (kinh) versus BDE(O-H), which are usually linear for phenols with similar steric crowding reacting by H-atom transfer, revealed that compound 9a was more than 2 orders of magnitude more reactive than expected. Although further mechanistic investigations are needed, it seems that the ortho-arrangement of an alkyltelluro group and hydroxyl should be considered a privileged structure for phenolic antioxidants.

  • 16.
    Johansson, Henrik
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi.
    Svartström, Olof
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för fysikalisk och analytisk kemi.
    Phadnis, Prasad
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi.
    Engman, Lars
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi.
    Karlsson Ott, Marjam
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för fysikalisk och analytisk kemi.
    Exploring a synthetic organoselenium compound for antioxidant pharmacotherapy: toxicity and effects on ROS-production2010Inngår i: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 18, nr 5, s. 1783-1788Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The organoselenium antioxidant 1 was previously found to act as a catalytic antioxidant in a two-phase lipid peroxidation system. In aqueous environment, selenide 1 quenched ABTS-radicals more efficiently than Trolox and ascorbic acid. The selenide dose-dependently scavenged reactive oxygen and nitrogen species more efficiently than Trolox for neutrophils and PMA-stimulated macrophages, with 50% inhibitory concentrations in the low micromolar range. In addition no sign of toxicity or effect on cell viability was seen when culturing five human cell lines in concentrations up to 200 microM of selenide 1 for up to seven days. We therefore feel that the compound would be a good candidate for future drug development for prevention or treatment of disorders caused by or involving free radical-mediated or oxidative tissue damage.

  • 17. Kawaguchi, Shin-ichi
    et al.
    Srivastava, Puneet
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi.
    Engman, Lars
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi.
    Palladium-catalyzed Sonogashira cross-coupling of organic tellurides with alkynes2011Inngår i: Tetrahedron Letters, ISSN 0040-4039, E-ISSN 1359-8562, Vol. 52, nr 32, s. 4120-4122Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Alkyl aryl tellurides and a tellurol ester were used as coupling partners in Pd(0)-catalyzed Sonogashira reactions. Microwave-assisted reactions of alkyl aryl tellurides with alkynes in the presence of Cut and catalytic amounts of Pd(PPh(3))(4) produced alkynyl arenes. Similarly, a tellurol ester on reaction with alkynes afforded alkynyl phenyl ketones in the presence of Cut and a catalytic amount of Pd(PPh(3))(4) at room temperature.

  • 18.
    Kirchhain, Arno
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Syntetisk organisk kemi.
    Yu, Wenbin
    Engman, Lars
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Syntetisk organisk kemi.
    Organochalcogen stabilizers efficiently protect model polyolefins exposed to chlorinated media2015Inngår i: Polymer degradation and stability, ISSN 0141-3910, E-ISSN 1873-2321, Vol. 118, s. 82-87Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The small amounts of chlorine dioxide that are routinely supplemented to drinking water as a disinfectant also cause a degradation of the polyolefin pipes that are used for distribution of the water. Commonly used phenolic antioxidants can extend the service life of the polymer but the expected lifetime is still much shorter than desired (50 years) due to depletion of the antioxidant in the surface zone exposed to the aqueous solution. In search for better stabilizers for the pipes, we have tested an organotellurium compound, 4-(N,N-dimethylamino)phenyl 3-phenoxypropyl telluride (1), as well as its corresponding selenium and sulphur analogues and a series of organotellurium compounds where the electron density at the heteroatom was varied. Stabilizers were dissolved in squalane, which is a liquid hydrocarbon that could serve as a model for a polyolefin. The oxidation induction time (OIT), determined after exposure of the squalane solution to an aqueous solution of 10 ppm of chlorine dioxide for various times was determined by DSC to indicate the loss of antioxidant protection. Whereas Irganox 1010 was only effective as a stabilizer for a few hours, many of the organochalcogen compounds were considerably more resistant (>91 h for compound 1) towards chlorine dioxide.

    Thermogravimetric analyses of antioxidants indicated insignificant decomposition below 200 °C and increasing stability for the lighter chalcogen compounds (telluride < selenide < sulfide). Among organotelluriums, stability increases with increasing electron density at the heteroatom. Oxidation potentials of stabilizers as determined by cyclic voltammetry correlated fairly well with their protective effect in squalane (OIT-values). We therefore hypothesize that these compounds act primarily as electron donors towards peroxyl radicals. As determined by 125Te NMR-spectroscopy, organotellurium compound 1 in the presence of an excess of chlorine dioxide failed to produce an oxidation product. This may be the clue to its long-lasting protective effect in the squalane-assay.

  • 19.
    Kumar, Sangit
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi, Organisk kemi I.
    Engman, Lars
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi, Organisk kemi I.
    Microwave-Assisted Copper-Catalyzed Preparation of Diaryl Chalcogenides2006Inngår i: J. Org. Chem., Vol. 71, s. 5400-5403Artikkel i tidsskrift (Fagfellevurdert)
  • 20.
    Kumar, Sangit
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi.
    Engman, Lars
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi.
    Valgimigli, Luca
    Amorati, Richard
    Grazia Fumo, Maria
    Franco Pedulli, Gian
    Antioxidant Profile of Ethoxyquin and Some of Its S, Se, and Te Analogues2007Inngår i: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 72, nr 16, s. 6046-6055Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    (Chemical Equation Presented) 6-(Ethylthio)-, 6-(ethylseleno)-, and 6-(ethyltelluro)-2,2,4-trimethyl-1,2-dihydroquinoline-three heavier chalcogen analogues of ethoxyquin-were prepared by dilithiation of the corresponding 6-bromodihydroquinoline followed either by treatment with the corresponding diethyl dichalcogenide (sulfur derivative) or by insertion of selenium/tellurium into the carbon-lithium bond, oxidation to a diaryl dichalcogenide, borohydride reduction, and finally alkylation of the resulting areneselenolate/ arenetellurolate. Ethoxyquin, its heavier chalcogen analogues, and the corresponding 6-PhS, 6-PhSe, and 6-PhTe derivatives were assayed for both their chain-breaking antioxidant capacity and their ability to catalyze reduction of hydrogen peroxide in the presence of a stoichiometric amount of a thiol reducing agent (thiol peroxidase activity). Ethoxyquin itself turned out to be the best inhibitor of azo-initiated peroxidation of linoleic acid in a water/chlorobenzene two-phase system. In the absence of N-acetylcysteine as a coantioxidant in the aqueous phase, it inhibited peroxidation as efficiently as α-tocopherol but with a more than 2-fold longer inhibition time. In the presence of 0.25 mM coantioxidant in the aqueous phase, the inhibition time was further increased by almost a factor of 2. This is probably due to thiol-mediated regeneration of the active antioxidant across the lipid-aqueous interphase. The ethyltelluro analogue 1d of ethoxyquin was a similarly efficient quencher of peroxyl radicals compared to the parent in the two-phase system, but less regenerable. Ethoxyquin was found to inhibit azo-initiated oxidation of styrene in the homogenous phase (chlorobenzene) almost as efficiently (k inh = (2.0 ± 0.2) × 106 M-1 s -1) as α-tocopherol with a stoichiometric factor n = 2.2 ± 0.1. At the end of the inhibition period, autoxidation was additionally retarded, probably by ethoxyquin nitroxide formed during the course of peroxidation. The N-H bond dissociation enthalpy of ethoxyquin (81.3 ± 0.3 kcal/mol) was determined by a radical equilibration method using 2,6-dimethoxyphenol and 2,6-di-tert-butyl-4-methylphenol as equilibration partners. Among the investigated compounds, only the tellurium analogues 1d and, less efficiently, 1g had a capacity to catalyze reduction of hydrogen peroxide in the presence of thiophenol. Therefore, analogue 1d is the only antioxidant which is multifunctional (chain-breaking and preventive) in character and which can act in a truly catalytic fashion to decompose both peroxyl radicals and organic hydroperoxides in the presence of suitable thiol reducing agents.

  • 21.
    Kumar, Sangit
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi.
    Johansson, Henrik
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi.
    Engman, Lars
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi.
    Valgimigli, Luca
    Amorati, Riccardo
    Grazia Fumo, Maria
    Pedulli, Gian Franco
    Regenerable Chain-Breaking 2,3-Dihydrobenzo[b]selenophene-5-ol Antioxidants2007Inngår i: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 72, nr 7, s. 2583-2595Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A series of 2,3-dihydrobenzo[b]selenophene-5-ol antioxidants was prepared by subjecting suitably substituted allyl 4-methoxyphenyl selenides to microwave-induced seleno-Claisen rearrangement/intramolecular Markovnikov hydroselenation followed by boron tribromide-induced O-demethylation. The novel antioxidants were assayed for their capacity to inhibit azo-initiated peroxidation of linoleic acid in a water/chlorobenzene two-phase system containing N-acetylcysteine as a thiol reducing agent in the aqueous phase. Antioxidant efficiency as determined by the inhibited rate of peroxidation, Rinh, increased with increasing methyl substitution (Rinh = 46−26 μM/h), but none of the compounds could match α-tocopherol (Rinh = 22 μM/h). Regenerability as determined by the inhibition time, Tinh, in the presence of the thiol regenerating agent decreased with increasing methyl substitution. Thus, under conditions where the unsubstituted compound 5a inhibited peroxidation for more than 320 min, α-tocopherol worked for 90 min and the trimethylated antioxidant 5g for 60 min only. Sampling of the aqueous phase at intervals during peroxidation using antioxidant 5a showed that N-acetylcysteine was continuously oxidized with time to the corresponding disulfide. In the absence of the regenerating agent, compounds 5 inhibited peroxidation for 50−60 min only. A (RO)B3LYP/LANL2DZdp//B3LYP/LANL2DZ model was used for the calculation of homolytic O−H bond dissociation enthalpies (BDE) and adiabatic ionization potentials (IP) of phenolic antioxidants 5. Both BDE (80.6−76.3 kcal/mol) and IP (163.2−156.0 kcal/mol) decrease with increasing methyl substitution. The phenoxyl radical corresponding to phenol 5g gave an intense ESR signal centered at g = 2.0099. The H−O bond dissociation enthalpy of the phenol was determined by a radical equilibration method using BHA as an equilibration partner. The observed BDE (77.6 ± 0.5 kcal/mol) is in reasonable agreement with calculations (76.3 kcal/mol). As judged by calculated log P values, the lipophilicity of compounds 5 increased slightly when methyl groups were introduced into the phenolic moiety (2.9 > C log P < 4.2). The capacity of compounds 5a (kinh = 3.8 × 105 M-1 s-1) and 5g (kinh = 1.5 × 106 M-1 s-1) to inhibit azo-initiated autoxidation of styrene in the homogeneous phase (chlorobenzene) was also studied. More efficient regeneration at the lipid−aqueous interphase is the most likely explanation why the intrinsically poorest antioxidant 5a can outperform its analogues as well as α-TOC in the two-phase system. Possible mechanisms of regeneration are discussed and evaluated.

  • 22.
    Kumar, Sangit
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi.
    Johansson, Henrik
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi.
    Kanda, Takahiro
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi.
    Engman, Lars
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi.
    Muller, Thomas
    Bergenudd, Helena
    Jonsson, Mats
    Pedulli, Gian Franco
    Amorati, Riccardo
    Valgimigli, Luca
    Catalytic chain-breaking pyridinol antioxidants2010Inngår i: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 75, nr 3, s. 716-725Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The synthesis of 3-pyridinols carrying alkyltelluro, alkylseleno, and alkylthio groups is described together with a detailed kinetic, thermodynamic, and mechanistic Study of their antioxidant activity. When assayed for their capacity to inhibit azo-initiated peroxidation of linoleic acid in a water/chlorobenzene two-phase system, tellurium-containing 3-pyridinols were readily regenerable by N-acetylcysteine contained in the aqueous phase. The best inhibitors quenched peroxyl radicals more efficiently than alpha-tocopherol, and the duration of inhibition was limited only by the availability of the thiol reducing agent. fn homogeneous phase, inhibition of styrene autoxidation absolute rate constants k(inh) for quenching of peroxyl radical were as large as 1 x 10(7) M-1 s(-1), thus Outperforming the best phenolic antioxidants including alpha-tocopherol. Tellurium-containing 3-pyridinols could be quantitatively regenerated in homogeneous phase by N-tert-butoxycarbonyl cysteine methyl ester, a lipid-soluble analogue of N-acetylcysteine. In the presence of an excess of the thiol, a catalytic mode of action was observed, similar to the one in the two-phase system. Overall, compounds bearing the alkyltelluro moiety ortho to the OH group were much more effective antioxidants than the corresponding para isomers. The origin of the high reactivity of these compounds was explored using pulse-radiolysis thermodynamic measurements, and a mechanism for their unusual antioxidant activity was proposed. The tellurium-containing 3-pyridinols were also found to catalyze reduction of hydrogen peroxide in the presence of thiol reducing agents, thereby acting as multifunctional (preventive and chain-breaking) catalytic antioxidants.

  • 23.
    Kumar, Sangit
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi.
    Johansson, Henrik
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi.
    Kanda, Takahiro
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi.
    Engman, Lars
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi.
    Müller, Thomas
    Jonsson, Mats
    Pedulli, Gian Franco
    Petrucci, Silvia
    Valgimigli, Luca
    Catalytic Chain-breaking Pyridinol Antioxidants2008Inngår i: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052, Vol. 10, nr 21, s. 4895-4898Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    When assayed for their capacity to inhibit azo-initiated peroxidation of linoleic acid in a water/chlorobenzene two-phase system, tellurium-containing 3-pyridinols were readily regenerable by N-acetylcysteine contained in the aqueous phase. The best inhibitors quenched peroxyl radicals more efficiently than alpha-tocopherol, and the duration of inhibition was limited only by the availability of the thiol reducing agent. The compounds were also found to catalyze reduction of hydrogen peroxide in the presence of thiol reducing agent.

  • 24.
    Kumar, Shailesh
    et al.
    IISER Bhopal.
    Yan, Jiajie
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC.
    Poon, Jia-fei
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC.
    Singh, Vijay P
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC.
    Lu, Xi
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Tillämpad materialvetenskap.
    Ott, Marjam Karlsson
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Tillämpad materialvetenskap.
    Engman, Lars
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC.
    Kumar, Sangit
    IISER Bhopal.
    Multifunctional Antioxidants: Regenerable Radical-Trapping and Hydroperoxide-Decomposing Ebselenols2016Inngår i: Angewandte Chemie International Edition, ISSN 1433-7851, E-ISSN 1521-3773, Vol. 55, nr 11, s. 3729-3733Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Regenerable, multifunctional ebselenol antioxidants were prepared that could quench peroxyl radicals more efficiently than -tocopherol. These compounds act as better mimics of the glutathione peroxidase enzymes than ebselen. Production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) in human mononuclear cells was considerably decreased upon exposure to the organoselenium compounds. At a concentration of 25m, the ebselenol derivatives showed minimal toxicity in pre-osteoblast MC3T3cells.

  • 25.
    Lu, Jun
    et al.
    Karolinska Institutet.
    Vlamis-Gardikas, Alexios
    Karolinska Institutet.
    Kandasamy, Karuppasamy
    Karolinska Institutet.
    Zhao, Rong
    Karolinska Institutet.
    Gustafsson, Tomas
    Karolinska Institutet.
    Engstrand, Lars
    Karolinska Institutet.
    Hoffner, Sven
    Karolinska Institutet.
    Engman, Lars
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Syntetisk organisk kemi.
    Holmgren, Arne
    Karolinska Institutet.
    Inhibition of Bacterial Thioredoxin Reductase: An Antibiotic Mechanism Targetting Bacteria Lacking Glutathione2013Inngår i: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 27, nr 4, s. 1394-1403Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

     Increasing antibiotic resistance makes the identification of new antibacterial principles an urgent task. The thioredoxin system including thioredoxinreductase (TrxR), thioredoxin (Trx), and NADPH plays critical roles in cellular DNA synthesis and defense against oxidative stress. Notably, TrxR is very different in structure and mechanism in mammals and bacteria. Ebselen [2-phenyl-1,2 benzisoselenazol-3(2H)-one], a well-known antioxidant and a substrate for mammalian TrxR and Trx, is rapidly bacteriocidal for methicillin-resistant Staphylococcus aureus by an unknown mechanism. We have discovered that ebselen is a competitive inhibitor of Escherichia coli TrxR with a K-i of 0.52 +/- 0.13 mu M, through reaction with the active site dithiol of the enzyme. Bacteria lacking glutathione (GSH) and glutaredoxin, in which TrxR and Trx are essential for DNA synthesis, were particularly sensitive to ebselen. In growth-inhibited E. coli strains, Trx1 and Trx2 were oxidized, demonstrating that electron transfer via thioredoxin was blocked. Ebselen and its sulfur analog ebsulfur were bactericidal for GSH-negative pathogens. Ebsulfur inhibited a clinically isolated Helicobacter pylori strain with a minimum inhibitory concentration value as low as 0.39 mu g/ml. These results demonstrate that bacterial Trx and TrxR are viable antibacterial drug targets using benzisoselenazol and benzisothiazol derivates.-Lu, J., Vlamis-Gardikas, A., Kandasamy, K., Zhao, R., Gustafsson, T. N., Engstrand, L., Hoffner, S., Engman, L., Holmgren, A. Inhibition of bacterial thioredoxin reductase: an antibiotic mechanism targeting bacteria lacking glutathione. 

  • 26. Lu, Jun
    et al.
    Vodnala, Suman K.
    Gustavsson, Anna-Lena
    Gustafsson, Tomas N
    Sjöberg, Birger
    Johansson, Henrik A
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC.
    Kumar, Sangit
    Tjernberg, Agneta
    Engman, Lars
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC.
    Rottenberg, Martin E
    Holmgren, Arne
    Ebsulfur is a benzisothiazolone cytocidal inhibitor targeting the trypanothione reductase of Trypanosoma brucei2013Inngår i: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 288, nr 38, s. 27456-27468Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Trypanosoma brucei is the causing agent of African trypanosomiasis. These parasites possess a unique thiol redox system required for DNA synthesis and defense against oxidative stress. It includes trypanothione and trypanothione reductase (TryR) instead of the thioredoxin and glutaredoxin systems of mammalian hosts. Here, we show that the benzisothiazolone compound ebsulfur (EbS), a sulfur analogue of ebselen, is a potent inhibitor of T. brucei growth with a favorable selectivity index over mammalian cells. EbS inhibited the TryR activity and decreased non-protein thiol levels in cultured parasites. The inhibition of TryR by EbS was irreversible and NADPH-dependent. EbS formed a complex with TryR and caused oxidation and inactivation of the enzyme. EbS was more toxic for T. brucei than for Trypanosoma cruzi, probably due to lower levels of TryR and trypanothione in T. brucei. Furthermore, inhibition of TryR produced high intracellular reactive oxygen species. Hydrogen peroxide, known to be constitutively high in T. brucei, enhanced the EbS inhibition of TryR. The elevation of reactive oxygen species production in parasites caused by EbS induced a programmed cell death. Soluble EbS analogues were synthesized and cured T. brucei brucei infection in mice when used together with nifurtimox. Altogether, EbS and EbS analogues disrupt the trypanothione system, hampering the defense against oxidative stress. Thus, EbS is a promising lead for development of drugs against African trypanosomiasis.

  • 27.
    Lu, Xi
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Tillämpad materialvetenskap.
    Mestres, Gemma
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Mikrosystemteknik.
    Singh, Vijay Pal
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Organisk kemi.
    Effati, Pedram
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Tillämpad materialvetenskap.
    Poon, Jia-Fei
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Organisk kemi.
    Engman, Lars
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Organisk kemi.
    Marjam, Karlsson Ott
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Tillämpad materialvetenskap.
    Selenium- and tellurium-based antioxidants for modulating inflammation and effects on osteoblastic activity2017Inngår i: Antioxidants, E-ISSN 2076-3921, Vol. 6, nr 13, s. 1-13Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Increased oxidative stress plays a significant role in the etiology of bone diseases. Heightened levels of H2O2 disrupt bone homeostasis, leading to greater bone resorption than bone formation. Organochalcogen compounds could act as free radical trapping agents or glutathione peroxidase mimetics, reducing oxidative stress in inflammatory diseases. In this report, we synthesized and screened a library of organoselenium and organotellurium compounds for hydrogen peroxide scavenging activity, using macrophagic cell lines RAW264.7 and THP-1, as well as human mono- and poly-nuclear cells. These cells were stimulated to release H2O2, using phorbol 12-myristate 13-acetate, with and without organochalogens. Released H2O2 was then measured using a chemiluminescent assay over a period of 2 h. The screening identified an organoselenium compound which scavenged H2O2 more effectively than the vitamin E analog, Trolox. We also found that this organoselenium compound protected MC3T3 cells against H2O2 -induced toxicity, whereas Trolox did not. The organoselenium compound exhibited no cytotoxicity to the cells and had no deleterious effects on cell proliferation, viability, or alkaline phosphatase activity. The rapidity of H2O2 scavenging and protection suggests that the mechanism of protection is due to the direct scavenging of extracellular H2O2. This compound is a promising modulators of inflammation and could potentially treat diseases involving high levels of oxidative stress.

  • 28.
    Malmström, Jonas
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Fysikalisk-kemiska institutionen.
    Jonsson, Mats
    Cotgreave, Ian A.
    Hammarström, Leif
    Institutionen för fotokemi och molekylärvetenskap.
    Sjödin, Martin
    Institutionen för fotokemi och molekylärvetenskap.
    Engman, Lars
    Institutionen för biokemi och organisk kemi.
    The Antioxidant Profile of 2,3-Dihydrobenzo[b]furan-5-ol and its 1-Thio, 1-Seleno, and 1-Telluro Analogues2001Inngår i: Journal of the American Chemical Society, Vol. 123, nr 15, s. 3434-3440Artikkel i tidsskrift (Fagfellevurdert)
  • 29. McNaughton, Michael
    et al.
    Engman, Lars
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Kemiska institutionen. Institutionen för biokemi och organisk kemi, Organisk kemi I. Organisk kemi.
    Birmingham, A.
    Powis, G.
    Cotgreave, I.A.
    Cyclodextrin-Derived Diorganyl Tellurides as Glutathione Peroxidase Mimics and Inhibitors of Thioredoxin Reductase and Cancer Cell Growth2004Inngår i: J. Med. Chem., nr 47, s. 233-239Artikkel i tidsskrift (Fagfellevurdert)
  • 30.
    Mestres, Gemma
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Tillämpad materialvetenskap.
    Santos, Carlos F
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Tillämpad materialvetenskap.
    Engman, Lars
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC.
    Persson, Cecilia
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Tillämpad materialvetenskap.
    Karlsson Ott, Marjam
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Tillämpad materialvetenskap.
    Scavenging effect of Trolox released from brushite cements2015Inngår i: Acta Biomaterialia, ISSN 1742-7061, E-ISSN 1878-7568, Vol. 11, s. 459-466Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In this study a brushite cement was doped with the chain-breaking antioxidant Trolox. The effect of the antioxidant on the physical properties of the cement was evaluated and the release of Trolox was monitored by UV spectroscopy. The ability of the Trolox set free to scavenge reactive oxygen species (ROS) released by macrophages was determined in vitro using a luminol-amplified chemiluminescence assay. Trolox did not modify the crystalline phases of the set cement, which mainly formed crystalline brushite after 7days in humid conditions. The setting time, compressive strength and morphology of the cement also remained unaltered after the addition of the antioxidant. Trolox was slowly released from the cement following a non-Fickian transport mechanism and nearly 64% of the total amount was released after 3days. Moreover, the capacity of Trolox to scavenge the ROS released by macrophages increased in a dose-dependent manner. Trolox-loaded cements are expected to reduce some of the first harmful effects of acute inflammation and can thus potentially protect the surrounding tissue during implantation of these as well as other materials used in conjunction.

  • 31.
    Poon, Jia-fei
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Syntetisk organisk kemi.
    Singh, Vijay P.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Biokemi.
    Engman, Lars
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Syntetisk organisk kemi.
    In Search of Catalytic Antioxidants-(Alkyltelluro)phenols, (Alkyltelluro)resorcinols, and Bis(alkyltelluro)phenols2013Inngår i: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 78, nr 12, s. 6008-6015Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    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-butyllithiutn 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 alpha-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.

  • 32.
    Poon, Jia-fei
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC.
    Singh, Vijay P
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC.
    Yan, Jiajie
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC.
    Engman, Lars
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC.
    Regenerable Antioxidants - Introduction of Chalcogen Substituents into Tocopherols2015Inngår i: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 21, nr 6, s. 2447-2457Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    To improve the radical-trapping capacity of the natural antioxidants, alkylthio-, alkylseleno-, and alkyltelluro groups were introduced into all vacant aromatic positions in β-, γ- and δ-tocopherol. Reaction of the tocopherols with electrophilic chalcogen reagents generated by persulfate oxidation of dialkyl dichalcogenides provided convenient but low-yielding access to many sulfur and selenium derivatives, but failed in the case of tellurium. An approach based on lithiation of the appropriate bromo-tocopherol, insertion of chalcogen into the carbon-lithium bond, air-oxidation to a dichalcogenide, and final borohydride reduction/alkylation turned out to be generally applicable to the synthesis of all chalcogen derivatives. Whereas alkylthio- and alkylseleno analogues were generally poorer quenchers of lipid peroxyl radicals than the corresponding parents, all tellurium compounds showed a substantially improved radical-trapping activity. Introduction of alkyltelluro groups into the tocopherol scaffold also caused a dramatic increase in the regenerability of the antioxidant. In a two-phase lipid peroxidation system containing N-acetylcysteine as a water-soluble co-antioxidant the inhibition time was up to six-fold higher than that recorded for the natural antioxidants.

  • 33.
    Poon, Jia-fei
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Organisk kemi.
    Yan, Jiajie
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Organisk kemi.
    Jorner, Kjell
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - Ångström, Oorganisk kemi.
    Ottosson, Henrik
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - Ångström, Oorganisk kemi.
    Donau, Carsten
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Organisk kemi.
    Singh, Vijay P.
    Department of Chemistry & Centre of Advanced Studies in Chemistry, Panjab University, Chandigarh, India.
    Gates, Paul J.
    School of Chemistry, University of Bristol, United Kingdom.
    Engman, Lars
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Organisk kemi.
    Substituent Effects in Chain-Breaking Aryltellurophenol Antioxidants2018Inngår i: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 24, nr 14, s. 3520-3527Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    2-Aryltellurophenols substituted in the aryltelluro or phenolic part of the molecule were prepared by lithiation of the corresponding O-THP-protected 2-bromophenol, followed by reaction with a suitable diaryl ditelluride and deprotection. In a two-phase system containing N-acetylcysteine as a co-antioxidant in the aqueous phase, all compounds quenched lipid peroxyl radicals more efficiently than α-tocopherol with 3 to 5-fold longer inhibition times. Compounds carrying electron donating para-substituents in the phenolic or aryltelluro part of the molecule showed the best results. The mechanism for quenching of peroxyl radicals was discussed in the light of calculated OH bond dissociation energies, deuterium labeling experiments and studies of thiol-consumption in the aqueous phase. 

  • 34.
    Poon, Jia-Fei
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Organisk kemi.
    Yan, Jiajie
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Organisk kemi.
    Singh, Vijay P
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Organisk kemi.
    Gates, Paul J
    Univ Bristol, Sch Chem, Bristol BS8 1TS, Avon, England.
    Engman, Lars
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Organisk kemi.
    Alkyltelluro Substitution Improves the Radical-Trapping Capacity of Aromatic Amines2016Inngår i: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 22, nr 36, s. 12891-12903Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The synthesis of a variety of aromatic amines carrying an ortho-alkyltelluro group is described. The new antioxidants quenched lipidperoxyl radicals much more efficiently than α-tocopherol and were regenerable by aqueous-phase N-acetylcysteine in a two-phase peroxidation system. The inhibition time for diaryl amine 9 b was four-fold longer than recorded with α-tocopherol. Thiol consumption in the aqueous phase was found to correlate inversely to the inhibition time and the availability of thiol is the limiting factor for the duration of antioxidant protection. The proposed mechanism for quenching of peroxyl radicals involves O-atom transfer from peroxyl to Te followed by H-atom transfer from amine to alkoxyl radical in a solvent cage.

  • 35.
    Poon, Jia-fei
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Organisk kemi.
    Yan, Jiajie
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Organisk kemi.
    Singh, Vijay P.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Organisk kemi.
    Gates, Paul J.
    School of Chemistry, University of Bristol, Bristol BS8 1TS, United Kingdom.
    Engman, Lars
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Organisk kemi.
    Regenerable Radical-Trapping Tellurobistocopherol Antioxidants2016Inngår i: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 81, nr 24, s. 12540-12544Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Tellurobistocopherols 911 were prepared by lithiation of the corresponding bromotocopherols, reaction with tellurium tetrachloride and reductive workup. Compounds 911 quenched linoleic-acid-derived peroxyl radicals much more efficiently than α-tocopherol in a chlorobenzene/water two-phase system. N-Acetylcysteine or tris(2-carboxylethyl)phosphine as co-antioxidants in the aqueous phase could regenerate the tellurobistocopherols and increase their inhibition times. Antioxidant 11 inhibited peroxidation for 7-fold longer than that recorded with α-tocopherol. Thiol consumption in the aqueous phase was monitored and found to be inversely related to the inhibition time.

  • 36.
    Pujari-Palmer, Shiuli
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Tillämpad materialvetenskap.
    Lu, Xi
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Tillämpad materialvetenskap.
    Singh, Vijay P.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Organisk kemi.
    Engman, Lars
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Organisk kemi.
    Pujari-Palmer, Michael
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Tillämpad materialvetenskap.
    Karlsson Ott, Marjam
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Tillämpad materialvetenskap.
    Incorporation and delivery of an organoselenium antioxidant from a brushite cement2017Inngår i: Materials letters (General ed.), ISSN 0167-577X, E-ISSN 1873-4979, Vol. 197, s. 115-119Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    An inflammatory reaction occurs following biomaterial implantation in the body, which produce toxic byproducts such as reactive oxygen species (ROS). Although ROS is required to clear the wound, excessive ROS can damage the tissue around the implant site, eventually leading to implant failure. One approach to control the inflammatory response is to incorporate an antioxidant into the biomaterial in order to scavenge ROS produced by activated phagocytes. In the present study, an organoselenium antioxidative compound was incorporated into a brushite cement, with the goal of scavenging ROS generated from activated primary human mononuclear leukocytes (MNCs), in vitro. The effect of the antioxidant on the physical properties of brushite cement, and its release from the cement were investigated via compressive strength, setting time, phase composition, and UV spectroscopy analysis. The physical properties of brushite remained unchanged following incorporation of the antioxidant. The antioxidant was slowly released from the cement, following a non-Fickian transport mechanism, with approximately 60% of the loaded antioxidant released over five days. The released antioxidant was then tested for its ability to scavenge ROS released by MNCs using the luminol amplified chemiluminescence assay. The results show that antioxidative released at both early stages (24 h) and late stages (120 h) retained its scavenging capacity and effectively reduced ROS production. These results indicate that brushite cements loaded with organoselenium compounds can modulate ROS production after implantation and potentially modulate the inflammatory response to improve device integration.

  • 37.
    Reiser, Kathrin
    et al.
    Karolinska Inst, Div Clin Microbiol, Dept Lab Med, F68, Huddinge, Sweden..
    Mathys, Leen
    Katholieke Univ Leuven, Rega Inst Med Res, Minderbroederstr 10, Leuven, Belgium..
    Curbo, Sophie
    Karolinska Inst, Div Clin Microbiol, Dept Lab Med, F68, Huddinge, Sweden..
    Pannecouque, Christophe
    Katholieke Univ Leuven, Rega Inst Med Res, Minderbroederstr 10, Leuven, Belgium..
    Noppen, Sam
    Katholieke Univ Leuven, Rega Inst Med Res, Minderbroederstr 10, Leuven, Belgium..
    Liekens, Sandra
    Katholieke Univ Leuven, Rega Inst Med Res, Minderbroederstr 10, Leuven, Belgium..
    Engman, Lars
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC.
    Lundberg, Mathias
    Karolinska Inst, Div Clin Microbiol, Dept Lab Med, F68, Huddinge, Sweden..
    Balzarini, Jan
    Katholieke Univ Leuven, Rega Inst Med Res, Minderbroederstr 10, Leuven, Belgium..
    Karlsson, Anna
    Karolinska Inst, Div Clin Microbiol, Dept Lab Med, F68, Huddinge, Sweden..
    The Cellular Thioredoxin-1/Thioredoxin Reductase-1 Driven Oxidoreduction Represents a Chemotherapeutic Target for HIV-1 Entry Inhibition2016Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, nr 1, artikkel-id e0147773Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background The entry of HIV into its host cell is an interesting target for chemotherapeutic intervention in the life-cycle of the virus. During entry, reduction of disulfide bridges in the viral envelope glycoprotein gp120 by cellular oxidoreductases is crucial. The cellular thioredoxin reductase-1 plays an important role in this oxidoreduction process by recycling electrons to thioredoxin-1. Therefore, thioredoxin reductase-1 inhibitors may inhibit gp120 reduction during HIV-1 entry. In this present study, tellurium-based thioredoxin reductase-1 inhibitors were investigated as potential inhibitors of HIV entry. Results The organotellurium compounds inhibited HIV-1 and HIV-2 replication in cell culture at low micromolar concentrations by targeting an early event in the viral infection cycle. Time-of-drug-addition studies pointed to virus entry as the drug target, more specifically: the organotellurium compound TE-2 showed a profile similar or close to that of the fusion inhibitor enfuvirtide (T-20). Surface plasmon resonance-based interaction studies revealed that the compounds do not directly interact with the HIV envelope glycoproteins gp120 and gp41, nor with soluble CD4, but instead, dose-dependently bind to thioredoxin reductase-1. By inhibiting the thioredoxin-1/thioredoxin reductase-1-directed oxidoreduction of gp120, the organotellurium compounds prevent conformational changes in the viral glycoprotein which are necessary during viral entry. Conclusion Our findings revealed that thioredoxin-1/thioredoxin reductase-1 acts as a cellular target for the inhibition of HIV entry.

  • 38.
    Shanks, David
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Kemiska institutionen, Avdelningen för organisk kemi.
    Al-Maharik, Nawaf
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Kemiska institutionen, Avdelningen för organisk kemi.
    Malmström, Jonas
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Kemiska institutionen, Avdelningen för organisk kemi.
    Engman, Lars
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Kemiska institutionen, Avdelningen för organisk kemi.
    Eriksson, Petter
    Stenberg, Bengt
    Reitberger, Torbjörn
    Improved Antioxidant Formulations for Polymeric Materials: Synergistic Protective Effects in Combinations of Organotellurium Compounds with Conventional Phenolic Antioxidants or Thiols2003Inngår i: Polymer degradation and stability, ISSN 0141-3910, E-ISSN 1873-2321, Vol. 81, nr 2, s. 261-271Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    As judged by differential scanning calorimetry experiments at 190 °C and chemiluminescence measurements at 150 °C, addition of 0.10–0.30 wt.% of certain organotellurium compounds to polypropylene caused a notable protection against oxidation of the material. The best stabilizers (diaryl telluride 3 and alkyl aryl telluride 4), offered a similar degree of protection as commercial stabilizer formulations comprising a mixture of Irganox® 1010 and Irgafos® 168 (0.1 wt.% of each). The protective effect of the organotelluriums was substantially improved in combinations with sterically hindered phenols or thiols. The protection was often much better than the added effects of the individual components and, thus, can be considered as synergistic. Evaluation of a series of stabilizers where tellurium had been exchanged for selenium and sulfur (compounds 2) showed that the synergistic protective effect was unique for tellurium.

  • 39.
    Shanks, David
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Kemiska institutionen, Avdelningen för organisk kemi.
    Berlin, Stefan
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Kemiska institutionen, Avdelningen för organisk kemi.
    Besev, Magnus
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Kemiska institutionen, Avdelningen för organisk kemi.
    Ottosson, Henrik
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Kemiska institutionen, Avdelningen för organisk kemi.
    Engman, Lars
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Kemiska institutionen, Avdelningen för organisk kemi.
    On the origin of cis selectivity in the cyclization of N-protected 2-substituted 3-aza-5-hexenyl radicals: a density functional study2004Inngår i: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 69, nr 5, s. 1487-1491Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Cyclization of the N-dimethylphosphinoyl-2-methyl-3-aza-5-hexenyl radical has been studied at the UB3LYP/6-31+G(d)//UB3LYP/6-31G(d) hybrid density functional level. The corresponding radical precursor has been synthesized and found to give cis/trans ratios of up to 10/1 in reductive radical cyclizations. The relative energies of reactant and transition state conformers were determined. In discord with the Beckwith-Houk model, it has been found that chair-axial transition states, which lead to cis products, are lowest in energy, rationalizing the observed experimental diastereoselectivity.

  • 40.
    Shanks, David
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi, Organisk kemi I.
    Engman, Lars
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi, Organisk kemi I.
    Pach, Mayte
    Norrby, Thomas
    Probing the antioxidative properties of combinations of an organotellurium compound, BHT and thiol in oil2006Inngår i: Lubrication Science, ISSN 0954-0075, E-ISSN 1557-6833, Vol. 18, nr 2, s. 87-94Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Differential scanning calorimetry experiments with an unsaturated polyolester oil at 190˚C showed that an organotellurium compound in combination with a thiol or a sterically hindered phenol (BHT) could act in a synergistic fashion to protect the material form oxidation. Under more realistic conditions for an oil antioxidant (elevated temperature in the presence of oxygen, water and a copper coil; rotating pressure vessel oxidation test) the antioxidant protection offered by BHT itself at similar concentrations. In order for the novel antioxidant systems to become useful for protection of oils and fluids, more robust organotellurium compounds must be prepared.

  • 41.
    Shanks, David
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi, Organisk kemi I. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi, Organisk kemi II. Organisk kemi.
    Frisell, Håkan
    Ottosson, Henrik
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi, Organisk kemi I. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi, Organisk kemi II. Organisk kemi.
    Engman, Lars
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi, Organisk kemi I. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi, Organisk kemi II. Organisk kemi.
    Design principles for a-tocopherol analogues2006Inngår i: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 4, s. 846-852Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    An (RO)B3LYP/LANL2DZdp//B3LYP/LANL2DZ model for the prediction of the homolytic bond dissociation enthalpy (BDE) and adiabatic ionisation potential (IP) of phenolic antiocidants containing heavy chalcogens has been developed. The model has been used to probe the relationship between geometry, chalcogen substitution and activity for a series of a-tocopherol analogues of varying ring size. From this, a series of design principles for cyclic antioxidants has emerged, embodied by the compound 4-hydroxy-2,2,3,5,6-pentamethylbenzoselenete (4c). This compound is predicted to have a BDE comparable to a-tocopherol, and should act in a dual chain-breaking and hydroperoxide-decomposing manner, by analogy with other selenide antioxidants. The stability of chalcogen-substituted benzoxetes was considered, and the as yet unsynthesised benzotelluretes are predicted to be stable. Finally, an attempt was made to determine antioxidant mechanism by considering calculated BDE and IP data together with experimental rate data.

  • 42.
    Singh, Vijay P
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Syntetisk organisk kemi.
    Poon, Jia-fei
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Syntetisk organisk kemi.
    Butcher, Ray J.
    Department of Chemistry, Howard University, USA..
    Lu, Xi
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Tillämpad materialvetenskap.
    Mestres, Gemma
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Tillämpad materialvetenskap.
    Karlsson Ott, Marjam
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Tillämpad materialvetenskap.
    Engman, Lars
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Syntetisk organisk kemi.
    Effect of a Bromo Substituent on the Glutathione Peroxidase Activity of a Pyridoxine-like Diselenide2015Inngår i: The Journal of Organic Chemistry, Vol. 50, nr 15, s. 7385-7395Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In search for better mimics of the glutathioneperoxidase enzymes, pyridoxine-like diselenides 6 and 11,carrying a 6-bromo substituent, were prepared. Reaction of2,6-dibromo-3-pyridinol 5 with sodium diselenide provided 6via aromatic nucleophilic substitution of the 2-bromosubstituent. LiAlH4 caused reduction of all four ester groupsand returned 11 after acidic workup. The X-ray structure of 6showed that the dipyridyl diselenide moiety was kept in analmost planar, transoid conformation. According to NBOanalysis,this was due to weak intramolecular Se···O (1.1 kcal/mol) and Se···N-interactions (2.5 kcal/mol). That the 6-bromo substituent increased the positive charge on seleniumwas confirmed by NPA-analysis and seen in calculated andobserved 77Se NMR-shifts. Diselenide 6 showed a more than 3-fold higher reactivity than the corresponding des-bromocompound 3a and ebselen when evaluated in the coupled reductase assay. Experiments followed for longer time (2 h) confirmedthat diselenide 6 is a better GPx-catalyst than 11. On the basis of 77Se-NMR experiments, a catalytic mechanism for diselenide 6was proposed involving selenol, selenosulfide and seleninic acid intermediates. At low concentration (10 μM) where it showedonly minimal toxicity, it could scavenge ROS produced by MNC- and PMNC-cells more efficiently than Trolox.

  • 43.
    Singh, Vijay P.
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Syntetisk organisk kemi.
    Poon, Jia-fei
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Syntetisk organisk kemi.
    Engman, Lars
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Syntetisk organisk kemi.
    Turning Pyridoxine into a Catalytic Chain-Breaking and Hydroperoxide-Decomposing Antioxidant2013Inngår i: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 78, nr 4, s. 1478-1487Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Vitamin B6 is involved in a variety of enzymatic transformations. Some recent findings also indicate an antioxidant role of the vitamin in biological systems. We set out to turn pyridoxine (la) into a catalytic chain-breaking and hydroperoxide-decomposing antioxidant by replacing the 2-methyl substituent with an alkyltelluro group. Target molecules 12 and derivatives 14, 17, 18, and 20 thereof were accessed by subjecting suitably substituted 2-halopyridin-3-ols to aromatic substitution using sodium alkanetellurolates as nucleophiles and then LAH-reduction of ester groups. The novel pyridoxine compounds were found to inhibit azo-initiated peroxidation of linoleic acid an order of magnitude more efficiently than alpha-tocopherol in a water/chlorobenzene two-phase system containing N-acetylcysteine as a reducing agent in the aqueous phase. The most lipid-soluble pyridoxine derivative 20c was regenerable and could inhibit peroxidation for substantially longer time (>410 min) than alpha-tocopherol (87 min). The chalcogen-containing pyridoxines could also mimic the action of the glutathione peroxidase enzymes. Thus, compound 20a catalyzed reduction of hydrogen peroxide three times more efficiently than Ebselen in the presence of glutathione as a stoichiometric reducing agent

  • 44.
    Singh, Vijay P.
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Organisk kemi. Centre of Advanced Studies in Chemistry, Panjab University, India.
    Yan, Jiajie
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Organisk kemi.
    Poon, Jia-fei
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Organisk kemi.
    Gates, Paul J.
    School of Chemistry, University of Bristol, United Kingdom.
    Butcher, Ray J.
    Department of Chemistry, Howard University, USA.
    Engman, Lars
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Organisk kemi.
    Chain-Breaking Phenolic 2,3-Dihydrobenzo[b]selenophene Antioxidants: Proximity Effects and Regeneration Studies2017Inngår i: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 23, nr 60, s. 15080-15088Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Phenolic 2,3-dihydrobenzo[b]selenophene anti-oxidants carrying the OH-group ortho (9), meta (10, 11) and para (8) to the Se were prepared by seleno-Claisen rearrangement/intramolecular hydroselenation. Meta-isomer (11) was studied by X-ray crystallography. The radical-trapping activity and regenerability of compounds 8-11 were evaluated using a two-phase system where linoleic acid was undergoing peroxidation in the lipid phase while regeneration of the antioxidant by co-antioxidants (N-acetylcysteine, glutathione, dithiothreitol, ascorbic acid, tris(carboxyethyl)phosphine hydrochloride) was ongoing in the aqueous layer. Compound 9 quenched peroxyl radicals

    more efficiently than α-tocopherol. It also provided the most long-lasting antioxidant protection. With thiol co-antioxidants it could inhibit peroxidation for more than five-fold longer than the natural product. Regeneration was more efficient when the aqueous phase pH was slightly acidic. Since calculated O-H bond dissociation energies for 8-11 were substantially larger than for α-tocopherol, an antioxidant mechanism involving O-atom transfer from peroxyl to selenium was proposed. The resulting phenolic selenoxide/alkoxyl radical would then exchange a hydrogen atom in a solvent cage before antioxidant regeneration at the aqueous lipid interphase.

  • 45.
    Singh, Vijay
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Syntetisk organisk kemi.
    Poon, Jia-fei
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Syntetisk organisk kemi.
    Butcher, Ray
    Dpt of Chemistry, Howard University.
    Engman, Lars
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Syntetisk organisk kemi.
    Pyridoxine-derived organoselenium compounds with glutathione peroxidase-like and chain-breaking antioxidant activity2014Inngår i: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 20, nr 39, s. 12563-12571Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    One of the vitamin B6 vitamers, pyridoxine, wasmodified to incorporate selenium in various oxidation statesin place of the methyl group in position 2. Such compoundswere conveniently accessed by treatment of bis-4,5-(carbo-ethoxy)-2-iodo-3-pyridinol with disodium diselenide andLiAlH4-reduction. After work-up, selone7was isolated ingood yield as an air-stable crystalline material. Hydrogenbonding to the neighboring hydroxyl group, as revealed bythe short intramolecular Se···H distance in the crystal struc-ture is likely to provide extra stabilization to the compound.Computational studies showed that selone7is more stablethan the corresponding selenol tautomer by 12.2 kcalmol1.Hydrogen peroxide oxidation of the selone7afforded di-selenide12, and, on further oxidation, seleninic acid13.Treatment of the seleninic acid with thiophenol provided anisolable selenosulfide14. The glutathione peroxidase-likeproperties of the pyridoxine-derived compounds were as-sessed by using the coupled reductase method. Seleninicacid13was found to be twofold more active than ebselen.The chain-breaking capacity of the pyridoxine compoundswere studied in a water/chlorobenzene membrane modelcontaining linoleic acid as an oxidizable substrate andN-ace-tylcysteine as a thiol reducing agent. Diselenide15couldmatcha-tocopherol when it comes to reactivity towardsperoxyl radicals and inhibition time.

  • 46.
    Singh, Vijay
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC.
    Poon, Jia-fei
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC.
    Engman, Lars
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC.
    Catalytic Antioxidants: Regenerable Tellurium Analogues of Vitamin E2013Inngår i: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052, Vol. 15, nr 24, s. 6274-6277Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In an effort to improve the chain-breaking capacity of the natural antioxidants, an octyltelluro group was introduced next to the phenolic moiety in β- and δ-tocopherol. The new vitamin E analogues quenched peroxyl radicals more efficiently than α-tocopherol and were readily regenerable by aqueous N-acetylcysteine in a simple membrane model composed of a stirring chlorobenzene/water two-phase system. The novel tocopherol analogues could also mimic the action of the glutathione peroxidase enzymes.

  • 47. Smirnova, Joulia
    et al.
    Engman, Lars
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Kemiska institutionen. Institutionen för biokemi och organisk kemi, Organisk kemi I. Organisk kemi.
    Andersson, Carl-Magnus
    Malm, Johan
    An organoiron approach to thyroid hormone analogues2005Inngår i: Journal of Organo metallic Chemistry, Vol. 690, s. 1784-1792Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    An approach to thyroid hormone analogues was proposed involving sequential substitution of cationic cyclopentadienyl(1.4-dichlorobenzene)iron(II) complexes with phenoxide/thiophenoxide and hydroxide/amine, followed by decomplexation. Although the selectivity for monosubstitution with phenolates and thiophenolates was poorer than previously observed, it was often possible to control the reaction with sterically less demanding phenolates of intermediate nucleophilicity. The subsequent introduction of a polar substituent into the monosubstituted product was successful with amine nucleophiles. A modified approach, based on the reverse order of substitution was also attempted. Whereas clean monosubstitution with hydroxide/hydroxide equivalents was unsuccessful, cyclopentadienyl(N-alkyl-1-chloro-4-aminobenzene)iron(II) complexes could be prepared in fair yields and further substituted with nucleophiles such as thiophenolates.

  • 48.
    Srivastava, Puneet
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi.
    Engman, Lars
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för biokemi och organisk kemi.
    A radical cyclization route to cyclic imines2010Inngår i: Tetrahedron Letters, ISSN 0040-4039, E-ISSN 1359-8562, Vol. 51, nr 8, s. 1149-1151Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A novel route to cyclic imines based on 5-exo radical cyclization is explored. The radical precursors are imines prepared from allylamine and readily available alpha-phenylselenenyl ketones.

  • 49. Stuhr-Hansen, Nicolai
    et al.
    Beckers, Edwin H. A.
    Engman, Lars
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Kemiska institutionen. Institutionen för biokemi och organisk kemi, Organisk kemi I. organisk kemi.
    Janssen, René A.J.
    Organoselenium-Substituted Poly(p-phenylenevinylene)2005Inngår i: Heteroatom Chemistry, Vol. 16, nr 7, s. 656-662Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A new type of conjugated polymer, organoselenium substituted poly(p-pheylenevinylene) (PPV), was synthesized from the corresponding alkylselenenyl p-xylylene dibromide via a Gilch route using potassium tert-butoxide in THF. The p-xylylene dibromide precursors were synthesized by reacting lithiated bis(methoxymethyl)benzenes with elemental selenium, followed by alkylation of the generated selenolates. As a final demasking step, the bromomethyl functions were liberated by ether cleavage using boron tribromide. Bis-alkylselenenyl PPV was obtained with an average molecular weight Mw of approximately 300,000 g/mol and with polydispersity Mw/Mn=2. Due to low solubility, monoalkylselenenyl PPV was obtained with a considerably lower average molecular weight in the proximity of 16,000 g/mol and with a polydispersity slightly larger than 3. Absorption and flourescence spectroscopy revealed that the bis-alkylselenenyl PPV is extensively conjugated.

  • 50.
    Yan, Jiajie
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC.
    Poon, Jia-fei
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC.
    Singh, Vijay P
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC.
    Gates, Paul
    Engman, Lars
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC.
    Regenerable thiophenolic radical-trapping antioxidants2015Inngår i: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052, Vol. 17, nr 24, s. 6162-6165Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Diphenyl disulfides carrying alkyltelluro groups in the o-, m-, and p-positions were prepared using ortho-lithiation and lithium halogen exchange reactions. The novel antioxidants showed only minimal inhibitory effect on the azo-initiated peroxidation of linoleic acid in chlorobenzene until reduced to the corresponding thiophenols by tris(2-carboxyethyl)phosphine (TCEP). The best in situ generated thiophenol (from 7c) under these conditions quenched peroxyl radicals more efficiently than α-tocopherol with an almost 3-fold increase in inhibition time.

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