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  • 1.
    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 Ebselenols2016Ingår i: Angewandte Chemie International Edition, ISSN 1433-7851, E-ISSN 1521-3773, Vol. 55, nr 11, s. 3729-3733Artikel i tidskrift (Refereegranskat)
    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.

  • 2.
    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 activity2017Ingår i: Antioxidants, E-ISSN 2076-3921, Vol. 6, nr 13, s. 1-13Artikel i tidskrift (Refereegranskat)
    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.

  • 3.
    Poon, Jia-fei
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Organisk kemi.
    Exploring Catalytic Tellurium-Based Antioxidants: Synthesis and Evaluation2016Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    This thesis is concerned with the synthesis and evaluation of various tellurium-based chain-breaking antioxidants. The purpose is to find novel regenerable compounds with improved radical-trapping capacity.

    In the first part of this work, we explore the possibilities to incorporate tellurium into tocopherols and aromatic amines. Overall, tocopherols carrying alkyltelluro groups are better radical-trapping agents than the corresponding sulfur- and selenium analogues. Among them, 7-octyltelluro δ-tocopherol showed a ca. 17-fold higher reactivity than recorded for α-tocopherol and much better regenerability. Even longer inhibition times were recorded for the corresponding bis(tocopheryl) tellurides. In the aromatic amine series, diphenyl amines carrying alkyltelluro groups were shown to function as efficient radical-quenchers capable of inhibiting peroxidation for 460 min in the presence of N-acetylcysteine. Thiol-consumption experiments suggested that the long inhibition times are due to efficient quenching of in-situ formed alkoxyl radicals in a solvent cage.

    In the second part of the thesis, we study how the antioxidant properties are affected by variations in the electron density at tellurium and the number of alkyltelluro substituents in the molecule. Evaluation of a series of aryltelluro phenols carrying electron donating and electron withdrawing groups in the para-position of the aryl moiety suggested that a high electron density at the heteroatom prolonged the inhibition time. Among alkyltelluro phenols, alkyltelluro resorcinols and bis(alkyltelluro) phenols, phenols carrying alkyltelluro groups in both ortho positions were superior when it comes to radical-trapping activity and regenerability.

    Delarbeten
    1. Catalytic Antioxidants: Regenerable Tellurium Analogues of Vitamin E
    Öppna denna publikation i ny flik eller fönster >>Catalytic Antioxidants: Regenerable Tellurium Analogues of Vitamin E
    2013 (Engelska)Ingår i: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052, Vol. 15, nr 24, s. 6274-6277Artikel i tidskrift (Refereegranskat) Published
    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.

    Nationell ämneskategori
    Naturvetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-213569 (URN)10.1021/ol403131t (DOI)000329077700042 ()
    Tillgänglig från: 2013-12-28 Skapad: 2013-12-28 Senast uppdaterad: 2017-12-06Bibliografiskt granskad
    2. Regenerable Antioxidants - Introduction of Chalcogen Substituents into Tocopherols
    Öppna denna publikation i ny flik eller fönster >>Regenerable Antioxidants - Introduction of Chalcogen Substituents into Tocopherols
    2015 (Engelska)Ingår i: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 21, nr 6, s. 2447-2457Artikel i tidskrift (Refereegranskat) Published
    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.

    Nationell ämneskategori
    Kemi
    Identifikatorer
    urn:nbn:se:uu:diva-243231 (URN)10.1002/chem.201405895 (DOI)000348510400023 ()
    Anmärkning

    De två första författarna delar förstaförfattarskapet.

    Tillgänglig från: 2015-02-05 Skapad: 2015-02-05 Senast uppdaterad: 2017-12-05Bibliografiskt granskad
    3. Regenerable Radical-Trapping Tellurobistocopherol Antioxidants
    Öppna denna publikation i ny flik eller fönster >>Regenerable Radical-Trapping Tellurobistocopherol Antioxidants
    Visa övriga...
    2016 (Engelska)Ingår i: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 81, nr 24, s. 12540-12544Artikel i tidskrift (Refereegranskat) Published
    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.

    Nationell ämneskategori
    Organisk kemi
    Identifikatorer
    urn:nbn:se:uu:diva-302464 (URN)10.1021/acs.joc.6b02450 (DOI)000390180100051 ()
    Anmärkning

    Authors in list of papers in thesis: Poon, J.; Yan, J.; Gates, P.; Engman, L.

    Tillgänglig från: 2016-09-04 Skapad: 2016-09-04 Senast uppdaterad: 2017-11-21Bibliografiskt granskad
    4. Alkyltelluro Substitution Improves the Radical-Trapping Capacity of Aromatic Amines
    Öppna denna publikation i ny flik eller fönster >>Alkyltelluro Substitution Improves the Radical-Trapping Capacity of Aromatic Amines
    Visa övriga...
    2016 (Engelska)Ingår i: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 22, nr 36, s. 12891-12903Artikel i tidskrift (Refereegranskat) Published
    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.

    Nyckelord
    antioxidants; amines; chain-breaking activity; organotellurium; regenerable
    Nationell ämneskategori
    Organisk kemi
    Identifikatorer
    urn:nbn:se:uu:diva-302460 (URN)10.1002/chem.201602377 (DOI)000383758200044 ()27484352 (PubMedID)
    Forskningsfinansiär
    Vetenskapsrådet, 621-2011-4006
    Tillgänglig från: 2016-09-04 Skapad: 2016-09-04 Senast uppdaterad: 2017-11-21Bibliografiskt granskad
    5. In Search of Catalytic Antioxidants-(Alkyltelluro)phenols, (Alkyltelluro)resorcinols, and Bis(alkyltelluro)phenols
    Öppna denna publikation i ny flik eller fönster >>In Search of Catalytic Antioxidants-(Alkyltelluro)phenols, (Alkyltelluro)resorcinols, and Bis(alkyltelluro)phenols
    2013 (Engelska)Ingår i: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 78, nr 12, s. 6008-6015Artikel i tidskrift (Refereegranskat) Published
    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.

    Nationell ämneskategori
    Naturvetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-205014 (URN)10.1021/jo400703w (DOI)000320979500020 ()
    Tillgänglig från: 2013-08-13 Skapad: 2013-08-13 Senast uppdaterad: 2017-12-06Bibliografiskt granskad
  • 4.
    Poon, Jia-Fei
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Syntetisk organisk kemi.
    Alao, John Patrick
    Sunnerhagen, Per
    Dinér, Peter
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Syntetisk organisk kemi.
    Azastilbenes: a cut-off to p38 MAPK inhibitors2013Ingår i: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 11, nr 27, s. 4526-4536Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Inhibitors with vicinal 4-fluorophenyl/4-pyridine rings on a five- or six-membered heterocyclic ring are known to inhibit the p38 mitogen-activated protein kinase (MAPK), which is a potential target for rheumatoid arthritis and several different types of cancer. Several substituted azastilbene-based compounds with vicinal 4-fluorophenyl/4-pyridine rings were designed using computational docking, synthesized, and evaluated in a cell-free radiometric p38[small alpha] assay. The biochemical evaluation shows that the best inhibition (down to 110 nM) is achieved for azastilbene-based compounds having an isopropylamine substituent in the 2-position of the pyridine ring. The inhibition of p38 signaling in human breast cancer cells was observed for two of the compounds.

  • 5.
    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)phenols2013Ingår i: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 78, nr 12, s. 6008-6015Artikel i tidskrift (Refereegranskat)
    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.

  • 6.
    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 Tocopherols2015Ingår i: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 21, nr 6, s. 2447-2457Artikel i tidskrift (Refereegranskat)
    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.

  • 7.
    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 Antioxidants2018Ingår i: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 24, nr 14, s. 3520-3527Artikel i tidskrift (Refereegranskat)
    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. 

  • 8.
    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 Amines2016Ingår i: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 22, nr 36, s. 12891-12903Artikel i tidskrift (Refereegranskat)
    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.

  • 9.
    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 Antioxidants2016Ingår i: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 81, nr 24, s. 12540-12544Artikel i tidskrift (Refereegranskat)
    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.

  • 10.
    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 Diselenide2015Ingår i: The Journal of Organic Chemistry, Vol. 50, nr 15, s. 7385-7395Artikel i tidskrift (Refereegranskat)
    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.

  • 11.
    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 Antioxidant2013Ingår i: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 78, nr 4, s. 1478-1487Artikel i tidskrift (Refereegranskat)
    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

  • 12.
    Singh, Vijay P.
    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.
    Yan, Jiajie
    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.
    Karlsson Ott, Marjam
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Tillämpad materialvetenskap.
    Butcher, Ray J.
    Howard Univ, Dept Chem, Washington, DC 20059 USA.
    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.
    Nitro-, Azo-, and Amino Derivatives of Ebselen: Synthesis, Structure, and Cytoprotective Effects2017Ingår i: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 82, nr 1, s. 313-321Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Novel azo-bis-ebselen compounds 7 were prepared by reduction of 7-nitro-2-aryl-1,2-benzisoselenazol-3(2H)ones 3 and 6 with sodium benzenetellurolate; NaTeC6H5, and by reaction of 2-bromo-3-nitrobenzamides with Na2Se2. The X-ray structure of 7b showed that the molecule, due to strong intramolecular secondary Se center dot center dot center dot N interactions, is completely planar. Azo-compounds 7 upon further reaction with NaTeC6H5 were reductively cleaved to provide 2 equiv of the corresponding aromatic amine. The weak Se-N bond was not stable enough to survive the reaction conditions, and diselenides 8 were isolated after workup. Whereas azo-bis-ebselens 7 were poor mimics of the glutathione peroxidase (GPx)-enzymes, nitroebselens 3, 6, and 11b and diselenides 8 were 3-6-fold more active than ebselen. Based on Se-77 NMR. spectroscopy, a catalytic cycle for diselenide 8b, involving aminoebselen 14, was proposed. As assessed by chemiluminescence measurements, the good GPx-mimics could reduce production of reactive oxygen species (ROS) in stimulated human mononuclear cells more efficiently than Trolox. No toxic effects of the, compounds were seen in MC3T3-cells at 25 mu M.

  • 13.
    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 Studies2017Ingår i: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 23, nr 60, s. 15080-15088Artikel i tidskrift (Refereegranskat)
    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.

  • 14.
    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 activity2014Ingår i: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 20, nr 39, s. 12563-12571Artikel i tidskrift (Refereegranskat)
    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.

  • 15.
    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 E2013Ingår i: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052, Vol. 15, nr 24, s. 6274-6277Artikel i tidskrift (Refereegranskat)
    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.

  • 16.
    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 antioxidants2015Ingår i: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052, Vol. 17, nr 24, s. 6162-6165Artikel i tidskrift (Refereegranskat)
    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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