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Publications (10 of 16) Show all publications
Poon, J.-f., Yan, J., Jorner, K., Ottosson, H., Donau, C., Singh, V. P., . . . Engman, L. (2018). Substituent Effects in Chain-Breaking Aryltellurophenol Antioxidants. Chemistry - A European Journal, 24(14), 3520-3527
Open this publication in new window or tab >>Substituent Effects in Chain-Breaking Aryltellurophenol Antioxidants
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2018 (English)In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 24, no 14, p. 3520-3527Article in journal (Refereed) Published
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. 

National Category
Organic Chemistry
Research subject
Chemistry with specialization in Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-329202 (URN)10.1002/chem.201704811 (DOI)000426764400024 ()29266496 (PubMedID)
Funder
Stiftelsen Olle Engkvist Byggmästare, 1016/159ÅForsk (Ångpanneföreningen's Foundation for Research and Development), 16-364
Note

Poon, J. and Yan, J. are equally contributing.

Available from: 2017-09-10 Created: 2017-09-10 Last updated: 2018-05-22Bibliographically approved
Singh, V. P., Yan, J., Poon, J.-f., Gates, P. J., Butcher, R. J. & Engman, L. (2017). Chain-Breaking Phenolic 2,3-Dihydrobenzo[b]selenophene Antioxidants: Proximity Effects and Regeneration Studies. Chemistry - A European Journal, 23(60), 15080-15088
Open this publication in new window or tab >>Chain-Breaking Phenolic 2,3-Dihydrobenzo[b]selenophene Antioxidants: Proximity Effects and Regeneration Studies
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2017 (English)In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 23, no 60, p. 15080-15088Article in journal (Refereed) Published
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.

Keywords
chain-breaking antioxidants, phenols, dihydrobenzoselenophenes, lipid peroxidation, co-antioxidants
National Category
Organic Chemistry
Research subject
Chemistry with specialization in Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-329201 (URN)10.1002/chem.201702350 (DOI)000413768900018 ()28857289 (PubMedID)
Available from: 2017-09-10 Created: 2017-09-10 Last updated: 2018-02-23Bibliographically approved
Singh, V. P., Poon, J.-f., Yan, J., Lu, X., Karlsson Ott, M., Butcher, R. J., . . . Engman, L. (2017). Nitro-, Azo-, and Amino Derivatives of Ebselen: Synthesis, Structure, and Cytoprotective Effects. Journal of Organic Chemistry, 82(1), 313-321
Open this publication in new window or tab >>Nitro-, Azo-, and Amino Derivatives of Ebselen: Synthesis, Structure, and Cytoprotective Effects
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2017 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 82, no 1, p. 313-321Article in journal (Refereed) Published
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.

National Category
Organic Chemistry Engineering and Technology
Identifiers
urn:nbn:se:uu:diva-312514 (URN)10.1021/acs.joc.6b02418 (DOI)000391781900030 ()27966348 (PubMedID)
Funder
ÅForsk (Ångpanneföreningen's Foundation for Research and Development), 16-364Stiftelsen Olle Engkvist Byggmästare, 2016/159Carl Tryggers foundation , CTS 13:346
Available from: 2017-01-10 Created: 2017-01-10 Last updated: 2017-11-29Bibliographically approved
Lu, X., Mestres, G., Singh, V. P., Effati, P., Poon, J.-F., Engman, L. & Marjam, K. O. (2017). Selenium- and tellurium-based antioxidants for modulating inflammation and effects on osteoblastic activity. Antioxidants, 6(13), 1-13
Open this publication in new window or tab >>Selenium- and tellurium-based antioxidants for modulating inflammation and effects on osteoblastic activity
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2017 (English)In: Antioxidants, E-ISSN 2076-3921, Vol. 6, no 13, p. 1-13Article in journal (Refereed) Published
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.

Keywords
antioxidants, reactive oxygen species, inflammation
National Category
Immunology Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Engineering and Technology
Identifiers
urn:nbn:se:uu:diva-315564 (URN)10.3390/antiox6010013 (DOI)000398677900012 ()
Available from: 2017-02-15 Created: 2017-02-15 Last updated: 2017-05-18Bibliographically approved
Poon, J.-F., Yan, J., Singh, V. P., Gates, P. J. & Engman, L. (2016). Alkyltelluro Substitution Improves the Radical-Trapping Capacity of Aromatic Amines. Chemistry - A European Journal, 22(36), 12891-12903
Open this publication in new window or tab >>Alkyltelluro Substitution Improves the Radical-Trapping Capacity of Aromatic Amines
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2016 (English)In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 22, no 36, p. 12891-12903Article in journal (Refereed) 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.

Keywords
antioxidants; amines; chain-breaking activity; organotellurium; regenerable
National Category
Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-302460 (URN)10.1002/chem.201602377 (DOI)000383758200044 ()27484352 (PubMedID)
Funder
Swedish Research Council, 621-2011-4006
Available from: 2016-09-04 Created: 2016-09-04 Last updated: 2017-11-21Bibliographically approved
Poon, J.-f. (2016). Exploring Catalytic Tellurium-Based Antioxidants: Synthesis and Evaluation. (Doctoral dissertation). Uppsala: Acta Universitatis Upsaliensis
Open this publication in new window or tab >>Exploring Catalytic Tellurium-Based Antioxidants: Synthesis and Evaluation
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
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.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. p. 72
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 1423
Keywords
antioxidant, tellurium, selenium, radical-trapping, chain-breaking, ROS, glutathione peroxidase, tocopherol, aromatic amine, oxidative stress
National Category
Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-302475 (URN)978-91-554-9684-5 (ISBN)
Public defence
2016-10-27, B41, BMC, Husargatan 3, Uppsala, 09:30 (English)
Opponent
Supervisors
Available from: 2016-10-03 Created: 2016-09-04 Last updated: 2016-10-03
Kumar, S., Yan, J., Poon, J.-f., Singh, V. P., Lu, X., Ott, M. K., . . . Kumar, S. (2016). Multifunctional Antioxidants: Regenerable Radical-Trapping and Hydroperoxide-Decomposing Ebselenols. Angewandte Chemie International Edition, 55(11), 3729-3733
Open this publication in new window or tab >>Multifunctional Antioxidants: Regenerable Radical-Trapping and Hydroperoxide-Decomposing Ebselenols
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2016 (English)In: Angewandte Chemie International Edition, ISSN 1433-7851, E-ISSN 1521-3773, Vol. 55, no 11, p. 3729-3733Article in journal (Refereed) Published
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.

National Category
Natural Sciences Engineering and Technology
Identifiers
urn:nbn:se:uu:diva-280006 (URN)10.1002/anie.201510947 (DOI)000371521000034 ()26879742 (PubMedID)
Funder
Swedish Research CouncilCarl Tryggers foundation , 13:346, 13:120
Available from: 2016-03-07 Created: 2016-03-07 Last updated: 2017-11-30Bibliographically approved
Poon, J.-f., Yan, J., Singh, V. P., Gates, P. J. & Engman, L. (2016). Regenerable Radical-Trapping Tellurobistocopherol Antioxidants. Journal of Organic Chemistry, 81(24), 12540-12544
Open this publication in new window or tab >>Regenerable Radical-Trapping Tellurobistocopherol Antioxidants
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2016 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 81, no 24, p. 12540-12544Article in journal (Refereed) 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.

National Category
Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-302464 (URN)10.1021/acs.joc.6b02450 (DOI)000390180100051 ()
Note

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

Available from: 2016-09-04 Created: 2016-09-04 Last updated: 2017-11-21Bibliographically approved
Singh, V. P., Poon, J.-f., Butcher, R. J., Lu, X., Mestres, G., Karlsson Ott, M. & Engman, L. (2015). Effect of a Bromo Substituent on the Glutathione Peroxidase Activity of a Pyridoxine-like Diselenide. The Journal of Organic Chemistry, 50(15), 7385-7395
Open this publication in new window or tab >>Effect of a Bromo Substituent on the Glutathione Peroxidase Activity of a Pyridoxine-like Diselenide
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2015 (English)In: The Journal of Organic Chemistry, Vol. 50, no 15, p. 7385-7395Article in journal (Refereed) Published
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.

National Category
Chemical Sciences Engineering and Technology
Research subject
Chemistry with specialization in Organic Chemistry; Engineering Science with specialization in Materials Science
Identifiers
urn:nbn:se:uu:diva-259460 (URN)10.1021/acs.joc.5b00797 (DOI)000359393500007 ()
Funder
Swedish Research CouncilCarl Tryggers foundation , CTS 13:120 13:346
Available from: 2015-08-04 Created: 2015-08-04 Last updated: 2015-09-22Bibliographically approved
Poon, J.-f., Singh, V. P., Yan, J. & Engman, L. (2015). Regenerable Antioxidants - Introduction of Chalcogen Substituents into Tocopherols. Chemistry - A European Journal, 21(6), 2447-2457
Open this publication in new window or tab >>Regenerable Antioxidants - Introduction of Chalcogen Substituents into Tocopherols
2015 (English)In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 21, no 6, p. 2447-2457Article in journal (Refereed) 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.

National Category
Chemical Sciences
Identifiers
urn:nbn:se:uu:diva-243231 (URN)10.1002/chem.201405895 (DOI)000348510400023 ()
Note

De två första författarna delar förstaförfattarskapet.

Available from: 2015-02-05 Created: 2015-02-05 Last updated: 2017-12-05Bibliographically approved
Organisations
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ORCID iD: ORCID iD iconorcid.org/0000-0002-5568-7415

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