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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
Pujari-Palmer, S., Lu, X., Singh, V. P., Engman, L., Pujari-Palmer, M. & Karlsson Ott, M. (2017). Incorporation and delivery of an organoselenium antioxidant from a brushite cement. Materials letters (General ed.), 197, 115-119
Open this publication in new window or tab >>Incorporation and delivery of an organoselenium antioxidant from a brushite cement
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2017 (English)In: Materials letters (General ed.), ISSN 0167-577X, E-ISSN 1873-4979, Vol. 197, p. 115-119Article in journal (Refereed) Published
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.

Keywords
Antioxidants, Reactive oxygen species, Calcium phosphate cements, Inflammation, Biomaterial, Drug delivery
National Category
Materials Engineering
Identifiers
urn:nbn:se:uu:diva-322444 (URN)10.1016/j.matlet.2017.03.139 (DOI)000399500300031 ()
Funder
Carl Tryggers foundation , CTS 13:346Magnus Bergvall Foundation, 2015-01111Stiftelsen Längmanska kulturfonden, 16-2-41
Available from: 2017-05-23 Created: 2017-05-23 Last updated: 2017-05-23Bibliographically 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
Gustafsson, T., Osman, H., Werngren, J., Hoffner, S., Engman, L. & Holmgren, A. (2016). Ebselen and analogs as inhibitors of Bacillus anthracis thioredoxin reductase and bactericidal antibacterials targeting Bacillus species, Staphylococcus aureus and Mycobacterium tuberculosis. Biochimica et Biophysica Acta - General Subjects, 1860(6), 1265-1271
Open this publication in new window or tab >>Ebselen and analogs as inhibitors of Bacillus anthracis thioredoxin reductase and bactericidal antibacterials targeting Bacillus species, Staphylococcus aureus and Mycobacterium tuberculosis
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2016 (English)In: Biochimica et Biophysica Acta - General Subjects, ISSN 0304-4165, E-ISSN 1872-8006, Vol. 1860, no 6, p. 1265-1271Article in journal (Refereed) Published
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.

National Category
Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-282979 (URN)10.1016/j.bbagen.2016.03.013 (DOI)000375165300022 ()26971857 (PubMedID)
Funder
Swedish Research Council
Available from: 2016-04-08 Created: 2016-04-08 Last updated: 2017-11-30Bibliographically approved
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
Reiser, K., Mathys, L., Curbo, S., Pannecouque, C., Noppen, S., Liekens, S., . . . Karlsson, A. (2016). The Cellular Thioredoxin-1/Thioredoxin Reductase-1 Driven Oxidoreduction Represents a Chemotherapeutic Target for HIV-1 Entry Inhibition. PLoS ONE, 11(1), Article ID e0147773.
Open this publication in new window or tab >>The Cellular Thioredoxin-1/Thioredoxin Reductase-1 Driven Oxidoreduction Represents a Chemotherapeutic Target for HIV-1 Entry Inhibition
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2016 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 1, article id e0147773Article in journal (Refereed) Published
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.

National Category
Infectious Medicine
Identifiers
urn:nbn:se:uu:diva-279593 (URN)10.1371/journal.pone.0147773 (DOI)000369528200050 ()26816344 (PubMedID)
Funder
Swedish Research Council, AK 521-2010-2828Swedish Research Council, LE 621-2011-4006The Karolinska Institutet's Research Foundation
Available from: 2016-03-02 Created: 2016-03-02 Last updated: 2017-11-30Bibliographically 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
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0001-7751-629x

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