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Exploring Novel Catalytic Chalcogenide Antioxidants
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry. (Lars Engman)
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis is concerned with the synthesis and evaluation of regenerable chalcogen containing antioxidants. Variously substituted 2,3-dihydrobenzo[b]selenophene-5-ol antioxidants were evaluated in order to gain information about structure/reactivity-relationships. Within the series explored, the most regenerable unsubstituted compound inhibited lipid peroxidation for more than 320 minutes when assayed in a two-phase lipid peroxidation model in the presence of N-acetylcysteine (NAC). α-Tocopherol which could inhibit lipid peroxidation for 90 minutes under similar conditions was therefore easily outperformed. The antioxidant activity of the parent was also documented in an aqueous environment. The best catalyst quenched/inhibited ROS production by neutrophils and PMA-stimulated macrophages more efficiently than Trolox. In addition, over a period of seven days, no disruption in proliferation for the cell lines used was observed when exposed to our synthetic compound or Trolox at a concentration of 60 µM.

3-Pyridinols substituted with alkyltelluro groups in the ortho-position were more regenerable in the two-phase model than their corresponding para-substituted analogues in the presence of NAC and also inhibited autoxidation of styrene in a catalytic fashion in homogenous phase in the presence of N-tert-butoxycarbonyl cysteine methyl ester (LipCys), a lipid-soluble analogue of NAC. The best inhibitors quenched peroxyl radicals more efficiently than α-tocopherol. They could also catalyze reduction of organic hydroperoxides in the presence of thiols and therefore mimic the action of the glutathione peroxidase enzymes. Mechanisms for the catalysis are proposed.

Octylthio, octylseleno and octyltelluro analogues of butylated hydroxyanisole (BHA) were synthesized and evaluated. Among these, the tellurium compound was superior to α-tocopherol in the presence of NAC both when it comes to quenching capacity and regenerability.  Organochalcogen substituent effects in phenolic compounds were studied by using EPR, IR and computational methods.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2010. , p. 71
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 742
Keywords [en]
antioxidant, tellurium, selenium, catalytic, toxicity, ROS, neutrophil, glutathione peroxidase mimic, macrophage.
National Category
Organic Chemistry
Research subject
Chemistry with specialization in Organic Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-122485ISBN: 978-91-554-7803-2 (print)OAI: oai:DiVA.org:uu-122485DiVA, id: diva2:310998
Public defence
2010-06-03, B41, BMC, Husargatan 3, 751 23, Uppsala, 10:15 (English)
Opponent
Supervisors
Available from: 2010-05-11 Created: 2010-04-13 Last updated: 2010-05-18
List of papers
1. Regenerable Chain-Breaking 2,3-Dihydrobenzo[b]selenophene-5-ol Antioxidants
Open this publication in new window or tab >>Regenerable Chain-Breaking 2,3-Dihydrobenzo[b]selenophene-5-ol Antioxidants
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2007 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 72, no 7, p. 2583-2595Article in journal (Refereed) Published
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.

Keywords
Sulfur containing aminoacid, Reaction mechanism, Lipids, Regeneration, Styrene derivatives, Autoxidation, Lipophilicity, EPR spectrometry, Organic free radical, Phenols, Ionization potential, Heat of dissociation, Hydrogen bond, Homolysis, Theoretical study, Density functional method, Organic disulfide, Oxidation, Inhibition, α-Tocopherol, Reaction rate, Reducing agent, Thiol, Acetylcysteine, Water, Peroxidation, Azo compound, Demethylation, Markownikoff rule, Intramolecular reaction, Claisen rearrangement, Microwave, Organic selenide, Allylic compound, Chemical synthesis, Antioxidant
National Category
Chemical Sciences
Identifiers
urn:nbn:se:uu:diva-10499 (URN)10.1021/jo0700023 (DOI)000245118900041 ()17335240 (PubMedID)
Available from: 2007-03-27 Created: 2007-03-27 Last updated: 2017-12-11Bibliographically approved
2. Exploring a synthetic organoselenium compound for antioxidant pharmacotherapy: toxicity and effects on ROS-production
Open this publication in new window or tab >>Exploring a synthetic organoselenium compound for antioxidant pharmacotherapy: toxicity and effects on ROS-production
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2010 (English)In: Bioorganic & Medicinal Chemistry, ISSN 0968-0896, E-ISSN 1464-3391, Vol. 18, no 5, p. 1783-1788Article in journal (Refereed) Published
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.

Keywords
Antioxidant, organoselenium compound, toxicity, ROS, neutrophil, macrophage, ABTS
National Category
Chemical Sciences
Identifiers
urn:nbn:se:uu:diva-119635 (URN)10.1016/j.bmc.2010.01.057 (DOI)000274957100004 ()20156690 (PubMedID)
Available from: 2010-02-26 Created: 2010-02-26 Last updated: 2017-12-12Bibliographically approved
3. Catalytic Chain-breaking Pyridinol Antioxidants
Open this publication in new window or tab >>Catalytic Chain-breaking Pyridinol Antioxidants
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2008 (English)In: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052, Vol. 10, no 21, p. 4895-4898Article in journal (Refereed) Published
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.

National Category
Chemical Sciences
Identifiers
urn:nbn:se:uu:diva-105658 (URN)10.1021/ol801983n (DOI)000260534500047 ()18828593 (PubMedID)
Available from: 2009-06-05 Created: 2009-06-05 Last updated: 2017-12-13Bibliographically approved
4. Catalytic chain-breaking pyridinol antioxidants
Open this publication in new window or tab >>Catalytic chain-breaking pyridinol antioxidants
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2010 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 75, no 3, p. 716-725Article in journal (Refereed) Published
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.

National Category
Chemical Sciences
Identifiers
urn:nbn:se:uu:diva-115972 (URN)10.1021/jo902226t (DOI)000273982900022 ()20073487 (PubMedID)
Available from: 2010-02-17 Created: 2010-02-17 Last updated: 2017-12-12Bibliographically approved
5. Never Ending Antioxidant Protection - A Regenerable BHA-Analogue
Open this publication in new window or tab >>Never Ending Antioxidant Protection - A Regenerable BHA-Analogue
(English)Manuscript (preprint) (Other (popular science, discussion, etc.))
Identifiers
urn:nbn:se:uu:diva-122481 (URN)
Available from: 2010-04-13 Created: 2010-04-13 Last updated: 2010-05-11
6. Organochalcogen Substituents in Phenolic Antioxidants
Open this publication in new window or tab >>Organochalcogen Substituents in Phenolic Antioxidants
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2010 (English)In: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052, Vol. 12, no 10, p. 2326-2329Article in journal (Refereed) Published
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.

National Category
Chemical Sciences
Identifiers
urn:nbn:se:uu:diva-122483 (URN)10.1021/ol100683u (DOI)000277531000040 ()20405887 (PubMedID)
Available from: 2010-04-13 Created: 2010-04-13 Last updated: 2017-12-12Bibliographically approved
7. Appendix: Supplementary Material
Open this publication in new window or tab >>Appendix: Supplementary Material
(English)Manuscript (preprint) (Other (popular science, discussion, etc.))
Identifiers
urn:nbn:se:uu:diva-122484 (URN)
Available from: 2010-04-13 Created: 2010-04-13 Last updated: 2010-05-11

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