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Catalytic chain-breaking pyridinol antioxidants
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry. (Lars Engman)
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2010 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 75, no 3, 716-725 p.Article 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.

Place, publisher, year, edition, pages
2010. Vol. 75, no 3, 716-725 p.
National Category
Chemical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-115972DOI: 10.1021/jo902226tISI: 000273982900022PubMedID: 20073487OAI: oai:DiVA.org:uu-115972DiVA: diva2:296028
Available from: 2010-02-17 Created: 2010-02-17 Last updated: 2017-12-12Bibliographically approved
In thesis
1. Exploring Novel Catalytic Chalcogenide Antioxidants
Open this publication in new window or tab >>Exploring Novel Catalytic Chalcogenide Antioxidants
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. 71 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 742
Keyword
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:nbn:se:uu:diva-122485 (URN)978-91-554-7803-2 (ISBN)
Public defence
2010-06-03, B41, BMC, Husargatan 3, 751 23, Uppsala, 10:15 (English)
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Supervisors
Available from: 2010-05-11 Created: 2010-04-13 Last updated: 2010-05-18

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