Antioxidant profile of ethoxyquin and some of its S, Se, and Te analogues.
6-(Ethylthio)-, 6-(ethylseleno)-, and 6-(ethyltelluro)-2,2,4-trimethyl-1,2-dihydroquinoline-three heavier chalcogen analogues of ethoxyquin-were prepared by dilithiation of the corresponding 6-bromodihydroquinoline followed either by treatment with the corresponding diethyl dichalcogenide (sulfur derivative) or by insertion of selenium/tellurium into the carbon-lithium bond, oxidation to a diaryl dichalcogenide, borohydride reduction, and finally alkylation of the resulting areneselenolate/arenetellurolate. Ethoxyquin, its heavier chalcogen analogues, and the corresponding 6-PhS, 6-PhSe, and 6-PhTe derivatives were assayed for both their chain-breaking antioxidative capacity and their ability to catalyze reduction of hydrogen peroxide in the presence of a stoichiometric amount of a thiol reducing agent (thiol peroxidase activity). Ethoxyquin itself turned out to be the best inhibitor of azo-initiated peroxidation of linoleic acid in a water/chlorobenzene two-phase system. In the absence of N-acetylcysteine as a coantioxidant in the aqueous phase, it inhibited peroxidation as efficiently as alpha-tocopherol but with a more than 2-fold longer inhibition time. In the presence of 0.25 mM coantioxidant in the aqueous phase, the inhibition time was further increased by almost a factor of 2. This is probably due to thiol-mediated regeneration of the active antioxidant across the lipid-aqueous interphase. The ethyltelluro analogue 1d of ethoxyquin was a similarly efficient quencher of peroxyl radicals compared to the parent in the two-phase system, but less regenerable. Ethoxyquin was found to inhibit azo-initiated oxidation of styrene in the homogeneous phase (chlorobenzene) almost as efficiently (kinh = (2.0 +/- 0.2) x 106 M-1 s-1) as alpha-tocopherol with a stoichiometric factor n = 2.2 +/- 0.1. At the end of the inhibition period, autoxidation was additionally retarded, probably by ethoxyquin nitroxide formed during the course of peroxidation. The N-H bond dissociation enthalpy of ethoxyquin (81.3 +/- 0.3 kcal/mol) was determined by a radical equilibration method using 2,6-dimethoxyphenol and 2,6-di-tert-butyl-4-methylphenol as equilibration partners. Among the investigated compounds, only the tellurium analogues 1d and, less efficiently, 1g had a capacity to catalyze reduction of hydrogen peroxide in the presence of thiophenol. Therefore, analogue 1d is the only antioxidant which is multifunctional (chain-breaking and preventive) in character and which can act in a truly catalytic fashion to decompose both peroxyl radicals and organic hydroperoxides in the presence of suitable thiol reducing agents.
Kumar
Sangit
S
Department of Biochemistry and Organic Chemistry, Uppsala University, Box 576, SE-751 23 Uppsala, Sweden.
Engman
Lars
L
Valgimigli
Luca
L
Amorati
Riccardo
R
Fumo
Maria Grazia
MG
Pedulli
Gian Franco
GF
D000975:Antioxidants / Q000737:chemistry*; D002384:Catalysis; D002625:Chemistry, Organic / Q000379:methods*; D002722:Chlorobenzenes / Q000737:chemistry; D004578:Electron Spin Resonance Spectroscopy; D005015:Ethoxyquin / Q000737:chemistry*; D007700:Kinetics; D019787:Linoleic Acid / Q000737:chemistry; D008956:Models, Chemical; D019163:Reducing Agents / Q000494:pharmacology; D012643:Selenium / Q000737:chemistry*; D013455:Sulfur / Q000737:chemistry*; D013691:Tellurium / Q000737:chemistry*; D013997:Time Factors; D014867:Water / Q000737:chemistry
D000975:Antioxidants; D002722:Chlorobenzenes; D019163:Reducing Agents; D014867:Water; D013455:Sulfur; D019787:Linoleic Acid; D005015:Ethoxyquin; D012643:Selenium; C031294:chlorobenzene; D013691:Tellurium