A water-soluble quaternary ammonium analog of alpha-tocopherol, that scavenges lipoperoxyl, superoxyl and hydroxyl radicals.
The new water-soluble ammonium-analog of alpha-tocopherol (vitamin E) (compound 1: 3,4-dihydro-6-hydroxy-N,N, N-2,5,7,8-heptamethyl-2H-1-benzopyran-2-ethanaminium 4-methylbenzenesulfonate) and its tertiary amine derivative (compound 2: 3,4-dihydro-2-(2-dimethylaminoethyl)-2,5,7,8-tetramethyl-2H-1-benzopyran -6-ol hydrochloride) were investigated as scavengers of oxygen-derived free radicals. Compounds 1 and 2 were at least 40 times more potent inhibitors of Fe-driven heart microsomal lipid peroxidation than Trolox. While the alpha-tocopherol analogs had the same potency as scavengers of xanthine/xanthine oxidase-generated superoxyl radicals, the thiol compounds D,L-penicillamine and N-2-mercaptopropionyl glycine reacted at a much slower rate. The O-acetyl derivatives of compounds 1 and 2 were not scavengers of superoxyl radicals. Considerable differences between the alpha-tocopherol analogs were observed in their competition with 2-deoxyribose for hydroxyl radicals (OH.). Compound 2 was equipotent with Trolox and thiourea, whereas the reactivity of these substances was diminished by more than 30% as compared to compound 1. Although showing lower reactivity, the O-acetyl derivatives of compounds 1 and 2 were active nevertheless as OH.-scavengers. The previously reported high potency of compound 1 in reducing infarct size during myocardial ischemia/reperfusion appears to be due to its radical-scavenging properties, likely to be enhanced by its previously described cardioselectivity.
Bolkenius
F N
FN
Marion Merrell Dow Research Institute, Strasbourg, France.
Grisar
J M
JM
De Jong
W
W
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001921:Brain; D002839:Chromans / Q000494:pharmacology; D003855:Deoxyribose / Q000378:metabolism; D003864:Depression, Chemical; D016166:Free Radical Scavengers; D005609:Free Radicals; D007700:Kinetics; D050356:Lipid Metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D008861:Microsomes / Q000187:drug effects; D009206:Myocardium; D010084:Oxidation-Reduction; D010100:Oxygen / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D012995:Solubility; D024505:Tocopherols; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology
D000975:Antioxidants; D002839:Chromans; D016166:Free Radical Scavengers; D005609:Free Radicals; C067190:MDL 73404; C071522:3,4-dihydro-2-(2-dimethylaminoethyl)-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol; D014810:Vitamin E; D008315:Malondialdehyde; D003855:Deoxyribose; D024505:Tocopherols; C010643:6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid; D010100:Oxygen