Cardioselective ammonium, phosphonium, and sulfonium analogues of alpha-tocopherol and ascorbic acid that inhibit in vitro and ex vivo lipid peroxidation and scavenge superoxide radicals.
Analogues of alpha-tocopherol and ascorbic acid with permanently cationic substituents, i.e., phosphonium (8, 9), sulfonium (11), acylhydrazinium (13, 14), and ammonium (1, 16, 21), were synthesized, and the 2R and 2S enantiomers of the alpha-tocopherol analogues 1, 8, 11, and 13 were separated. The compounds were found to scavenge lipoperoxyl and superoxide radicals in vitro and accumulate in heart tissue (cardioselectivity) as demonstrated by measurement of ex vivo inhibition of lipid peroxidation in mouse heart homogenates and confirmed by HPLC determination of drug concentrations for 1 and 11. The 2R and 2S enantiomers of 1 inhibited ex vivo lipid peroxidation to an equal extent. Thus the in vivo uptake into myocytes (cardioselectivity) is independent of the geometry at the chiral center and common to permanently cationic compounds.
Grisar
J M
JM
Marion Merrell Dow Research Institute, Strasbourg, France.
Marciniak
G
G
Bolkenius
F N
FN
Verne-Mismer
J
J
Wagner
E R
ER
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D001205:Ascorbic Acid / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D016166:Free Radical Scavengers / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D015227:Lipid Peroxidation / Q000187:drug effects*; D051379:Mice; D009943:Organophosphorus Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D000644:Quaternary Ammonium Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D013237:Stereoisomerism; D013452:Sulfonium Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D013481:Superoxides / Q000378:metabolism* / Q000633:toxicity; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology
D000319:Adrenergic beta-Antagonists; D016166:Free Radical Scavengers; D009943:Organophosphorus Compounds; D000644:Quaternary Ammonium Compounds; D013452:Sulfonium Compounds; D013481:Superoxides; D014810:Vitamin E; D001205:Ascorbic Acid