Studies on scavengers of active oxygen species. 1. Synthesis and biological activity of 2-O-alkylascorbic acids.
A novel series of 2-O-alkylascorbic acids (5a-u) was synthesized, and their scavenging activities against active oxygen species as well as their suppressive effects on the arrhythmias in rat heart ischemia-reperfusion models were evaluated. Some 2-O-alkylascorbic acids (5e-1) exhibited potent inhibiting activities against lipid peroxidation in rat brain homogenates and in alleviating effects in the ischemia-reperfusion models. Studies on the structure-activity relationship demonstrated that a free 3-enolic hydroxyl group and the longer alkyl chains substituted on the 2-hydroxyl group of ascorbic acid were beneficial for the biological and pharmacological activities. 2-O-Octadecylascorbic acid (5k, CV-3611), one of the most potent and promising compounds, markedly inhibited lipid peroxidation (IC50 = 4.3 X 10(-6) M) and alleviated myocardial lesions induced by ischemia-reperfusion at an oral dose of 1 mg/kg in rats.
Kato
K
K
Central Research Division, Takeda Chemical Industries, Ltd., Osaka, Japan.
Terao
S
S
Shimamoto
N
N
Hirata
M
M
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000188:drug therapy; D001205:Ascorbic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D008026:Ligation; D019787:Linoleic Acid; D008041:Linoleic Acids / Q000378:metabolism; D008054:Lipid Peroxides / Q000378:metabolism; D008297:Male; D008823:Micelles; D010100:Oxygen; D051381:Rats; D013329:Structure-Activity Relationship
D008041:Linoleic Acids; D008054:Lipid Peroxides; D008823:Micelles; D019787:Linoleic Acid; D001205:Ascorbic Acid; D010100:Oxygen