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.