Kato K, Terao S, Shimamoto N, Hirata M
Central Research Division, Takeda Chemical Industries, Ltd., Osaka, Japan.
J Med Chem. 1988 Apr;31(4):793-8. doi: 10.1021/jm00399a019.
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.
合成了一系列新型的2-O-烷基抗坏血酸（5a-u），并评估了它们对活性氧的清除活性以及对大鼠心脏缺血再灌注模型中心律失常的抑制作用。一些2-O-烷基抗坏血酸（5e-1）在大鼠脑匀浆中表现出对脂质过氧化的强效抑制活性，并在缺血再灌注模型中具有缓解作用。构效关系研究表明，抗坏血酸2-羟基上的游离3-烯醇式羟基和较长的烷基链有利于生物和药理活性。2-O-十八烷基抗坏血酸（5k，CV-3611）是最有效且最有前景的化合物之一，在大鼠口服剂量为1mg/kg时，能显著抑制脂质过氧化（IC50 = 4.3×10(-6) M）并减轻缺血再灌注引起的心肌损伤。
