Antioxidant and radical scavenging properties of 8-oxo derivatives of xanthine drugs pentoxifylline and lisofylline

摘要

The antioxidant and radical scavenging properties of 8-oxo derivatives of pentoxifylline, lisofylline, enprofylline (3-propyl xanthine), and 1,7-dimethyl enprofylline were studied in vitro. The results show that 8-oxopentoxifylline and 8-oxolisofylline are signifi-cantly better hydroxyl and peroxyl radical scavengers and more potent inhibitors of t-butylhydroperoxideinduced lipid peroxidation in human erythrocyte membranes than the parent drugs. The ydroxyl radical scavenging property of 8-oxoenprofylline and its analogue 1,7-dimethyl-8-oxoenprofylline is marginally etter than their corresponding xanthines. Interestingly, 1,7-dimethyl-8-oxoenprofylline is an effective inhibitor of lipid peroxidation whereas enprofylline, 1,7-dimethylenprofylline, and 8-oxoenprofylline exhibit significantly less activity. All the 8-oxo derivatives tested are better hydroxyl radical scavengers than uric acid, a natural antioxidant and a free radical scavenger in humans. The rate constant for the reaction between 8-oxopentoxifylline and hydroxyl radical is $1.6-4.2 imes 10^{10} M^{-1} s^{-1}$ which is comparable to that of dimethyl sulfoxide $(1.4-1.6 imes 10^{10} M^{-1} s^{-1})$ and better than that of mannitol $(1.9-2.5 imes 10^9 M^{-1} s^{-1})$, the known hydroxyl radical cavengers. Both 8-oxo pentoxifylline $(IC_{50}, 1.8 pm 0.08 mu M)$ and 8-oxolisofylline $(IC_{50}, 2.2 pm 0.13 mu M)$ are as efficient peroxyl radical scavengers as uric acid $(IC_{50}, 1.9 pm 0.05 mu M)$. The results presented clearly indicate that the anti-inflammatory property of pentoxifylline and lisofylline is exerted more through their 8-oxo derivatives than through the parent drugs.