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

Abstract

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 significantly better hydroxyl and peroxyl radical scavengers and more potent inhibitors of t-butylhydroperoxide-induced lipid peroxidation in human erythrocyte membranes than the parent drugs. The hydroxyl radical scavenging property of 8-oxoenprofylline and its analogue 1,7-dimethyl-8-oxoenprofylline is marginally better 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 × 10¹⁰ M^-1 s^-1 which is comparable to that of dimethyl sulfoxide (1.4-1.6 × 10¹⁰ M^-1 s^-1) and better than that of mannitol (1.9-2.5 × 10⁹ M^-1 s^-1), the known hydroxyl radical scavengers. Both 8-oxo pentoxifylline (IC₅₀, 1.8 ± 0.08 μM) and 8-oxolisofylline (IC₅₀, 2.2 ± 0.13 μM) are as efficient peroxyl radical scavengers as uric acid (IC₅₀, 1.9 ± 0.05 μM). 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.