title: 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 x 10(10) M(-1) s(-1) which is comparable to that of dimethyl sulfoxide (1.4-1.6 x 10(10) M(-1) s(-1)) and better than that of mannitol (1.9-2.5 x 10(9) M(-1) s(-1)), the known hydroxyl radical scavengers. Both 8-oxo pentoxifylline (IC(50), 1.8 +/- 0.08 microM) and 8-oxolisofylline (IC(50), 2.2 +/- 0.13 microM) are as efficient peroxyl radical scavengers as uric acid (IC(50), 1.9 +/- 0.05 microM). 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.
authors.affiliation: Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India.
authors.forename: V B
authors.initials: VB
authors.lastname: Bhat
authors.forename: K M
authors.initials: KM
authors.lastname: Madyastha
mesh_terms: D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism; D016166:Free Radical Scavengers / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D017665:Hydroxyl Radical / Q000378:metabolism; D020128:Inhibitory Concentration 50; D015227:Lipid Peroxidation / Q000187:drug effects; D010431:Pentoxifylline / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D010545:Peroxides / Q000378:metabolism; D014527:Uric Acid / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D014970:Xanthines / Q000737:chemistry / Q000494:pharmacology
chemical_list: C442146:1,7-dimethyl-8-oxoenprofylline; C442145:8-oxoenprofylline; C442144:8-oxolisofylline; C442143:8-oxopentoxifylline; D000975:Antioxidants; D016166:Free Radical Scavengers; D010545:Peroxides; D014970:Xanthines; D014527:Uric Acid; C049375:perhydroxyl radical; D017665:Hydroxyl Radical; C034347:enprofylline; C025189:lisofylline; D010431:Pentoxifylline