Efficient scavenging of hydroxyl radicals and inhibition of lipid peroxidation by novel analogues of 1,3,7-trimethyluric acid

• Published in: Life sciences (1973) Vol. 70; no. 4; pp. 381 - 393
• Main Authors: Bhat, Vadiraja B., Sridhar, G.R., Madyastha, K.M.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 14-12-2001
• Subjects: 1,3,7-Trimethyluric acid analogues; Antioxidant; Dose-Response Relationship, Drug; Erythrocyte Membrane - drug effects; Erythrocyte Membrane - metabolism; Free Radical Scavengers - metabolism; Humans; Hydroxyl radical; Hydroxyl Radical - metabolism; Lipid peroxidation; Lipid Peroxidation - drug effects; Oxidants - metabolism; Scavenging; Uric Acid - analogs & derivatives; Uric Acid - pharmacology; Lipid peroxidation; Antioxidant; Scavenging; Hydroxyl radical; 1,3,7-Trimethyluric acid analogues
• ISSN: 0024-3205; 1879-0631
• DOI: 10.1016/S0024-3205(01)01484-9

New water-soluble analogues of 1,3,7-trimethyluric acid with N-1 methyl replaced by various groups were prepared and evaluated for their ability to scavenge hydroxyl radicals as well as their protective potential against lipid peroxidation in erythrocyte membranes. The deoxyribose degradation method indicates that all the analogues tested effectively scavenge hydroxyl radicals and some of them show better activity than uric acid and methyluric acids. These effects are shown to be concentration dependent and are more potent at low concentrations (10–50 μM). Among the analogues tested, 1-butenyl-, 1-propargyl- and 1-benzyl-3,7-dimethyluric acids show high hydroxyl radical scavenging property with a reaction rate constant (Ks) of 3.2–6.7 × 10
10 M
−1 S
−1, 2.3–3.7 × 10
10 M
−1 S
−1 and 2.4–3.7 × 10
10 M
−1 S
−1, respectively. The effectiveness of these analogues as hydroxyl radical scavengers appears to be better than mannitol (Ks, 1.9–2.5 × 10
9 M
−1 S
−1). With the exception of 1-pentyl- and 1-(2′-oxopropyl)-3,7-dimethyluric acids, all other analogues tested are effective inhibitors of tert-butylhydroperoxide-induced lipid peroxidation in human erythrocyte membranes. All the analogues tested are susceptible to peroxidation in the presence of hemoprotein and hydrogen peroxide. The present study has pointed out that it is possible to significantly enhance the antioxidant property of 1,3,7-trimethyluric acid by structural modification at N-1 position. Such compounds may be useful as antioxidants
in vivo.