Long-chain-substituted uric acid and 5,6-diaminouracil derivatives as novel agents against free radical processes: synthesis and in vitro activity

• Published in: Journal of medicinal chemistry 1993-05, Vol.36 (10), p.1465-1473
• Main Authors: Fraisse, Laurent, Verlhac, Jean Baptiste, Roche, Beatrice, Rascle, Marie Claude, Rabion, Alain, Seris, Jean Louis
• Format: Article
• Language: English
• Subjects: Animals; Antioxidants - chemical synthesis; Antioxidants - chemistry; Antioxidants - pharmacology; Cattle; Chemistry; Exact sciences and technology; Free Radical Scavengers; Heterocyclic compounds; Heterocyclic compounds with several n hetero atoms in the same ring, in separated rings or in fused rings; Lipid Peroxidation - drug effects; Mitochondria, Heart - drug effects; Mitochondria, Heart - metabolism; Organic chemistry; Preparations and properties; Pyrimidines - chemical synthesis; Pyrimidines - chemistry; Pyrimidines - pharmacology; Structure-Activity Relationship; Uracil - analogs & derivatives; Uric Acid - analogs & derivatives
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00062a020

A new series of N-alkylated uric acids (2,6,8-purinetrione) and 5,6-diaminouracils (5,6-diamino-2,4-pyrimidinedione) were synthesized, and their activities against free radicals were evaluated. Long-chain derivatives of both series exhibited a large inhibitory activity against oxygen radical induced lipid peroxidation in bovine heart mitochondria (IC50 lower than 1 microM), compared to the reference antioxidants trolox C or alpha-tocopherol. This activity appeared related to (i) the ability of these compounds to reduce the stable radical 1,1-diphenyl-2-picrylhydrazyl and (ii) their lipophilicity estimated by log P determination. In order to study the scavenging mechanisms of diaminouracils and urate derivatives against lipid radicals, they were also tested against the azo-initiated peroxidation of either methyl linoleate in organic solvents or a liposomal suspension of dilinoleoylphosphatidylcholine. Urate derivatives reacted moderately with lipid radicals and were slowly consumed, significantly affecting the propagation of the peroxidation. Diaminouracils strongly reduced the propagation rate. They were quickly consumed and were able to deactivate about 1 mol of lipid radical per mole of compound in organic solvent. Dodecyl urates and decyl- and dodecyldiaminouracils were chosen for further in vitro investigation and in vivo evaluation.