LONG-CHAIN-SUBSTITUTED URIC-ACID AND 5,6-DIAMINOURACIL DERIVATIVES ASNOVEL AGENTS AGAINST FREE-RADICAL PROCESSES - SYNTHESIS AND INVITRO ACTIVITY

A new series of N-alkylated uric acids (2,6,8-purinetrione) and 5,6-di aminouracils (5,6-diamino-2,4-pyrimidinedione) were synthesized, and t heir activities against free radicals were evaluated. Long-chain deriv atives of both series exhibited a large inhibitory activity against ox ygen radical induced lipid peroxidation in bovine heart mitochondria ( IC50 lower than 1 muM), compared to the reference antioxidants trolox C or alpha-tocopherol. This activity appeared related to (i) the abili ty of these compounds to reduce the stable radical 1,1-diphenyl-2-picr ylbydrazyl and (ii) their lipophilicity estimated by log P determinati on. In order to study the scavenging mechanisms of diaminouracils and urate derivatives against lipid radicals, they were also tested agains t 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 slo wly consumed, significantly affecting the propagation of the peroxidat ion. Diaminouracils strongly reduced the propagation rate. They were q uickly consumed and were able to deactivate about 1 mol of lipid radic al per mole of compound in organic solvent. Dodecyl urates and decyl- and dodecyldiaminouracils were chosen for further in vitro investigati on and in vivo evaluation.