Biochemical properties of anti-inflammatory drugs—V: Uncoupling of oxidative phosphorylation by some γ-resorcyl and other dihydroxybenzol compounds

Abstract

Some new derivatives of 2, 6-dihydroxybenzoic (γ-resorcylic) acid were prepared and characterised. Many lipophilic derivatives of γ-resorcylic acid and of 2, 4, 6-trihydroxybenzoic acid uncouple phosphorylation in liver mitochondria and inhibit ATP-linked biosynthetic reactions in a connective tissue (cartilage). Of over 40 hydroxybenzoyl compounds examined, 5-phenylazo-γ-resorcylic acid and γ-resorcylanilide were the most potent drugs in vitro. γ-Resorcylic acid itself is devoid of these in vitro drug activities but two of its potential metabolites, γ-resorcylaldehyde and N- γ-resorcylglycine (2, 6-dihydroxyhippuric acid), were potent uncouplers of oxidative phosphorylation. These findings are discussed in the light of controversial reports that γ-resorcylic acid is/is not an antirheumatic drug. The uncoupling activity of γ-resorcyl derivatives was related to their p K a ′s (< 8) and their considerable lipophilic character. This last property could in turn be related to intramolecular hydrogen bonding between the ortho phenolic groups and the carbonyl function. γ-Resorcylic acid was excreted largely unchanged in the urine after its ingestion by two healthy subjects: no evidence was obtained that it was conjugated with glycine in vivo.