Biochemical properties of anti-inflammatory drugs—III.: Uncoupling of oxidative phosphorylation in a connective tissue (cartilage) and liver mitochondria by salicylate analogues: Relationship of structure to activity

Abstract

At low drug levels, sodium salicylate and other drugs which uncouple oxidative phosphorylation in liver and muscle mitochondria selectively inhibit (i) the incorporation of inorganic phosphate into organic phosphates and (ii) the incorporation of inorganic sulphate into polysaccharide sulphates by bovine cartilage in vitro, without inhibiting the oxidation of glucose or octanoate by this tissue. Processes (i) and (ii) are also inhibited by respiratory inhibitors (nitrogen atmosphere, cyanide). It is concluded that salicylate will uncouple oxidative phosphorylation in connective tissues, as well as in muscle, kidney, liver etc. The relationship of chemical structure to activity in uncoupling phosphorylation in cartilage and in rat liver mitochondria, was studied for 80 salicylate analogues. The partial structures given in figure 1 were essential for uncoupling activity: within this structural requirement, potency was governed by lipophilic character. The following compounds were notably more active than salicylate in vitro: o.hydroxynaphthoates, phenylsalicylates, 2-mercaptobenzoate and lipophilic N-substituted derivatives of PAS, salicylamide and anthranilic acid. N-Salicyloylanthranilate, 3,5-diiodosalicylate and 5-phenylazosalicylate were the most active drugs in vitro uncovered in this survey. Nitrosalicylates were much less active than the corresponding nitrophenols.