Nonclassical Antimetabolites XXII: Simulation of 5′-Phosphoribosyl Binding V. Inhibition of Succinoadenylate Kinosynthetase by 6-Mercapto-9-purinylalkanoic Acid Derivatives of 4- and 5-Aminosalicylic Acid

Abstract

4- and 5-(6-Mercapto-9H-purine-9-ylvaleramido)salicylic acids (VII and XII) were relatively good inhibitors of succinoadenylate kinosynthetase, being about one-fourth as effective as thioinosinic acid (IX). The only further structural change that allowed retention of inhibition was variation of the valeryl bridge. Removal of the phenolic hydroxyl of VII, replacement of carboxyl group of XII by nitro, or replacement of the salicylic acid moiety by γ-butyric acid led to a decrease in inhibitory properties, thus indicating that both the phenolic hydroxyl and the carboxyl of the salicylate moiety are complexed with the enzyme. The binding of VII and related molecules was finally traced to the acylamino salicylate moiety, and there was no purine binding. Whether the salicylate moiety is simulating the enzyme binding of the phosphate moiety cannot as yet be certain, but appears unlikely.