6-Chloropurine and 6-chlorouric acid as substrates and inhibitors of purine-oxidizing enzymes.

Various examples of oxidation of purine molecules in positions 8 and 2 by xanthine oxidase have been reported. The conversions of the natural purine substrates, xanthine and hypoxanthine to uric acid (I) and of adenine to 2,8-dihydroxy-6-aminopurine, are well known. The oxidation of the purine antimetabolites, 6-mercaptopurine to 6-thiouric acid (2)) 2,6-diaminopurine to 2,6-diamino-6-hydroxy purine (3), adenine l-N-oxide to 8-hydroxy adenine l-N-oxide (9), and of 2-azaadenine and 2-azahypoxanthine, to the respective 8-hydroxy products (4) have more recently been described. The synthetic antimetabolite 6-chloropurine (5) has been shown to possess essentially the same carcinostatic properties in man and experimental animals (6-8) as the more widely used B-substituted purine antimetabolites but, unlike these, does not inhibit the growth of various purine-dependent bacteria.’ In addition, the ready reactivity of its A-halo substituent, which has made 6-chloropurine a useful intermediate in the synthesis of other purines (5), offered a promising means of converting trace quantities of starting drug and metabolites to known compounds for which reliable isolation procedures are available. These unique physiological and chemical properties of 6-chloropurine have prompted a study of its metabolism, the aspects in vitro of which are described here.