INHIBITORS OF NUCLEOSIDE METABOLISM

Abstract

When incubated with hypoxanthine and guanosine, intact human erythrocytes synthesize inosine, which appears in the incubation medium. This system was employed to test 143 variously substituted purines and purine analogues as potential inhibitors of nucleoside metabolism; 26 inhibitory compounds were detected, all of which inhibited inosine synthesis by intact erythrocytes, but failed to inhibit the same reaction in preparations of disrupted erythrocytes. These compounds also inhibited the uridine-supported synthesis of inosine by intact Ehrlich ascites tumor cells in vitro.Most of these inhibitors were 6-mercaptoethers of purine (or 2-aminopurine) ribonucleoside. A wide variety of substituent groups on the sulfur atom, ranging from methyl (but not hydrogen) to p-nitrobenzyl, imparted inhibitory activity. 2-Arnino-6-(p-nitrobenzylmercapto) purine ribonucleoside, the most effective agent found, inhibited inosine synthesis by 74% when the ratio of guanosine concentration to that of inhibitor was 1000.Compounds with important inhibitory activity had particular substituent groups at both positions 6 and 9 on the purine ring; if present separately, the active substituent groups imparted much less inhibitory activity than when present together on the same molecule. The only 6-position substituents found to impart inhibitory activity were mercapto, chloro, and iodo groups. Ribosyl, arabinosyl, tetrahydro-2-pyranyl, and n-butyl substituents at position 9 produced inhibitory compounds when a 6-mercaptoether substituent was present.