Pyrazolopyrimidines as inhibitors and substrates of xanthine oxidase.

A variety of purine and azapurine analogues have been shown to serve as substrates for and inhibitors of xanthine oxidase. Thus, in addition to its usual substrates, hypoxanthine and xanthine, and its demonstrated activity on certain pterines (I), pyrimidines (2)) and aldehydes (3), the following purine analogues are oxidized by xanthine oxidase: adenine (4), 2-azaadenine (5), 6-mercaptopurine (6), 2-azahypoxanthine (5), guanine (7)) and 2,6-diaminopurine (8). Several of these compounds have already been shown to be inhibitors of this enzyme as well. It has been demonstrated in this laboratory that 8-azaguanine, an effective antitumor agent, although not a substrate, is a potent xanthine oxidase inhibitor (9). The synthesis of a new series of pyrazolo(3,4-d)pyrimidines has been reported recently (10). Some of these purine analogues have demonstrated antitumor activity (11, 12). These pyrazolopyrimidines differ from purines in that a pyrazole ring instead of an imidazole ring is attached to the pyrimidine moiety. This leads to the numbering system shown below. It was deemed desirable, therefore, to study further the inhibitor and substrate specificities of xanthine oxidase by ascertaining whether these pyrazolopyrimidines serve as inhibitors of xanthine oxidase and whether they are also oxidizable by this enzyme. Likewise, the possibility of correlating their potency as xanthine oxidase inhibitors with their carcinostatic effectiveness was considered worthy of examination.