Structure-activity relationships among purines related to 6-mercaptopurine.

The systematic investigation of purities as antagonists of nucleic acid synthesis in bacteria, viruses, and neoplasms has been under way in these laboratories for a number of years (6, 29, 30, 33, 47, 49). The purines and their analogs have been studied in a wide variety of biological sys tems in an attempt to correlate details of chemical structure with activity. Studies with Lactobacillus casei (14, 23, 30) revealed certain structureactivity relationships which formed the basis for further syntheses and for the examination of these compounds against neoplastic growth. The finding that 6-mercaptopurine (6-MP) is inhibitory to Sarcoma 180 (8) and produces a high percentage of regressions of this tumor led to a more intensive study of its activity in other animal tumors (8, 45, 48), its mechanism of action in microorganisms (20, 21, 36), and its metabolic fate in the mouse (12) and in man (28). Clinical investigation (35) showed it to be effective in producing remissions in human leukemias. The studies presented here deal with the rela tionship between structure and activity among substances related to 6-mercaptopurine. Studies of this type are in order quite generally to deter mine the structural specificities of biological activities. They possess both informational and practical significance, since an improvement in the therapeutic index of the drug under consideration is always a possible outcome. In the present study, no outstanding derivative other than thioguanine has been discovered, but a number of derivatives have been found to possess antitumor activity of