Structure-antitumor activity relationship of purin-6-yl alkyl disulfides

Antitumor activity and toxicity to host of newly synthesized disulfide derivatives of 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG) were examined in murine ascites sarcoma-180 system (total packed cell volume method) by parenteral administration. The compounds tested were 6-alkyl disulfides (carbon number of alkyl group: 2, 3, 4, 5, 6, 7, 8, 10, and 14), 6-branched-alkyl disulfides (iso-propyl, sec-butyl, and tert-butyl), and 6-aralkyl disulfide (naphthyryl). Most disulfide derivatives of 6-MP and 6-TG showed higher antitumor activity (lower ED50) and higher toxicity to host (lower LD50) than parent compounds, but ratios of increase in activity and toxicity were different with each other. The compounds with higher chemotherapeutic index (LD50/ED50) than parent compounds were alpha-naphthyryl (8.7) disulfide in a series of 6-MP (7.5) derivatives; and sec-butyl (27), tert-butyl (24), octyl (23), decyl (26), and alpha-naphthyryl (28) disulfides in a series of 6-TG (14) derivatives. These 6-TG derivatives were promising for antitumor agents.