Structure-activity relationships and cross-resistance observed on evaluation of a series of purine analogs against experimental neoplasms.

Extensive efforts by the Burroughs-Wellcome group, the Sloan-Kettering group, and others have led to a considerable knowledge of purine antagonists that inhibit the growth of bacteria, experimental neoplasms, and human leukemias (18). Although 6-mercaptopurine (6-MP) is the most widely employed purine antagonist from the clinical standpoint, "related compounds, thioguanine, 6-chloropurine, 6-methylpurine, and purine also inhibit the growth of S-180" (11). The specificity of action of 6-MP against Sarcoma 180 (S-180) has been examined by synthesis and assay of a variety of related compounds (10). Generally, substitution led to less active compounds or inactive compounds, with the exception of ~-amino-6-mercaptopurine (thioguanine) which, though more toxic than 6-MP, had about the same therapeutic index. I t was observed that a number of 6-substituted derivatives of 6-MP, such as 6methylthiopurine or 6-benzylthiopurine, were inhibitory to S-180 but possessed no advantage from the standpoint of therapeutic index. Replacement of the ~-amino group of thioguanine by alkylamino, arylamino, or heterocyclic amino groups resulted in compounds with markedly lower activity (10). Elion eta/. have observed that a 6-MP-resistant line of Lactobacillus casei is :cross-resistant to thioguanine, but this mutant is sensitive to inhibition by ~,6-diaminopurine, purine, 8-azaadenine, 8azaguanine, or amethopterin (15). Hutchison found that, while Streptococcusfaecalis could utilize hypoxanthine, adenine, xanthine, or guanine for growth on a folic acid-free medium, a 6-MPresistant line of this organism could use only xanthine under similar conditions (19). Paralleling this limited metabohc capacity of the 6-MP-resistant S. faecalis, it was observed that 8-azaxanthine was a very effective inhibitor of growth of the resistant as well as the sensitive line.