Donald A. Clarke, G. Elion, G. Hitchings
May 1, 1958
Citations
0
Influential Citations
62
Citations
Quality indicators
Journal
Cancer research
Abstract
Summary The specificity of action of 6-mercaptopurine (6-MP) against Sarcoma 180 has been examined through the synthesis and testing of 102 related substances. The substitution of a variety of other groups, e.g., alkyl, halogen, cyano, and carboxy for the mercapto group led in general to less active or inactive compounds. Other changes on the purine nucleus such as substitution at positions 2 and 8 or alkylation of the ring nitrogens resulted, in general, in loss of activity. The exception to this was the 2-amino-derivative (thioguanine) which, like 6-MP, is a close analog of a natural purine. Thioguanine was active against Sarcoma 180 at about 1/20 the dosage of 6-MP but had about the same therapeutic index. Replacement of the 2-amino group of thioguanine by alkylamino, arylamino, or heterocyclic amino groups lowered the activity markedly. The abilities of the substances to exert antimetabolic effects in the growth of Lactobacillus casei also were examined. The two most active substances, 6-mercaptopurine and thioguanine, are clearly antagonists of the corresponding natural oxygen-containing purines. A number of derivatives exerted similar effects in both biological systems; however, several substances, which are essentially inactive microbiologically, exerted antitumor effects. Since these are found chiefly among S-substituted derivatives, the possibility was considered of metabolic cleavage of such substances with formation of the parent mercaptan.