478 R. E. HANDSCHUMACHER AND A. D. WELCH 



ing the relationship of structure to action, 6 the more interesting derivatives 

 generally closely resemble the naturally occurring purines. As will be ap- 

 parent in the discussion to follow, the primary sites of action of many of 

 these derivatives cannot be strictly defined at the present time, but their 

 biological activities are clearly related to nucleic acid metabolism and in 

 some cases have been responsible for the attainment of desirable therapeutic 

 effects in human disease. 



1. 6-Mercaptopurine 



Among the very large number of purine analogs 159 - 161 which have been 

 prepared, 6-mercaptopurine (IX) is still regarded as the most useful thera- 

 peutic agent of this type in cancer chemotherapy. Although definitive state- 

 ments concerning its mechanism of action as an inhibitor of growth can- 

 not be made, several areas in which it functions as an antimetabolite have 

 been demonstrated. This compound was prepared 162 as one of a large series 

 of 2- and 6-substituted purine derivatives containing mercapto or substi- 



SH SH 



tuted mercapto groups. Mercaptopurine may be considered an analog of 

 either hypoxanthine or adenine and indeed it is in the formation or function 

 of these purine derivatives that the most prominent inhibitory activity of 

 this antimetabolite is expressed. 



Results from the preliminary screening of mercaptopurine as an inhibitor 

 of the growth of Lactobacillus cased 160 and experimental tumors 163 indicated 

 the biological activity of the compound. Although initial tests on sarcoma- 

 180 in mice disclosed only borderline activity, transplants from the tumors 

 following mercaptopurine treatment frequently were noted to be nonviable. 

 Subsequent studies by many workers, using this and other transplantable 

 neoplasms, have confirmed the antitumor activity and led to the widespread 

 use of the compound in the treatment of certain types of leukemia. 164 ' 165 



162 G. B. Elion, E. Burgi, and G. H. Hitchings, ./. Am. ('hem. Soc. 74, 411 (1952). 



163 D. A. Clarke, F. S. Philips, S. S. Sternberg, C. C. Stock, G. B. Elion, and G. H. 

 Hitchings, Cancer Research 13, 593 (1953). 



164 H. E. Skipper, J. R. Thomson, G. B. Elion, and G. H. Hitchings, Cancer Research 

 14, 294 (1954). 



165 Summarized in Ann. N. Y. Acad. Sci. 60, 365-499 (1954). 



