39. ANTIMETABOLITES AND NUCLEIC ACID METABOLISM 477 



for glutamine; however, if this is the case, these amino acids should be com- 

 petitive inhibitors of glutamine in the isolated enzyme systems. In spite of 

 the fact that azaserine and DON cause profound inhibition of the growth 

 of a variety of experimental neoplasms, the use of these agents in the treat- 

 ment of human cancer has been disappointing. Remission of acute leukemia 

 in children has been observed, but it is usually of very short duration; how- 

 ever, combinations of azaserine and mercaptopurine appear to delay the 

 evolution of populations of cells which are resistant to these agents in both 

 experimental neoplasms and acute leukemia in children. 

 Two other analogs of glutamine, 7-glutamylhydrazine 



H 2 N— NH— CO— CE>- CH 2 — CH(NH 2 )— COOH 

 and O-carbamylserine 



H 2 N— CO— 0— CH 2 — CH(NHo)— COOH 



have been demonstrated to inhibit the animation of formylglycinamide 

 ribonucleotide, but they are much weaker antagonists than azaserine or 

 DON. 141 More recently O-carbazylserine 



H 2 N— NH— CO— O— CH 2 — CH(NH 2 )— COOH 



has been synthesized and reported to have a similar inhibitory action on 

 the animation reactions required in the synthesis of purines and pyrimi- 

 dines. 157 However, this is an interpretation of microbial growth studies with 

 Streptococcus lactis, and the corresponding enzymic results are not available. 



IV. Structural Analogs of Purines and Their Metabolic Activity 



Although the presence of purines in the nucleic acids had been well es- 

 tablished by the turn of the century, it has only been during the last fifteen 

 years that purposeful attempts have been made to design purine analogs 

 with the specific aim of interfering with nucleic acid synthesis or function. 

 A considerable portion of the progress in this field can be attributed to the 

 synthetic efforts of workers at the Wellcome Research Laboratories (U.S.A.) 

 where a program of synthesis of purine (and pyrimidine) analogs was begun 

 in 1942. 158 159 Since that time a large number of compounds have been pre- 

 pared and examined for biological activity in microbial 160 or experimental 

 tumor systems. 161 Although much information has been obtained concern- 



157 T. J. McCord, J. M. Ravel, C. G. Skinner, and W. Shive, J. Am. Chem. Soc. 80, 

 3762 (1958). 



158 (i. H. Hitchings and G. B. Elion, Ann. N. Y. Acad. Sci. 60, 195 (1954). 



169 Ci. H. Hitchings and G. B. Elion, Proc. 3rd Intern. Congr. Biochem., Brussels, 1955 



p. 55 (1956). 

 l6 « (i. B. Elion, G. H. Hitchings, and H. Vander Werff, J. Biol. Chem. 192, 505 (1951). 

 161 1). A. Clarke, G. B. Elion, G. H. Hitchings, and C. C. Stock, Cancer Research 18, 



445 (1958). 



