39. ANTIMETABOLITES AND NUCLEIC ACID METABOLISM 473 



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



(VII) 



N=N=CH— CO— CHo— CH 2 — CH(NH 2 )— COOH 

 (VIII) 



These closely related compounds, each produced by a strain of Streptomyces, 

 exhibit considerable chemical reactivity as a result of the diazo function. 

 Synthesis of each of these compounds has been devised and only the l- 

 isomers are active as biological inhibitors. Both azaserine and DON are 

 unstable, and below pH 2 evolve nitrogen at room temperature with com- 

 plete loss of biological activity. Alkaline solutions of azaserine also slowly 

 lose inhibitory activity as a result of migration of the diazo-acetyl group 

 from the hydroxyl to the amino group of the serine moiety. Despite their 

 names, which imply a structural similarity to serine or norleucine, azaserine 

 and DON are both structural analogs of L-glutamine 



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



as will be evidenced by an examination of their molecular configurations. 



The original biological studies with azaserine attempted to relate its ac- 

 tion to inhibition of the synthesis of amino acids or proteins, because the 

 antimicrobial activity could be prevented by a variety of amino acids; in 

 particular, leucine, phenylalanine, tyrosine, and tryptophan were effec- 

 tive. 127 " 129 In contrast to these results with azaserine, inhibition of the growth 

 of E. coli by DON could not be prevented by an excess of any of the amino 

 acids. 130 



In the first report of an effect of these compounds on nucleic acid me- 

 tabolism, a profound inhibition b} r azaserine of the incorporation of formate- 

 C 14 into the nucleic acids of sarcoma-180, adenocarcinoma E 771, liver, and 

 intestine, was noted. 131 These findings were quickly followed by studies 

 which indicated that the primary site of action was probably the conversion 

 of formylglycinamide to formylglycinamidine (each as the ribonucleotide) 132 

 (see Chapter 35). Using soluble enzyme preparations from pigeon liver, the 



125 R. D. Westland, S. A. Fusari, and H. M. Crooks, Abstr. 129th Meeting Am. Chem. 

 Soc, Dallas, Texas p. 14M (1956). 



126 H. A. DeWald and A. M. Moore, Abstr., 129th Meeting Am. Chem. Soc, Dallas, 

 Texas p. 13M (1956). 



127 L. Kaplan and C. C. Stock, Federation Proc. 13, 239 (1954). 



128 H. C. Reilley, Proc. Assoc. Cancer Research 1, 40 (1954). 



129 H. Halvorson, Antibiotics & Chemotherapy 4, 948 (1954). 



130 R. E Maxwell and V. S. Nickel, Antibiotics & Chemotherapy 7, 81 (1957). 



131 H. E. Skipper, L. L. Bennett, Jr., and F. M. Schabel, Jr., Federation Proc. 13, 298 

 (1954). 



132 S. C. Hartman, B. Levenberg, and J. M. Buchanan, J. Am. Chem. Soc. 77, 501 

 (1954). 



