150 PTEROYLGLUTAMIC ACID 



(liscnissioii will l)e confined to representatives of the main types of antago- 

 nists and to a description of their more important biological effects. 



The principle classes of compounds which function as PCtA antagonists 

 or in some cases possess PGA-Hke activity are shown in Table V. 



1. Substituted Pyrimidines 



Since pyrimidines are formed by PGA-catalyzed reactions, it is not sur- 

 prising that substituted pyrimidines function as PGA antagonists under 

 certain conditions. A large number of pyrimidines have been prepared and 

 their growth-promoting or growth-inhibiting actions determined. In many 

 cases the antagonistic action is not reversed by PGA and must therefore 

 be regarded primarily as an inhibition of pyrimidine or purine function. 



Detailed information on pyrimidine and purine antagonists has been 

 compiled in the excellent reviews of Hitchings et al.^^ and Wright.^- 



Replacement of the 5-methyl group of thymine (5-methyluracil) by 

 hydroxy, bromine, amino, or nitro groups produces compounds which in- 

 hibit the growth of L. casei (Hitchings ei al.^^). Of these compounds, 5-nitro- 

 uracil was reversed competitively by PGA, 5-aminouracil and 5-bromo- 

 uracil were competitively reversed by thymine, and 5-hydroxyuracil by 

 uracil. 



Of special interest are the 2,4-diaminopyrimidines and their substituted 

 ring systems which include the 2,4-diaminopurines and pteridines. Hitch- 

 ings et al.^ found that nearly all 2,4-diaminopyrimidines inhibited L. casei 

 in the presence of PGA and in the absence of a purine. A possible structural 

 similarity betw'een the PGA antagonist 2,4-diamino-5-p-chlorophenoxy- 

 pyrimidine and the antimalarial paludrine suggested that the former com- 

 pound may have antimalarial properties and the latter may have anti-PGA 

 activity (Falco et al}^). 



" L. J. Daniel, L. C. Norris, M. L. Scott, and G. F. Heuser, /. Biol. Chem. 169, 689 



(1947). 

 B6 D. W. Woolley and A. Pringle, J. Biol. Chem. 174, 327 (1948). 

 " B. L. Hutchings, J. H. Mowat, J. J. Oleson, E. L. R. Stokstad, J. H. Boothe, C. W. 



Waller, R. B. Angler, J. Semb, and Y. SubbaRow, /. Biol. Chem. 170, 323 (1947). 



68 D. B. Cosulich and J. M. Smith, Jr., J. Am. Chem. Soc. 70, 1922 (1948). 



69 D. R. Seeger, J. M. Smith, Jr., and M. E. Hultquist, /. Am. Chem. Soc. 69, 2567 

 (1947). 



6" P. C. Edwards, D. Starling, A. M. Mattocks, and H. E. Skipper, Science 107, 119 



(1948). 

 «i G. B. Hitchings, G. B. Elion, E. A. Falco, P. B. Russell, and H. Vander Werff, 



Ann. N. Y. Acad. Sci. 62, 1318 (1950). 

 ^^ L. D. Wright, Vitamins and Hormones 9, 131 (1951). 



63 G. B. Hitchings, G. B. Elion, and E. A. Falco, /. Biol. Chem. 185, 643 (1950). 

 «" G. B. Hitchings, G. li. Elion, H. Vander Worff, and E. A. Falco, J. Biol. Chem. 



174, 765 (1948). 

 " E. A. P^alco, G. B. Hitchings, P. B. Russell, and H. Vander WerfT, Nattire 164, 107 



(1949). 



