V, SPECIFICITY OF ACTION 157 



wliich shows that P(!A is liccomiiiji; less effective in reversing the action of 

 the aiitajioiiist. This is characteristic of systems in whicli iiiliihilion occurs 

 at more than one step in the reaction series. 



7. I-Amixopteroylglutamic Acid Derivatives 



This class of compounds is iniique among the PGA antagonists. They 

 are highly potent antagonists for both microorganisms and animals and 

 have pro\-ed to be the most effective of the Pr,A antagonists in treatment 

 of experimental and clinical Icukemias. 



TABLE VII 

 Some Derivatives of Pteroylglutamic Acid and Their Biological Effects" 



Inhibition* of S . faecalis R 



at three PGA levels, 7/ml. Toxicity for animals, p. p.m. of purified 

 of culture medium PG.A-deficient diet for LDion 



• PGA derivative 10 100 1000 Mice Rats Chicks Reverse"^ 



Crude "x-methyl" 30 20 30 1000 1000 1000 + 



9-IMetliyl 300 400 400 30-1000 + 



10-Methyl 



9,10-Dimethyl 



4- Ami no 



4-.\mino-9-methyl 



4-.\mino-10-methyl 2 0.5 0.3 1 3 5 - 



4-Amino-9,10-dimethyl 0.4 0.2 0.2 3 3 3 - 



" Courtesy Ann. N. Y. Acad. Sci. (Jukes et o/.'*). 



Inhibition ratio to PGA for half-maximum growth. 

 ' Reversible by PGA over a wide range. 

 ''Slight PGA-likeefifect. 



A number of derivatives containing an amino group in place of the 

 4-hydroxy group of the pteridine ring have been prepared (Seeger et al.^^). 

 The replacement of the glutamic acid by alanine in 4-amino PGA results 

 in almost complete loss of antagonist activity (Wright et al?^). Introduction 

 of methyl groups in the 9 and 10 positions increases the activity for S. fae- 

 calis R.^* 



In contrast to the effects of "x methyl PGA" and 9-methyl PGA, which 

 are readily reversible by PGA, the inhibitory action of 4-amino PGA and 

 related compounds cannot be completely counteracted by PGA. In aS. 

 faecalis the ratio of 4-amino PGA to PGA for half-maximum inhibition is 

 26G at 0.003 y of PGA and 0.07 at 0.3 7 per milliliter. This shows that PGA 

 becomes less effective at higher concentrations of the antagonist, a feature 



" T. H. Jukes, A. L. Franklin, and E. L. R. Stokstad, .l/?/(. N. Y. Acad. Sci. 52, 1336 



(1950). 

 8" D. Seeder, J. M. Smitli, Jr., and M. K. Ilultquist, /. Am. Chem. Soc. 69, 2567 (1947). 



