584 THE BIOCHEMISTRY OF B VITAMINS 



4-Amino-4-desoxyfolic Acid and Related Analogues 



A series of synthetic analogues of folic acid which have an amino group 

 in place of the 4-hydroxyl of the pteridyl moiety of folic acid are char- 

 acterized by very potent inhibitory activities; with few exceptions these 

 either are not prevented or are prevented only to a limited extent by 

 folic acid. The analogues are extremely toxic for a majority of the organ- 

 isms which require folic acid, and cause symptoms which are character- 

 istic of folic acid deficiency even though folic acid does not in many 

 instances show appreciable ability to prevent the toxic manifestations. 

 The biological activities of analogues of this type are indicated in Table 

 20. 



4-Amino-4-desoxyfolic Acid [N- (4- Amino -4- desoxypteroyl-L- glutamic 

 Acid]. From Table 20, it is apparent that 2-amino-4-desoxyfolic acid 

 inhibits markedly the growth of Streptococcus faecalis R; however, the 

 various members of the folic acid group have very little effect on the 

 amount of inhibitor necessary to prevent growth of the organism. 129 Only 



NH 2 



N 



f \ 



h 



N C C— CH 2 — NH— ^ J— CO— NH— CH— CH 2 — CH 2 — COOH 



H 2 N— C C CH ^ ==/ ^ COOH 



N N 



Jf.-amino-4-desoxy folic acid [N-(Jt.-amino-J t .-desoxy'pteroyl)-ij-glutamic acid] 



about a three-fold increase in the concentration of the analogue is neces- 

 sary to obtain the same degree of growth inhibition when the folic acid 

 concentration is increased one hundred-fold. Growth stimulated by 

 pteroic acid is most susceptible to the inhibitor, and no effect on the 

 toxicity is noted by increasing one hundred-fold the concentration of 

 pteroic acid. 129 



The toxicity of the analogue becomes apparent in chicks at a concen- 

 tration of 1 mg per kg of diet containing 0.5 mg of folic acid. At 5 mg 

 per kg of the diet, the 4-amino analogue is lethal for all the chicks. 129 

 The onset of the symptoms is rapid in comparison with dietary depletions. 

 To prevent the lethal effects of 4 mg of analogue per kg of diet, approxi- 

 mately 96 mg of folic acid per kg of diet are required. Intermediate 

 concentrations of folic acid permit partial survivals, but there is little 

 inhibition of growth of chicks surviving sub-lethal concentrations of the 

 analogue. 129 



A similar situation exists with rats. As little as 10 y per day or 1 mg 



