ANALOGUES 



Amino-folic Acids 



A compound derived from pteroylglutamic acid by the replacement 

 of the hydroxyl group by an amino group also had growth-inhibitory 

 activity.29 This was N-[4-{[(2 : 4-diamino-6-pteridyl)-methyl]-amino}- 

 benzoylj-glutamic acid, generally referred to as 4-aminopteroylglutamic 

 acid or Aminopterin ; it was prepared from 2:4:5: 6-tetraamino- 

 pyrimidine by a reaction analogous to that used for the preparation of 

 pteroylglutamic acid. The compound had inhibition ratios for 

 half-maximum inhibition of the growth of S. faecalis R of 1-9, 07 and 

 0-4 at pteroylglutamic acid concentrations of 0-003, 0-005 ^-^d o-oi 

 /xg. per 10 ml. respectively. The compound was highly toxic to mice 

 and, at levels less than 0-3 mg. per kg. of diet, the toxicity was partially 

 neutralised by pteroylglutamic acid, but this had no effect with 

 amounts of i to 3 mg. per kg. of diet.^° 



4-Aminopteroylglutamic acid was also an antagonist for pteroyl- 

 glutamic acid in rats and chickens, and here also the inhibition was 

 not strictly competitive in nature. ^^ It produced folic acid deficiency 

 in rats, with loss of weight, hypoplasia of the bone-marrow and intes- 

 tinal lesions v^ith diarrhoea, ^2 ^nd abnormalities in chick embryos 

 that were not prevented by large doses of folic acid.^^ In dogs, 

 4-aminopteroylglutamic acid produced a sprue-like syndrome with 

 diarrhoea, peripheral leucopenia, depletion of the bone marrow and 

 changes in the blood picture ; ^* haematological changes were also 

 produced when the compounds were administered to guinea-pigs.^^ 

 Pteroylaspartic acid and 7-methylfolic acid did not produce these 

 changes, although they potentiated the effect of 4-aminopteroyl- 

 glutamic acid. 



4-Aminopteroylglutamic acid depressed the response of the oviducts 

 of frogs to oestradiol, whereas folic acid potentiated the effect. The 

 effect of Aminopterin was not reversed by folic acid in 100 -fold con- 

 centration. It is suggested that folic acid antagonists may exert 

 their inhibitory effects by interfering with folic acid utilisation, de- 

 pressing nucleic acid synthesis and retarding the rate of cell division. ^^ 

 Aminopterin also interfered with the depressive influence of oestradiol 

 on the rat prostate. ^^ 



4-Aminopteroylglutamic acid inhibited the growth of E. coli, but 

 the inhibition was not reversed by pteroylglutamic acid, although it 

 was reversed by thymidine or a liver extract. Lactobacillus leich- 

 mannii was also inhibited by 4-aminopteroylglutamic acid and in this 

 instance the inhibition was reversed by pteroylglutamic acid at low 

 concentrations of inhibitor and by thymidine at higher concentra- 

 tions.^^ 



Aminopterin had no effect on the growth of psittacosis virus. ^® 



521 



