THE FOLIC ACID GROUP 587 



characteristically caused by other analogues. At 3 mg per kg of diet, the 

 analogue is fatally toxic to all the rats, moderate anemia, leucopenia and 

 granulocytopenia developing shortly before death. This fatal effect of the 

 minimum lethal concentration is prevented only by high concentrations 

 of folic acid (100 mg per kg of diet). Gross examination at autopsy does 

 not reveal the usual lesions and pathology observed with other folic acid 

 analogues. The viscera are normal in appearance, with no lesions or 



NH 2 



C N CH 3 



N C C— CH 2 — N— (' \>— CO— NH— CH— CH 2 — CH 2 — COOH 



I 

 COOH 



. / \ • 



N N 



4-amino-4-desoxy-N 10 -methylfolic acid 



pathological changes other than a slight enteritis. Animals administered 

 lethal amounts of the analogue seldom died before the fifth or sixth day, 

 but all the animals susceptible to that concentration died within the 

 second week. Animals surviving beyond the second week after admin- 

 istration of the analogue were not subsequently affected. 131 



It is interesting that different patterns of symptoms are obtained with 

 various analogues of folic acid. 



A slight growth-retarding effect of 4-amino-4-desoxy-N 10 -methylfolic 

 acid (3 mg per kg of diet containing 0.1 mg of folic acid) on chicks is 

 prevented by folic acid (10 mg per kg of diet). 131 



The analogue also causes marked cytological changes in the blood 

 islets of 6- to 8-day old chick embryos. Folic acid, but neither liver ex- 

 tracts nor vitamin B 12 , alters this effect. 139 



Other 2,4-Diaminopteridyl Analogues of Folic Acid. Both 4-amino-4- 

 desoxypteroic acid and 4-amino-9,N 10 -dimethyl-4-desoxyfolic acid are 

 effective inhibitory analogues of folic acid for Streptococcus faecalis R, 

 as indicated in Table 20. 122, 124 - 130 4-Amino-4-desoxypteroyl-L-aspartic 

 acid has some activity in inhibiting neoplastic growth (p. 593). A prelim- 

 inary report indicates that the aspartic analogue is toxic for mice, rats 

 and dogs, and produces pathologic changes similar to those caused by 

 the other 4-amino-4-desoxypteroyl derivatives. 140a 



Substituted Pteridines and Pyrimidines 



2,4-Diamino- and Related Pteridines. The first indication of the 

 great affinity of certain 4-aminopteridines for enzymes related to the 

 utilization of folic acid in biological systems was reported by Daniel, 

 et al. 140 They found that a group of 2,4-diaminopteridines synthesized by 



