THE FOLIC ACID COMPLEX 



Replacement of the 4-hydroxy group by the 4- thiol group did not 

 appreciably reduce the activity, possibly on account of the lability of 

 this group, but replacement of the 2-hydjoxy group or of both hydroxy 

 groups gave compounds of low activity. Replacement of either 

 hydroxy group by an amino group weakened the activity, giving 

 compounds with only one-tenth the potency. The amino compounds 

 appeared to be effective per se and not by conversion into thymine. 



Another derivative of uracil that stimulated the growth of L. 

 helveticus was orotic acid, uracil-4-carboxylic acid.^ 



In addition to replacing folic acid in the nutrition of micro- 

 organisms, thymine has also been shown '^ to bring about remissions 

 in Addisonian pernicious anaemia and in macrocytic anaemia, provided 

 very high doses (4-5 g. or more daily) were given. When attempts 

 were made to relieve the symptoms of folic acid deficiency in animals 

 by means of thymine, however, it was found to be completely in- 

 effective,® nor did it increase growth or affect haemoglobin formation 

 in the chick. ^ 



Histidine could replace folic acid for growth and acid production 

 of 5. faecalis R, possibly by conversion into a pyrimidine compound.^^ 



Pteridines and Analogues 



A number of compounds have been prepared in which the pteridine 

 ring is replaced by another heterocyclic ring. Most of these proved 

 to be growth inhibitors (page 516), but N-{4-(4-quinazoline)-benzoyl}- 

 glutamic acid ^^ had i/iooo to 1/10,000 the growth promoting activity 

 of folic acid for S. faecalis R. 



Formyl-folic acid, prepared by heating pteroylglutamic acid with 

 formic acid and acetic anhydride (cf. the preparation of rhizopterine, 

 page 476) was found to be as effective as folic acid in stimulating the 

 growth of S. faecalis R and L. helveticus. '^'^ N^^-Nitrosopteroyl glut- 

 amic acid was as effective as the parent compound on 5. faecalis and 

 on chicks. ^2° 



Daniel et al.^ examined the effect of some sixty compounds, mainly 

 substituted pteridines, on growth and haemoglobin formation in 

 chicks. Several compounds, e.g. 2-amino-4 : 6-dihydroxy-7-carboxy- 

 pteridine, 2 : 4-dihydroxy-6(or 7)-hydroxy-7(or 6)-carboxymethyl- 

 pteridine, 2-amino-4-hydroxy-6(or 7)-hydroxy-7(or 6)-methyl pteridine 

 and 2 : 4-dihydroxy-6(or 7)-hydroxy-7(or 6)-methylpteridine increased 

 the weight of the chicks, but had no effect on haemoglobin formation. 

 Other compounds, e.g, 2"amino-4-hydroxy-7-carboxypteridine, 2 : 4- 

 diamino-7-carboxypteridine, 2 : 4-dihydroxy-7-carboxypteridine and 

 2-mercapto-4-hydroxy-7-carboxypteridine had little or no effect on 

 growth but stimulated haemoglobin formation. Some compounds had 

 an inhibitory effect on either growth or haemoglobin formation or 



514 



