456 R. E. HANDSCHUMACHER AND A. D. WELCH 



II. Compounds Which Interfere with the Formation 

 of Folic Acid -Derived Coenzymes 



1. aminopterin (4-amino-4-deoxypteroylglutamic acidj and 



amethopterin (4-amino-4-deoxy-10-methylpteroyl- 



glutamic acid; Methotrexate) 



H 2 N— C 



HoN— C 



(II) 



Aminopterin (R=H) and amethopterin (R=CH 3 ) 



11 The term "folic acid" hasoften been used generically to include various compounds 

 with related biological activites; however, in this chapter, for reasons of brevity, 

 the term is used synonymously with pteroylglutamic acid. Also, when appropriate, 

 the simplified abbreviations of Huennekens et al. n are employed: folic acid, F; 

 dihydrofolic acid, FH 2 ; tetrahydrofolic acid, FH 4 ; the 5-formyl derivative of 

 FH 4 , / 8 FH 4 , is usually referred to as folinic acid, rather than citrovorum factor 

 (CF), since the organism used in the determination of the factor is now designated 

 Pediococcus cerevisiae (ATCC 8081) rather than Leuconostoc citrovorum. The term 

 leucovorin is retained for the synthetic form of / 6 FH 4 , of which only one of the 

 two enantiomorphs exhibits the biological activity of folinic acid. Some of the 

 earlier and also the more recent reviews in this field are listed below. 12-18 



12 F. M. Huennekens, M. J. Osborn, and H. R. Whitely, Science 128, 120 (1958). 



13 A. D. Welch and R. W. Heinle, Pharmacol. Revs. 3, 345 (1951). 



14 A. D. Welch and C. A. Nichol, Ann. Rev. Biochem. 21, 633 (1952). 



15 A. D. Welch, in "Enzymes: Units of Biological Structure and Function" (O. H. 

 Gaebler, ed.), p. 547. Academic Press, New York, 1956. 



16 G. R. Greenberg and L. Jaenicke, in "Chemistry and Biology of Purines" (G. E. 

 W.Wolstenholmeand C. M. O'Connor, eds.), p. 204. Little, Brown, Boston, Mass., 

 1957. 



17 G. N. Timmis, J. Pharm. and Pharmacol. 9, 81 (1957). 



