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



V. Structural Analogs of Pyrimidines and Their Effects 

 on Nucleic Acid Metabolism 



During the last decade, knowledge of the metabolism of pyrimidines 

 has increased greatly and agents have been sought which might influence 

 the synthesis or utilization of pyrimidine-containing compounds. The ex- 

 tensive background of information on the pyrimidine requirements of 

 certain strains of microorganisms has provided a valuable tool for screen- 

 ing potentially active compounds. 356 ' 357 Further interest was generated by 

 findings 358361 which indicated that marked differences in the capacity to 

 utilize preformed uracil are to be found in various mammalian tissues. 

 More recently, the important phenomenon of the "thymineless death" of 

 bacteria 362 also has stimulated interest in the potential usefulness of py- 

 rimidine antimetabolites as therapeutic agents. In some tumors there is a 

 greatly diminished activity of several enzymes involved in the catabolism 

 of pyrimidines, 363 ' 364 which are present in many tissues, but predominantly 

 in liver. Despite the newness of many of the antimetabolites to be dis- 

 cussed, much can be said about their specific mechanisms of action. 



1. 5-Fluoropyrimidim:s 



The similarities in the physical and chemical properties of the 5-halo- 

 genouracils and thymine have prompted extensive study of the actions of 

 such compounds in the synthesis and utilization of thymine derivatives 

 for DNA formation. The first member of the fluorine-substituted pyrim- 

 idines, 5-fluorouracil (XIII) was not synthesized until 1957. 365 This syn- 

 thesis, unlike that of the previously known halogenated pyrimidines, was 

 not accomplished by direct replacement of hydrogen in the pyrimidine 

 ring. In the preparation, the diethyl ester of 2-fluoro-3-oxosuccinic acid 

 was condensed with >S-ethylisothiouronium bromide; hydrolysis of the 

 product gave 5-fluoroorotic acid (XIV), a compound of much interest per 

 se, which also could be decarboxylated to form 5-fluorouracil. This syn- 

 thetic route was particularly appropriate for the preparation 366 f rom thiourea- 



356 G. H. Hitchings and G. B. Elion, Cancer Research Suppl. 3, 66 (1955). 



357 J. L. Stokes, J. Bacteriol. 48, 201 (1944). 



358 R. J. Rutman, A. Cantarow, and K. E. Paschkis, Cancer Research 14, 119 (1954). 

 369 C. Heidelberger, K. C. Liebman, and E. Harbers, Cancer Research 17, 399 (1957). 



360 V. Lagerkvist and P. Reichard, Ada Chem. Scand. 8, 361 (1954). 



361 P. Reichard and O. Skold, Biochim. et Biophys. Acta 28, 376 (1958). 



362 S. S. Cohen, J. Bacteriol. 71, 588 (1956). 



363 E. S. Canellakis, J. Biol. Chem. 227, 701 (1957). 



364 V. R. Potter, A. F. Brumm, and F. J. Bollum, Proc. Am. Assoc. Cancer Research 

 2, 336 (1958). 



365 R. Duschinsky, E. Pleven, and C. Heidelberger, J. Am. Chem. Soc. 79, 4559 (1957). 



366 N. K. Chaudhuri, B. J. Montag, and C. Heidelberger, Cancer Research 18, 318 

 (1958). 



