39. ANTIMETABOLITES AND NUCLEIC ACID METABOLISM 



517 



5. Miscellaneous Pyrimidines 



A number of structural analogs of orotic acid have been investigated. Of the 5- 

 halogenated derivatives, 5-fluoroorotic acid has been discussed above; 5-chloroorotic, 

 though not extremely active, caused the accumulation of orotidylic acid in a super- 

 natant enzyme preparation from rat liver. The metabolism of this compound to a 

 nucleotide form also has been suggested. Recently the synthesis of the ethyl ester of 

 3-diazocitrazinic acid (3-diazo-4-carboxyethylpyridine-2,6-dione) was reported; this 

 derivative of pyridine (or of "de-aza" pyrimidine) inhibits the growth of L. bulgari- 

 cus, an effect which is prevented by orotic acid. 501 The possibility of "alkylation" 

 by the active diazo function of the enzyme normally responsible for condensation of 

 orotic acid with pyrophosphorylribose-5-phosphate is apparent. Another series of 

 orotic analogs has been prepared by substitution of a sulfonamide or alkyl or aryl 

 sulfone group for the carboxyl group of orotic acid. 502 These compounds, particularly 

 4(6) -uracil methylsulfone (XVII), are potent inhibitors of the growth of several 

 strains of Lactobacillus bulgaiicus, the effect of which is noncompetitive with respect 

 to orotic acid and other pyrimidine derivatives; however, crude RNA fractions will 

 overcome the inhibitory effects. 503 



<) 







HN 



0=C 



CH 



I ii 



C— S— CH 3 



' II 

 



HN 



s=c 



CH 



CH 



(XVII) 

 4(6)-Uracil methylsulfone 



H 



(XVIII) 

 2-Thiouracil 



Uracil methylsulfone also has been shown to inhibit the conversion of orotic acid 

 to orotidine-5'-phosphate in a competitive manner initially, but the kinetics shortly 

 become noncompetitive. 504 Inhibition of the growth of a number of tumors also has 

 been demonstrated with this uracil derivative 464, 505 ; however, recent studies of the 

 metabolic disposition of this agent showed that an exceedingly rapid nonenzymic 

 reaction with sulfhydryl groups occurred, a circumstance which results in the expul- 

 sion of the sulfone group and the formation of a 6-uracil-sulfide derivative of the 

 mercapto compound. 506 This finding appears to explain the shift to noncompetitive 

 kinetics in the enzyme study. The effect of uracil methylsulfone on pyrimidine me- 

 tabolism in tumors is not as clearly related to orotic acid. The uptake by suspensions 

 of Ehrlich ascites cells of orotic acid and formate into the thymine of DNA, but not 

 the incorporation of orotic acid into RNA pyrimidines, was blocked by this analog, 



501 Z. B. Papanastassiou, A. McMillan, V. J. Czebotar, and T. J. Bardos, Abstr. 

 135th Meeting Am. ('hem. Soc, Boston, Mass., p. UN (1959). 



602 S. B. Greenbaum, /. Am. Chew. Soc. 76, 6052 (1954). 



603 W. L. Holmes and A. 1). Welch, Cancer Research 16, 251 (1956). 

 50J W. L. Holmes, ./. Biol. Chein. 223, 677 (1956). 



505 J. J. Jaffe and J. It. Cooper, Cancer Research 18, 1089 (1958). 



506 J. It. Cooper, Cancer Research 18, 1084 (1958). 



