39. ANTIMETABOLITES AND NUCLEIC ACID METABOLISM 515 



served in hepatomas. 390 Minor effects of azauracil and azauridine on the 

 uridine phosphorylase and kinase activities of extracts of tumors 480 and 

 of bacteria 483 also have been noted. A recent report indicates that azauridine- 

 5'-diphosphate at high concentrations inhibits the polynucleotide phos- 

 phorylase of E. coli iSb ; however, the apparent lack of formation of this di- 

 phosphate in mammalian systems would seem to exclude this enzyme as a 

 site of action in animals. 479, 480 



Minor incorporation of azauracil into the RNA of S. faecalis has been 

 reported, but none was found in the DNA. 469 As might be predicted, none 

 of this analog was incorporated into mammalian nucleic acids. 475 ' 480 Aza- 

 uracil has been reported to increase the levels of hexosamine derivatives in 

 the soluble fraction from E. coli m (as does penicillin), and to prevent the 

 synthesis of orotic acid in E. coli under special conditions through a re- 

 ported negative feed-back reaction which is also activated by uracil. 487 The 

 deoxyribonucleoside of azauracil has been prepared by transfer of deoxy- 

 ribose from thymidine to the analog in the presence of suspensions of S. 

 faecalis cells 462 ; however, this derivative was inactive in several microbial 

 and mammalian systems in which it was tested. 488 In general, the inhibitory 

 activity of 6-azacytosine is not as great as that of the uracil analog; but 

 the growth of adenocarcinoma-755 in mice is remarkably sensitive to this 

 antimetabolite, since azacytosine is effective in doses about one-twenty-fifth 

 those of azauracil. 468 



The methyl derivative corresponding to thymine, i.e., 6-azathy- 

 mine, 460 ' 489 is an effective inhibitor of the growth of many microorganisms, 

 an effect which can be prevented in a competitive manner by either thy- 

 mine or thymidine. 490491 This analog prevented the growth not only of 

 organisms supplied with exogenous thymine or thymidine, but also of those 

 which synthesized thymine derivatives de novo. Incubation of azathymine 

 with washed cell suspensions of S. faecalis and thymidine resulted in the 

 formation of the deoxyribonucleoside, azathymidine, by a transdeoxyribosi- 

 dation process 381 ; this derivative exerts an even greater inhibitory effect 

 on the growth of certain strains of microorganisms. 492 Either azathymine 

 or azathymidine, when added to cultures of S. faecalis during the loga- 

 rithmic phase of growth, creates a lethal condition in the cells which results 



485 J. Skoda, J. Kara, Z. Sormova, and F. Sorm, Biochim. et Biophys. Acta 33, 579 

 (1959). 



486 Y. Takagi and N. Otsuji, Biochim. et Biophys. Acta 29, 227 (1958). 



487 R. A. Yates and A. B. Pardee, J. Biol. Chem. 227, 677 (1957). 



488 R. E. Davis and R. E. Handschumacher, unpublished results (1958). 



489 J. R. Bailey and L. Knox, J. Am. Chem. Soc. 29, 880 (1907). 



490 W. H. Prusoff, W. L. Holmes, and A. D. Welch, Cancer Research 14, 570 (1954). 



491 G. B. Elion, S. Singer, and G. H. Hitchings, J. Biol. Chem. 208, 477 (1954). 



492 W. H. Prusoff and A. D. Welch, J. Biol. Chem. 218, 929 (1956). 



