39. antimetabolites an'i) nucleic acid metabolism 511 



3. 5-Amino-, 5-Mercapto-, and 5-Hydroxypyrimidine Derivatives 



Methods have been devised for the synthesis of 5-aminouracil 44fi and the corre- 

 sponding ribose (aminouridine) 447 and deoxyribose (aminodeoxyuridine) 448 deriva- 

 tives. Formation of the deoxyribonucleoside of aminouracil by condensation with 

 deoxyribose-1 -phosphate has been demonstrated using a thymidine phosphorylase 

 from calf kidney. 436 It has been suggested 408 that aminouracil exerts its antimicrobial 

 activity 404 both as an ant i -folic acid agent and as an antagonist of thymine. Amino- 

 uracil, as well as 2-thio thymine, and also a nutritional deficiency of thymine, each 

 caused up to a fourfold increase in the 6-methylaminopurine content of the DNA of 

 E. coli 15T~ (an amount equivalent to 15% of the adenine). 449 The significance of this 

 purine, which itself inhibits microbial growth, in the nucleic acids of a number of 

 bacterial species is not understood; certainly, however, this compound must be taken 

 into account in any formulation of the synthesis and function of DNA. Aminouridine 

 inhibits the growth of Theiler's GD VII virus 4 ' 5 and a pyrimidine-requiring mutant 

 of Neurospora (1298), 443 and these effects are nullified by uridine. The compound 

 exhibited slight antitumor activity 450 and inhibited, in a relatively nonspecific man- 

 ner, the incorporation of radioactive phosphate, formate, and ureidosuccinate into 

 nucleic acid components by slices of rat liver and hepatoma. 322 ' 323 Aminodeoxyuridine 

 behaved as an antagonist of the pyrimidine deoxyribonucleosides in the growth of 

 E. coli K-12, an effect most effectively overcome by thymidine 448 ; the findings suggest 

 that the analog inhibited the synthesis of thymine nucleotides. 5-Hydroxyuridine 447 

 has many properties in common with 5-aminouridine as an inhibitor of the growth 

 of Xeurospora 1298 and Theiler's GD VII virus on chick embryo tissue. 415 This un- 

 natural ribonucleoside is also a potent inhibitor of adaptive enzyme formation in 

 yeast, 451 and the inhibition of E. coli by this compound can be prevented by uridine 

 or cytidine, but not by the corresponding free pyrimidines or by orotic acid. 452 How- 

 ever, the deoxyribonucleoside of 5-hydroxyuracil 416 differs from the corresponding 

 amino derivative in that inhibition of E. coli K-12 by this agent is prevented by de- 

 oxyuridine and deoxycytidine, but not by thymidine. 448 



A series of thymine antagonists has been prepared by the introduction of 5-mer- 

 capto, 5-disulfide, and 5-isothiouronium groups into uracil through diazotization of 

 5-aminouracil. 453 These compounds, particularly 5-mercaptouracil, effectively inhibit 

 the growth of L. leichmannii and their action is competitively reversed by thymine 

 or, more effectively, by thymidine. 409 The rate of growth of L. arabinosus and several 

 experimental tumors was only slightly inhibited, 409 but when combined with fluoro- 

 uracil at subeffective doses for either compound, significant inhibitions of the growth 

 of sarcoma-180 and adenocarcinoma-755 were noted. 454 Although these data have 



446 H. L. Wheeler and T. B. Johnson, J. Am. Chem. Soc. 31, 603 (1909). 



447 M. Roberts and D. W. Visser, J. Am. Chem. Soc. 74, 668 (1952). 



448 R. E. Beltz and D. W. Visser, J. Biol. Chem. 226, 1035 (1957). 



449 D. B. Dunn and J. D. Smith, Biochem. J. 68, 627 (1958). 



450 d yy Visser, in "Antimetabolites and Cancer" (C. P. Rhoads, ed.), p. 47. Am. 

 Assoc. Advancement Sci., Washington, D. C, 1955. 



451 S. Spiegelman, in "The Chemical Basis of Heredity" (W. D. McElroy and B. 

 Glass, eds.). p. 232. Johns Hopkins Press, Baltimore, Maryland, 1957. 



452 I. J. Slotnick, D. W. Visser, and S. C. Rittenberg, J. Biol. Chem. 203, 647 (1953). 



453 T. J. Bardos, R. R. Herr, and T. Enkoji, J. Am. Chem. Soc. 77, 960 (1955). 

 154 T. J. Bardos, A. Segaloff, and J. L. Ambrus, Nature 183, 619 (1959). 



