39. ANTIMETABOLITES AND NUCLEIC ACID METABOLISM 497 



Unsubstituted purine ribonucleoside (nebularine) has been isolated from a species 

 of mushroom 339 and the structure confirmed by synthesis/' 40 This ribonucleoside is 

 much more toxic (about 25-fold) than is free purine. 340 The formation of the mono-, 

 di-, and triphosphates of this ribonucleoside, in vivo and in vitro, 341 - 342 the partial 

 reversal of its cytotoxic action by adenine, 343 and the fact that a portion of the purine 

 ribonucleoside administered to rats is found in the adenine and guanine of the nu- 

 cleic acids, 341 would suggest an action related to ribonucleotide metabolism. The in- 

 ability of mammalian nucleoside phosphorylases to cleave purine ribonucleoside 342 

 and the equally ineffective reverse reaction (i.e., synthesis of the ribonucleoside from 

 free purine), 344 may account for the striking difference in the toxicities of these two 

 compounds. Mention also should be made of the inability of the polynucleotide phos- 

 phorylase of Azotobacter vinelandii to bring about phosphorolysis of purine ribonu- 

 cleoside diphosphate; thus, if the mechanisms of synthesis of RNA in the rat involve 

 a similar enzyme, the failure of purine ribonucleoside to appear in the nucleic acids 

 of the rat may be explained. 342 



Three other purine-containing antibiotics have been isolated: (a) nucleocidin, 

 a glycoside of adenine in which there is a sulfamic ester of the carbohydrate resi- 

 due 345 ; (b) cordycepin, a 9-glycosyl derivative of adenine in which the sugar is a 

 branched-chain deoxy-hexose 346 ; and (c) angustmycin-C, a 9-D-psicofuranosyl glyco- 

 side of adenine. 347 ' 348 Several other synthetic purines or purine derivatives, such as 

 6-chloropurine, 349 ' 350 6-methylpurine, and their ribonucleosides, 351 and 2-fluoro- 

 adenosine, 352 also are extremely toxic to cells in culture, as well as to whole animals, 353 

 but little evidence concerning the mechanism of action of these compounds is avail- 

 able. 



The methylated purines, caffeine, theobromine, and theophylline, which are mildly 

 mutagenic, 243 have been reported to inhibit both ribo- and deoxyribonucleoside phos- 

 phorylases at high concentrations, although they themselves are apparently not 

 substrates 354 ; accordingly, their incorporation into the nucleic acids of E. colt was 

 negligible. 355 



339 N. Lofgren, B. Liining, and H. Hedstrom, Acta Chem. Scand. 8, 670 (1954). 



340 G. B. Brown and V. S. Weliky, J. Biol. Chem. 204, 1019 (1953). 



341 M. P. Gordon and G. B. Brown, J. Biol. Chem. 220, 927 (1956). 



342 G. R. Barker, J. B. Lloyd, M. D. Montague, and N. F. Wood, Biochem. J. 72, 

 9P (1959). 



343 D. A. Clarke, F. S. Philips, S. S. Sternberg, and C. C. Stock, Proc. Am. Assoc. 

 Cancer Research 2, 10 (1955). 



344 M. P. Gordon, O. M. Intrieri, and G. B. Brown, /. Biol. Chem. 229, 641 (1957). 



345 C. W. Waller, J. B. Patrick, W. Fulmor, and W. E. Meyer, J. Am. Chem. Soc. 79, 

 1011 (1957). 



346 H. R. Bentley, K. G. Cunningham, and F. S. Spring, J. Chem. Soc. p. 2301 (1951). 



347 H. Yunsten, J. Antibiotics (Japan) All, 244 (1958), quoted from Schroeder and 

 Hoeksema. 348 



348 W. Schroeder and H. Hoeksema, J. Am. Chem. Soc. 81, 1767 (1959). 



349 A. C. Sartorelli and B. A. Booth, Proc. Am. Assoc. Cancer Research 3, 59 (1959). 



350 A. Bendich, P. J. Russell, Jr., and J. J. Fox, J. Am. Chem. Soc. 76, 6073 (1954). 



351 J. J. Biesele, Proc. 3rd Natl. Cancer Conf. p. 405 (1957). 



352 J. A. Montgomery and K. Hewson, J. Am. Chem. Soc. 79, 4559 (1957). 



353 F. S. Philips, S. S. Sternberg, L. Hamilton, and D. A. Clarke, Ann. X. Y. Acad. 

 Sci. 60, 283 (1954). 



354 A. L. Koch and W. A. Lamont, J. Biol. Chem. 219, 189 (1956). 



355 A. L. Korh, J. Biol. Chem. 219, 181 (1956). 



