496 R. E. HANDSCHUMACHER AND A. L>. WELCH 



give pyrazalo[3,4-d]pyrimidines have been extensively investigated. 326 Of a large 

 series, only the adenine analogs, the 4-amino or 4-alkylamino derivatives, inhibit 

 the growth of certain microorganisms or experimental tumors. Although the inhibi- 

 tory activity of these compounds is reversed by adenine, so also is it by certain other 

 pyrazalopyrimidines, a finding which suggests that the action of this type of com- 

 pound may not be specifically related to nucleotide metabolism. Further evidence 

 concerning this point is to be found in the inhibitory activity of the l-alkyl-4-amino 

 derivatives, since the normal point of attachment of ribose in these compounds is 

 blocked. However, these substances are sufficiently like the natural purines to be 

 substrates for xanthine oxidase and to inhibit the action of this enzyme on normal 

 purines, an effect which may be related to their biological properties. In this reaction, 

 pyrazaloadenine is converted into pyrazoloisoguanine, an even more effective in- 

 hibitor of xanthine oxidase. 327 ' 328 Furthermore, in the presence of a pyrophospho- 

 rylase from liver or yeast the ribonucleotides of both the adenine and guanine analogs 

 were formed. 329 



Among the antibiotics which contain a purine nucleoside structure, puromycin is 

 particularly interesting. It is an active trypanocidal agent 330 ' 331 and inhibitor of the 

 growth of other protozoa and multicellular organisms 332 ; in addition, the growth of 

 certain experimental neoplasms is suppressed by puromycin. 333 Each of these activ- 

 ities is exhibited more markedly by the aminonucleoside fragment of puromycin, 

 derived from 6-dimethylaminopurine, than by the parent compound. 334 The elegant 

 chemical studies on the structure and synthesis of this compound and related purine- 

 3'-amino-3'-deoxyribofuranosides, 335 as well as their biological properties, 332 have 

 been reviewed. Unfortunately, definitive statements concerning their effects on the 

 metabolism of nucleic acids cannot be made, except to note that certain unnatural 

 as well as natural purines will antagonize some but not all of the activities of this 

 type of compound. 336 - 337 Since 3'-amino-3'-deoxyadenosine also exhibited consider- 

 able inhibitory activity, the corresponding pyrimidine derivatives were prepared, 

 but these were inactive as inhibitors of the growth of trypanosomes or experimental 

 tumors. 338 



326 H. E. Skipper, R. K. Robins, and J. R. Thomson, Proc. Soc. Exptl. Biol. Med. 89, 

 594 (1955); Cancer Research 17, 579 (1957). 



327 P. Feigelson, J. D. Davidson, and R. K. Robins, J. Biol. Chem. 226, 993 (1957). 



328 P. Feigelson and J. D. Davidson, Cancer Research 18, 226 (1958). 



329 J. L. Way and R. E. Parks, Jr., J. Biol. Chem. 231, 467 (1958). 



330 R. I. Hewitt, W. S. Wallace, A. R. Gumble, E. R. Gill, and J. H. Williams, Am. J. 

 Trop. Med. Hyg. 2, 254 (1953). 



331 M. Agosin and T. von Brand, Antibiotics & Chemotherapy 4, 624 (1954). 



332 B. L. Hutchings, in "The Chemistry and Biology of Purines" (G. E. W. Wolsten- 

 holme and C. M. O'Connor, eds.), p. 177. Little, Brown, Boston, Mass., 1957. 



333 \y Troy, S. Smith, G. Personeus, L. Moser, E. James, S. J. Sparks, M. Stevens, 

 S. Halliday, D. McKenzie, and J. J. Oleson, in "Antibiotics Annual" (H. Welch 

 and F. Marti-Ibanez, eds.), p. 186. Medical Encyclopedia, New York, 1954. 



334 E. J. Tobie and B. Highman, Am. J. Trop. Med. Hyg. 5, 504 (1956). 



338 B. R. Baker, in "The Chemistry and Biology of Purines" (G. E. Wolstenholme 

 and C. M. O'Connor, eds.), p. 120. Little, Brown, Boston, Mass., 1957. 



336 R. I. Hewitt, A. R. Gumble, W. S. Wallace, and J. H. Williams, Antibiotics & 

 Chemotherapy 4, 1222 (1954). 



337 L. Bortle and J. J. Oleson, in "Antibiotics Annual" (H. Welch, ed.), p. 770. 

 Medical Encyclopedia, New York, 1955. 



338 H. M. Kissman and M. J. Weiss, J. Am. Chem. Soc. 80, 2575 (1958). 



