Nucleosides of azathioprine and thiamiprine as antiarthritics

J Med Chem. 1989 Jul;32(7):1471-5. doi: 10.1021/jm00127a013.


Azathioprine [Imuran; 6-[(1-methyl-4-nitro-1H-imidazol-5-yl)thio]-1H-purine] is a widely used immunosuppressive and antiarthritic drug. For the sake of comparison, the riboside, the 2'-deoxyriboside, and the arabinoside of azathioprine and its 2-amino congener, thiamiprine, were prepared by an enzymatic method. In vitro, the cytotoxicities of these aglycons and their nucleosides were similar (ED50 = 0.8-2 microM), except for the arabinosides, which were nontoxic (ED50 greater than 100 microM). In vivo, their activities were compared in the rat adjuvant arthritis model. The ribosides and 2'-deoxyribosides were less potent than their corresponding aglycons. The safety indexes of these nucleosides were comparable to those of the corresponding aglycons except for the 2'-deoxyriboside of azathioprine, which had an appreciably lower safety index than did azathioprine. Both arabinosides were inactive and nontoxic. All of the aglycons tested (6-mercaptopurine, azathioprine, 6-thioguanine, and thiamiprine) were of similar potency. However, azathioprine had a more favorable therapeutic index than did 6-mercaptopurine. Similarly, thiamiprine was safer than was 6-thioguanine. In this model, the S-(1-methyl-4-nitro-1H-imidazol-5-yl) moiety imparted greater safety to these thiopurines by decreasing toxicity but not affecting potency.

MeSH terms

  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal*
  • Arthritis, Experimental / drug therapy
  • Azathioprine / analogs & derivatives*
  • Azathioprine / pharmacology*
  • Azathioprine / therapeutic use
  • Cell Survival / drug effects
  • Cells, Cultured
  • Chemical Phenomena
  • Chemistry
  • Disease Models, Animal
  • Female
  • Humans
  • Nucleosides / pharmacology*
  • Rats


  • Anti-Inflammatory Agents, Non-Steroidal
  • Nucleosides
  • thiamiprine
  • Azathioprine