5'-O-phosphonomethyl-2',3'-dideoxynucleosides: synthesis and anti-HIV activity

J Med Chem. 1990 Sep;33(9):2481-7. doi: 10.1021/jm00171a023.


5'-O-Phosphonomethylation of different pyrimidine 2',3'-dideoxynucleosides was accomplished by reaction of the latter with diethyl [(p-toylsulfonyl)oxy]methanephosphonate (1) in the presence of sodium hydride. The base-phosphonomethylated (15-19) and sugar-phosphonomethylated (8-12) derivatives could be readily distinguished by 1H and 13C NMR and MS analysis. Protection of the uracil or thymine residue with a N3-benzoyl group failed to prevent base modification. However, O4-methyl-protected 2',3'-dideoxyuridine readily afforded the 5'-O-phosphonomethylated derivative 12, which was converted to both the 2',3'-didoxyuridine analogue 27 and the 2',3'-dideoxycytidine counterpart 29. The 5'-O-phosphonomethyl derivatives of 3'-deoxythymidine (23), 2',3'-dideoxyuridine, (27), 2',3'-dideoxycytidine (29), 3'-O-methylthymidine (26), and 3'-amino-3'-deoxythymidine (28) did not show an appreciable anti-HIV activity in MT-4 cells. In contrast, the 5'-O-phosphonomethyl derivatives of 3'-deoxy-3'-fluorothymidine (24) and 3'-azido-3'-deoxythymidine (25) inhibited HIV-1 cytopathogenicity by 50% at a concentration of approximately 1 microM.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antiviral Agents / chemical synthesis*
  • Antiviral Agents / pharmacology
  • Chemical Phenomena
  • Chemistry
  • Dideoxynucleosides / chemical synthesis*
  • Dideoxynucleosides / therapeutic use
  • HIV-1 / drug effects
  • Humans
  • Organophosphorus Compounds / chemical synthesis*
  • Organophosphorus Compounds / therapeutic use
  • Reverse Transcriptase Inhibitors
  • Structure-Activity Relationship


  • Antiviral Agents
  • Dideoxynucleosides
  • Organophosphorus Compounds
  • Reverse Transcriptase Inhibitors