Synthesis, solution conformation and anti-HIV activity of novel 3'-substituted-2',3'-dideoxy-5-hydroxymethyluridines and their 4,5-substituted analogues

Antivir Chem Chemother. 2003 May;14(3):127-38. doi: 10.1177/095632020301400302.


To decrease the toxicity of potent anti-HIV nucleosides 3'-azido-2',3'-dideoxythymidine (AZT) and 2',3'-dideoxy-3'-fluorothymidine (3'-FddThd, FLT), their new analogues, 3'-azido-2',3'-dideoxy-5-hydroxymethyluridine (3'-Az5HmddUrd) and 2',3'-dideoxy-3'-fluoro-5-hydroxymethyluridine (3'-F5HmddUrd), were synthesized. The reaction of 3'-azido-2',3'-dideoxyuridine (3'-AzddUrd) and 2',3'-dideoxy-3'-fluorouridine (3'-FddUrd) with formaldehyde, under strongly alkaline conditions and at elevated temperature, proceeded after 4 days to completion to afford the corresponding 5-hydroxymethyl derivatives 3'-Az5HmddUrd and 3'-F5HmddUrd in good yield. These compounds were also prepared by oxidation of AZT and FLT with the use of K2S2O8. 1H NMR analyses were subjected to the series of 3', 4 and 5-substituted pyrimidine 2'-deoxy- and 2',3'-dideoxynucleosides involving 3'-Az5HmddUrd and 3'-F5HmddUrd. Analysis of the sugar furanose ring puckering demonstrated that all 3'-fluorine derivatives exhibited strong domination of the S conformation (approximately 100%) while 3'-substitution by electron-donating groups, such as NH2, increased population of the N conformation. Experimentally observed substituent effect on the furanose ring puckering equilibrium was reconstructed in the 100 ps molecular dynamic trajectories obtained for AZT, FLT, dThd, 2',3'-ddThd and 3'-amino-2',3'-ddThd. It may be concluded that anti-HIV activity is linked to a direct interaction of the 3'-substituent with reverse transcriptase (RT) binding site. Anti-HIV activities of 3'-Az5HmddUrd and 3'-F5HmddUrd are lower than activity of AZT and FLT; however, 3'-Az5HmddUrd and 3'-F5HmddUrd are less toxic than AZT and FLT.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-HIV Agents / chemical synthesis*
  • Anti-HIV Agents / metabolism
  • Anti-HIV Agents / pharmacology
  • Cell Line
  • Deoxyuridine / analogs & derivatives*
  • Deoxyuridine / metabolism
  • Deoxyuridine / pharmacology
  • Dideoxynucleosides / chemical synthesis*
  • Dideoxynucleosides / metabolism
  • Dideoxynucleosides / pharmacology
  • HIV / drug effects
  • HIV / physiology
  • Humans
  • Magnetic Resonance Spectroscopy
  • Molecular Conformation
  • Reverse Transcriptase Inhibitors / metabolism
  • Reverse Transcriptase Inhibitors / pharmacology
  • Structure-Activity Relationship
  • Virus Replication / drug effects


  • Anti-HIV Agents
  • Dideoxynucleosides
  • Reverse Transcriptase Inhibitors
  • Deoxyuridine