D- and L-2',3'-didehydro-2',3'-dideoxy-3'-fluoro-carbocyclic nucleosides: synthesis, anti-HIV activity and mechanism of resistance

J Med Chem. 2007 Apr 19;50(8):1828-39. doi: 10.1021/jm061304k. Epub 2007 Mar 21.


Introducing 2'-fluoro substitution on the 2',3'-double bond in carbocyclic nucleosides has provided biologically interesting compounds with potent anti-HIV activity. As an extension of our previous works in the discovery of anti-HIV agents, D- and L-2',3'-unsaturated 3'-fluoro carbocyclic nucleosides were synthesized and evaluated against HIV-1 in human peripheral blood mononuclear (PBM) cells. Among the synthesized L-series nucleosides, compounds 18, 19, 26 and 28 exhibited moderate antiviral activity (EC50 7.1 microM, 6.4 microM, 10.3 microM, and 20.7 microM, respectively), while among the D-series, the guanosine analogue (35, D-3'-F-C-d4G) exhibited the most potent anti-HIV activity (EC50 0.4 microM, EC90 2.8 microM). However, the guanosine analogue 35 was cross-resistant to the lamivudine-resistant variants (HIV-1M184V). Molecular modeling studies suggest that hydrophobic interaction as well as hydrogen-bonding stabilize the binding of compound 35 in the active site of wild type HIV reverse transcriptase (HIV-RT). In the case of L-nucleosides, these two effects are opposite which results in a loss of binding affinity. According to the molecular modeling studies, cross-resistance of D-3'-F-C-d4G (35) to M184V mutant may be caused by the realignment of the primer and template in the HIV-RTM184V interaction, which destabilizes the RT-inhibitor triphosphate complex, resulting in a significant reduction in anti-HIV activity of the D-guanine derivative 35.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Anti-HIV Agents / chemical synthesis*
  • Anti-HIV Agents / chemistry
  • Anti-HIV Agents / pharmacology
  • Cells, Cultured
  • Drug Resistance, Viral*
  • Guanine / analogs & derivatives*
  • Guanine / chemical synthesis
  • Guanine / chemistry
  • Guanine / pharmacology
  • HIV Reverse Transcriptase / chemistry
  • HIV Reverse Transcriptase / genetics
  • HIV-1 / drug effects*
  • HIV-1 / genetics
  • Humans
  • Hydrogen Bonding
  • Leukocytes, Mononuclear / drug effects
  • Leukocytes, Mononuclear / virology
  • Models, Molecular
  • Mutation
  • Nucleosides / chemical synthesis*
  • Nucleosides / chemistry
  • Nucleosides / pharmacology
  • Reverse Transcriptase Inhibitors / chemical synthesis*
  • Reverse Transcriptase Inhibitors / chemistry
  • Reverse Transcriptase Inhibitors / pharmacology
  • Stereoisomerism
  • Structure-Activity Relationship


  • 9-(2,3-dideoxy-2,3-didehydro-3-fluoro-6-hydroxymethylcyclopent-2-enyl)guanine
  • Anti-HIV Agents
  • Nucleosides
  • Reverse Transcriptase Inhibitors
  • Guanine
  • HIV Reverse Transcriptase