A conformationally locked analogue of the anti-HIV agent stavudine. An important correlation between pseudorotation and maximum amplitude

J Med Chem. 2003 Jul 17;46(15):3292-9. doi: 10.1021/jm030116g.


The synthesis and biological evaluation of a bicyclo[3.1.0]hexene nucleoside designed as a conformational mimic of the anti-HIV agent stavudine (1, D4T) is described. The unsaturated methanocarbocyclic pseudosugar of N-MCD4T (2) was constructed from an iodo-substituted precursor by a DBU-catalyzed olefination reaction. Mitsunobu coupling with N(3)-benzoylthymine afforded the desired target after deprotection. Both D4T and N-MCD4T are in the North (N) hemisphere of the pseudorotational cycle but 70 degrees away from a perfect N (P = 0 degrees ) conformation toward the East and West hemispheres, respectively. Despite this large difference, the double bond reduces the puckering amplitude (nu(max)) of N-MCD4T to 6.81 degrees, and the superposition of both structures showed a RMS deviation of only 0.039 A. The combined structural analysis of P and nu(max) shows that while the value of P may differ substantially, the low nu(max) resolves the differences and becomes the dominant pseudorotational parameter. N-MCD4T is active against HIV-1 and HIV-2 in CEM, MT-2, and MT-4 cells, and while it is somewhat less potent than D4T, it also appears to be less toxic. The triphosphate (N-MCD4TTP) inhibits HIV reverse transcriptase with a 10-fold higher IC(50) than D4TTP. By virtue of its carbocyclic nature, N-MCD4T (2) is a more robust molecule stable to conditions that would cleave D4T.

MeSH terms

  • Animals
  • Anti-HIV Agents / chemical synthesis
  • Anti-HIV Agents / chemistry*
  • Anti-HIV Agents / pharmacology
  • Bridged Bicyclo Compounds / chemical synthesis*
  • Bridged Bicyclo Compounds / chemistry
  • Bridged Bicyclo Compounds / pharmacology
  • Cell Line
  • Crystallography, X-Ray
  • HIV Reverse Transcriptase / antagonists & inhibitors
  • HIV Reverse Transcriptase / chemistry
  • HIV-1 / drug effects
  • HIV-2 / drug effects
  • Humans
  • Lymphocytes / drug effects
  • Lymphocytes / virology
  • Molecular Conformation
  • Molecular Mimicry
  • Reverse Transcriptase Inhibitors / chemical synthesis
  • Reverse Transcriptase Inhibitors / chemistry*
  • Reverse Transcriptase Inhibitors / pharmacology
  • Stavudine / analogs & derivatives*
  • Stavudine / chemical synthesis
  • Stavudine / chemistry*
  • Stavudine / pharmacology
  • Stereoisomerism
  • Structure-Activity Relationship
  • Thymidine / analogs & derivatives
  • Thymidine / chemical synthesis*
  • Thymidine / chemistry
  • Thymidine / pharmacology


  • 1-(5-(hydroxymethyl)bicyclo(3.1.0)hex-3-en-2-yl)-5-methyl-1,3-dihydropyrimidine-2,4-dione
  • Anti-HIV Agents
  • Bridged Bicyclo Compounds
  • Reverse Transcriptase Inhibitors
  • Stavudine
  • HIV Reverse Transcriptase
  • Thymidine