Synthesis and conformational analysis of a locked analogue of carbovir built on a bicyclo[3.1.0]hex-2-enyl template

Nucleosides Nucleotides Nucleic Acids. 2003 Dec;22(12):2077-91. doi: 10.1081/ncn-120026631.

Abstract

The synthesis and biological evaluation of a carbovir analogue (5) built on a bicyclo[3.1.0]hex-2-enyl template is described. A conformational analysis using density functional theory at the B3LYP/6-31G* level has been carried out on the rigid pseudosugar template of 5, the cyclopentene moiety of carbovir and the bicyclo[3.1.0]hex-2-yl pseudosugars of two isomeric carbonucleosides (12 and 13) containing exo- and endo-fused cyclopropane rings. The results show that while the planar configuration of the fused cyclopentane ring of compound 5 helps retain weak anti-HIV activity, the ability of the cyclopentene ring of carbovir to easily adopt a planar or puckered conformation with little energy penalty may prove to be a crucial advantage. The bicyclo[3.1.0]hex-2-yl nucleosides 12 and 13 that were inactive against HIV exhibited stiffer resistance to having a planar, fused cyclopentane moiety.

MeSH terms

  • Anti-HIV Agents / chemical synthesis*
  • Anti-HIV Agents / chemistry
  • Anti-HIV Agents / pharmacology
  • Crystallography, X-Ray
  • Cyclopentanes / chemistry
  • Cyclopropanes / chemistry
  • Dideoxynucleosides / chemical synthesis*
  • Dideoxynucleosides / chemistry*
  • Dideoxynucleosides / pharmacology
  • Guanosine / analogs & derivatives*
  • HIV-1 / drug effects
  • HIV-2 / drug effects
  • Humans
  • Inhibitory Concentration 50
  • Magnetic Resonance Spectroscopy
  • Microbial Sensitivity Tests
  • Molecular Conformation
  • Molecular Structure
  • Stereoisomerism
  • Structure-Activity Relationship
  • T-Lymphocytes / virology
  • Thermodynamics

Substances

  • Anti-HIV Agents
  • Cyclopentanes
  • Cyclopropanes
  • Dideoxynucleosides
  • carbovir
  • Guanosine
  • cyclopropane