Synthesis, antiviral, and antitumor activity of 2-substituted purine methylenecyclopropane analogues of nucleosides

Bioorg Med Chem. 2006 Feb 15;14(4):1247-54. doi: 10.1016/j.bmc.2005.09.052. Epub 2005 Oct 18.

Abstract

The Z- and E-2-fluoro- and 2-chloropurine methylenecyclopropanes 9a,b and 10a,b as well as enantiomeric Z-isoguanine methylenecyclopropanes 11a,b and their phenyl phosphoralaninate pronucleotides 11c,d were synthesized and their antiviral activity against several viruses was evaluated. Fluoro analogues 9a and 10a were active against human cytomegalovirus but they were cytotoxic at approximately the same concentrations. Chloro derivatives 9b and 10b were non-cytotoxic and effective against Epstein-Barr virus in Daudi cells. Isoguanine analogues 11a-d lacked antiviral activity but pronucleotides 11c,d were substrates for porcine liver esterase. From the group of 9a,b and 10a,b, the fluoro analogues 9a and 10a exhibited antitumor activity but only the Z-isomer 9a had a selective effect.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Antiviral Agents / chemical synthesis*
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology*
  • Cell Line, Tumor
  • Cyclopropanes / chemistry*
  • Humans
  • Hydrolysis
  • Magnetic Resonance Spectroscopy
  • Mice
  • Molecular Structure
  • Nucleosides / chemical synthesis
  • Nucleosides / chemistry*
  • Nucleosides / pharmacology*
  • Nucleotides / chemistry
  • Purines / chemistry
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents
  • Antiviral Agents
  • Cyclopropanes
  • Nucleosides
  • Nucleotides
  • Purines
  • methylenecyclopropane