Nucleosides with self-complementary hydrogen-bonding motifs: synthesis and base-pairing studies of two nucleosides containing the imidazo[4,5-d]pyridazine ring system

Bioorg Med Chem. 2006 Sep 15;14(18):6359-67. doi: 10.1016/j.bmc.2006.05.043. Epub 2006 Jun 9.

Abstract

Synthesis and base-pairing studies of two 2'-deoxyribonucleosides, containing a common heterocyclic base, 7(4)-amino-5(6)H-imidazo[4,5-d]pyridazin-4(7)one (1 and 2), have been reported. The synthesis was accomplished by base-promoted deoxyribosylation of ethyl 5(4)-cyanoimidazole-4(5)-carboxylate (6), followed by ring-closure with hydrazine hydrate. The 1H NMR-based base-pair studies were conducted using DMF-d7 as a solvent by measuring changes in chemical shifts of the amino, hydrazide, imidazole H-2, and the sugar H-1' protons of the nucleosides with variations in concentrations and temperatures. Large downfield chemical shifts were observed for the NH, NH2, and to a lesser extent for the H-1' protons when the temperature was lowered from 25 to 0 degrees C, and then further down to -50 degrees C in 10 degree intervals. The observed experimental data are consistent with the results of molecular modeling studies. Nucleoside 2 exhibited low level antiviral activity against HIV-1 in CEM-SS cells with an IC50 of 89.2 microM. No cellular toxicity was observed at the highest concentration of the compound tested.

Publication types

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

MeSH terms

  • Anti-HIV Agents / chemical synthesis*
  • Anti-HIV Agents / chemistry*
  • Anti-HIV Agents / pharmacology
  • Base Pairing
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Deoxyribonucleosides / chemical synthesis*
  • Deoxyribonucleosides / chemistry*
  • Deoxyribonucleosides / pharmacology
  • HIV-1 / drug effects
  • Humans
  • Hydrogen Bonding
  • Magnetic Resonance Spectroscopy / methods
  • Microbial Sensitivity Tests
  • Models, Molecular
  • Molecular Structure
  • Nucleosides / chemistry*
  • Stereoisomerism
  • Structure-Activity Relationship
  • Temperature

Substances

  • 4-amino-1-((2'-deoxy)erythropentofuranosyl)-3H-imidazol(4,5-d)pyridazin-7(6H)-one
  • 7-amino-1-((2'-deoxy)erythropentofuranosyl)-1H-imidazol(4,5-d)pyridazin-4(5H)-one
  • Anti-HIV Agents
  • Deoxyribonucleosides
  • Nucleosides