title: Nucleosides with self-complementary hydrogen-bonding motifs: synthesis and base-pairing studies of two nucleosides containing the imidazo[4,5-d]pyridazine ring system.
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.
authors.affiliation: Laboratory for Drug Design and Synthesis, Department of Chemistry and Biochemistry, University of Maryland, Baltimore County, Baltimore, MD 21250, USA.
authors.forename: Ravi K
authors.initials: RK
authors.lastname: Ujjinamatada
authors.forename: Robin L
authors.initials: RL
authors.lastname: Paulman
authors.forename: Roger G
authors.initials: RG
authors.lastname: Ptak
authors.forename: Ramachandra S
authors.initials: RS
authors.lastname: Hosmane
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D020029:Base Pairing; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003853:Deoxyribonucleosides / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D006860:Hydrogen Bonding; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D009705:Nucleosides / Q000737:chemistry*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013696:Temperature
chemical_list: C514597:4-amino-1-((2'-deoxy)erythropentofuranosyl)-3H-imidazol(4,5-d)pyridazin-7(6H)-one; C514596:7-amino-1-((2'-deoxy)erythropentofuranosyl)-1H-imidazol(4,5-d)pyridazin-4(5H)-one; D019380:Anti-HIV Agents; D003853:Deoxyribonucleosides; D009705:Nucleosides