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

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 °C, and then further down to −50 °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 μM. No cellular toxicity was observed at the highest concentration of the compound tested.

1H NMR-based base-pair studies as well as the results of in vitro anti-HIV screening of two isomeric nucleosides containing the title heterocyclic ring system are reported.Figure optionsDownload as PowerPoint slide