3-Phenyl-5,6,7,8-tetrahydropyrimido[4,5-c]pyridazin-7-one as nucleobase substitute in DNA: synthesis of the 2′-deoxyribonucleoside, cyclonucleoside formation, and base pairing in oligonucleotides

A 5,6,7,8-tetrahydro derivative of 3-phenylpyrimido[4,5-c]pyridazin-7-one 2'-deoxyribonudeoside (3) was designed as a dC mimic to form silver-mediated base pairs in DNA duplexes as reported for pyrrolo-dC 1 and imidazole-dC 2. Compared to the fully aromatic molecule 4, the nucleobase of 3 is hydrogenated with carbon-5 in the sp(3) hybridization state and an additional hydrogen atom located at nitrogen-8. Under aromatization conditions, nucleoside 3 undergoes cyclization to the 5,5'-cyclonucleoside 6. The reaction, is clearly related to the cyclization reported for 8-azapurine nucleosides. Nucleoside 3 was converted to the phosphoramidite 13 and was incorporated in oligonucleotides. In a distinct tautomeric state nucleoside 3 can be considered as a dT mimic while in another as dC derivative. Consequently, compound 3 forms a base pair with dA and dG. However, the desired silver-mediated base pair proposed for two identical nucleoside 3 residues facing each other could not be detected. (C) 2015 Elsevier Ltd. All rights reserved.