Effect of Substituents on the Tautomerism of Pyridone Nucleoside Analogs

Abstract

Nucleobase analogs are important tools in medicine and chemical biology, as they offer molecular targeting options for the intervention in genetic processes. Pyridone C-nucleosides have been shown to pair with adenine in complementary strands, but a switch from the lactam to lactim form may change their base pairing preference. We synthesized 6-fluoropyridone analogs of aciclovir and cidofovir, which we assumed to be in the lactam form, but were found to lack activity against hepatitis B virus (HBV). Spectroscopic data then indicated that they are predominantly in the lactim form, with a hydrogen bonding pattern suitable for G. The tautomerism of fluoropyridones was then studied by UV-spectroscopy and quantum-chemical calculations. The UV spectroscopic pattern for either tautomer was corroborated by synthesizing N- and O-methylated model compounds, and measuring their spectra. The tautomeric equilibrium of selected other substituted pyridones is predicted, based on density-functional theory calculations.