Conformational analysis of nucleoside and nucleotide antibiotics possessing five-membered base rings. A comparison of the glycosyl barrier for purine, pyrimidine and imidazole rings

Abstract

The preferred conformations of the nucleosides comprising five-membered base rings viz., ribavirin, tetrazole, showdomycin and pyrazomycin and their 5'-nucleoside monophosphates have been explored by semiempirical potential energy calculations. The nature of the substituents on the five-membered base ring has been found to influence significantly the favoured glycosyl conformation and the hydrogen bonding between the base and the sugar. In the absence of any such hydrogen bonding, the imidazole nucleosides expectedly exhibit nearly 'free' rotation around the glycosyl bond for the commonly found C(3') endo and C(2') endo sugar ring conformations, thus increasing the probability of anti ⇋ high-anti r⇋ syn conformational interconversions as compared to common purine and pyrimidine nucleosides. However, the C(2') exo pucker imparts a high-energy barrier to glycosyl rotation, locking the base in the high-anti region. The conformation behaviour is significantly modified in the nucleoside 5'-monophosphates. The additional attractive interactions between the carboxamide and the phosphate groups favour the syn glycosyl conformation in the 5'-monophosphates of ribavirin as well as pyrazomycin smaller to guanosine 5'-monophosphate whereas the anti conformation is strongly favoured for the 5'-nucleotides of tetrazole and showdomycin similar to other common purine and pyrimidine nucleotides. The conformational properties of five-membered base ring nucleosides have a strong resemblance to purine nucleosides. Molecular modelling studies reveal that only the anti or high anti-glycosyl conformations of ribavirin can mimic the inosine base. It is suggested that experiments on the configurational isomers of ribavirin, viz., aravirin and cycloaravirin would conclusively establish the conformational specificity and biological function of ribavirin and analogues.