Synthesis and anti-HIV-1 activity of novel bicyclic nucleoside analogues restricted to an S-type conformation

Abstract

(1S,3R,4S)-3-Hydroxymethyl-1-(uracil-1-yl)-2,5-dioxabicyclo[2.2.1]heptane 9 and the corresponding cytosine derivative 10, nucleoside analogues with a novel bicyclic nucleoside structure 3, were synthesized in a few steps from the known 1-(3′-deoxy-β-D-psicofuranosyl)uracil 4. NOE experiments verified the bicyclic nucleosides to be restricted to the expected S-type furanose conformation while the nucleobase is in an anti-conformation. Both nucleosides proved to be devoid of anti-HIV activity in MT-4 cells, which further supports the hypothesis that conformational flexibility of the furanose ring in a nucleoside analogue is necessary to obtain both intracellular 5′-triphosphorylation and inhibition of HIV-1 reverse transcriptase.