The solid-state and solution conformations of 2′-deoxy-2′-fluoro-4′-substituted nucleosides

The conformational features of drugs are important with respect to their biological activity. In this report, we confirmed the solid-state conformation of 1-(4 '-azido-2 '-deoxy-2 '-fluoro-beta-d-arabinofuranosyl) cytosine using single-crystal X-ray crystallography and the conformations of three 2 '-deoxy-2 '-fluoro-4 '-substituted nucleosides in solution using Altona-Haasnoot's equations and Nuclear Overhauser effect spectroscopy (NOESY). Furthermore, we compared the preferred solid-state and solution conformation of these nucleosides with thermodynamics cycles to obtain more evidence of their conformations. The results showed 1-(4 '-azido-2 '-deoxy-2 '-fluoro-beta-d-arabinofuranosyl) cytosine was south type conformation (C-3 '-exo) in solid-state and three 4 '-substituted nucleosides were north type conformations (C-3 '-endo) in solution. The north type conformations in solution indicated these compounds were steady to acidic and enzymatic N-glycolysis.