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-β-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-β-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.
Keywords: 1H-NMR; NMR; nucleoside conformation; single-crystal X-ray crystallography; thermodynamics cycle.