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

Area of Science:

• Medicinal Chemistry
• Structural Biology
• Organic Chemistry

Background:

• Drug conformational features significantly influence biological activity.
• Understanding nucleoside conformations is key to developing effective antiviral and anticancer agents.
• Fluorinated nucleosides are important therapeutic candidates.

Purpose of the Study:

• To determine the solid-state conformation of 1-(4'-azido-2'-deoxy-2'-fluoro-β-d-arabinofuranosyl) cytosine.
• To elucidate the solution-state conformations of three 2'-deoxy-2'-fluoro-4'-substituted nucleosides.
• To compare solid-state and solution conformations using thermodynamic principles.

Main Methods:

• Single-crystal X-ray crystallography for solid-state analysis.
• Altona-Haasnoot's equations and Nuclear Overhauser effect spectroscopy (NOESY) for solution-state analysis.
• Thermodynamic cycle analysis for conformational comparison.

Main Results:

• 1-(4'-azido-2'-deoxy-2'-fluoro-β-d-arabinofuranosyl) cytosine adopted a south-type (C-3'-exo) conformation in the solid-state.
• Three 4'-substituted nucleosides exhibited north-type (C-3'-endo) conformations in solution.
• North-type conformations in solution suggest enhanced stability against acidic and enzymatic degradation.

Conclusions:

• Solid-state and solution conformations of fluorinated nucleosides can differ significantly.
• The determined north-type solution conformations indicate improved stability for therapeutic applications.
• This conformational data provides valuable insights for the design of novel nucleoside-based drugs.