Prolinol-based nucleoside phosphonic acids: synthesis and properties

Area of Science:

• Medicinal Chemistry
• Organic Synthesis
• Nucleoside Analogues

Background:

• Trans-4-hydroxy-L-proline is a valuable chiral building block.
• Nucleotide analogues are crucial in antiviral and anticancer drug development.
• Developing novel nucleoside phosphonic acids requires efficient synthetic strategies.

Purpose of the Study:

• To synthesize novel prolinol-based nucleotide analogues.
• To investigate the conformational properties of these analogues.
• To evaluate their potential cytotoxic and antiviral activities.

Main Methods:

• Synthesis of O-protected 4-mesyloxyprolinol-N-methylphosphonates via stereochemical inversion.
• Alkylation of nucleobases to yield alpha- and beta-nucleotide analogues (L- and D-series).
• Nuclear Magnetic Resonance (NMR) spectroscopy for conformational analysis in aqueous solution at varying pH.

Main Results:

• Successful synthesis of all diastereoisomeric O-protected 4-mesyloxyprolinol-N-methylphosphonates.
• Generation of alpha- and beta-nucleotide analogues in both L- and D-configurations.
• NMR studies revealed a consistent predominant conformer regardless of protonation state.

Conclusions:

• The synthetic route effectively produced diverse prolinol-based nucleotide analogues.
• Conformational analysis provided insights into the structural behavior of these compounds.
• The synthesized compounds did not exhibit significant cytotoxic or antiviral activity.