Acyclic nucleoside phosphonates containing the amide bond.

Area of Science:

• Medicinal Chemistry
• Organic Synthesis
• Antiviral Research

Background:

• Acyclic nucleoside phosphonates (ANPs) like acyclovir and tenofovir are crucial antiviral drugs.
• The P-CH2-O-CHR- fragment in ANPs influences their biological activity.
• Understanding linker rigidity and donor-acceptor properties is key to designing new ANPs.

Purpose of the Study:

• To synthesize and characterize novel ANPs by replacing the P-CH2-O-CHR- fragment with a P-CH2-HN-C(O)- residue.
• To investigate the influence of linker rigidity and donor-acceptor properties on the activity of these new ANPs.
• To evaluate the antiviral and antiproliferative potential of the synthesized compounds.

Main Methods:

• Synthesis of novel phosphonates via EDC coupling of ω-aminophosphonates and nucleobase-derived acetic acids.
• Structural confirmation and conformational analysis using 1H and 13C Nuclear Magnetic Resonance (NMR) spectroscopy.
• Antiviral assays against a broad spectrum of DNA and RNA viruses.
• Antiproliferative assays using L1210 and HeLa cell lines.

Main Results:

• Novel ANPs with a P-CH2-HN-C(O)- linkage were successfully synthesized in good yields.
• NMR data confirmed unrestricted rotation in methylene and 1,2-ethylidene linkers, and established antiperiplanar disposition in 1,3-propylidene linkers.
• The synthesized ANPs were inactive against a wide range of viruses up to 100 μM.
• Marginal antiproliferative activity was observed for a specific analog derived from (5-fluorouracyl-1-yl)acetic acid.

Conclusions:

• The replacement of the P-CH2-O-CHR- fragment with P-CH2-HN-C(O)- in ANPs did not yield potent antiviral agents.
• The synthesized compounds exhibit limited antiproliferative effects, suggesting potential for further structural optimization.
• This study provides insights into structure-activity relationships for ANPs with modified linker moieties.