Acyclic nucleoside phosphonates containing the amide bond: hydroxy derivatives

To study the influence of a linker rigidity and changes in donor-acceptor properties, three series of nucleotide analogs containing a P-X-HN-C(O)- residue (X=CH(OH)CH₂, CH(OH)CH₂CH₂, CH₂CH(OH)CH₂) as a replacement for the P-CH₂-O-CHR- fragment in acyclic nucleoside phosphonates, e.g., adefovir, cidofovir, were synthesized. EDC proved to provide good yields of the analogs from the respective ω-amino-1- or -2-hydroxyalkylphosphonates and nucleobase-derived acetic acids. New phosphorus-nucleobase linkers are characterized by two fragments of the restricted rotation within amide bonds and in four-atom units (P-CH(OH)-CH₂-N, P-CH(OH)-CH₂-C and P-CH₂-CH(OH)-C) in which antiperiplanar disposition of P and N/C atoms was deduced from ¹H and ¹³C NMR spectral data. The synthesized analogs P-X-HNC(O)-CH₂B [X=CH(OH)CH₂, CH(OH)CH₂CH₂, CH₂CH(OH)CH₂] appeared inactive in antiviral assays on a wide variety of DNA and RNA viruses at concentrations up to 100 μM, while two phosphonates showed cytostatic activity towards myeloid leukemia (K-562) and multiple myeloma cells (MM.1S) with IC₅₀ of 28.8 and 40.7 μM, respectively.