Acyclic nucleoside phosphonates containing the amide bond: hydroxy derivatives

ABSTRACT: 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)CH(2), CH(OH)CH(2)CH(2), CH(2)CH(OH)CH(2)) as a replacement for the P–CH(2)–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)–CH(2)–N, P–CH(OH)–CH(2)–C and P–CH(2)–CH(OH)–C) in which antiperiplanar disposition of P and N/C atoms was deduced from (1)H and (13)C NMR spectral data. The synthesized analogs P–X–HNC(O)–CH(2)B [X=CH(OH)CH(2), CH(OH)CH(2)CH(2), CH(2)CH(OH)CH(2)] 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 IC(50) of 28.8 and 40.7 μM, respectively. GRAPHICAL ABSTRACT: [Image: see text]