Acyclic nucleoside phosphonates containing the amide bond: hydroxy derivatives

• Published in: Monatshefte für Chemie 2019-01, Vol.150 (4), p.733-745
• Main Authors: Głowacka, Iwona E., Piotrowska, Dorota G., Andrei, Graciela, Schols, Dominique, Snoeck, Robert, Wróblewski, Andrzej E.
• Format: Article
• Language: English
• Subjects: Analogs; Analytical Chemistry; Atomic properties; Chemistry; Chemistry and Materials Science; Chemistry/Food Science; Deoxyribonucleic acid; DNA; Inorganic Chemistry; NMR; Nuclear magnetic resonance; Nucleosides; Organic Chemistry; Original Paper; Phosphonates; Physical Chemistry; Ribonucleic acid; RNA; Synthesis; Theoretical and Computational Chemistry
• ISSN: 0026-9247; 1434-4475
• DOI: 10.1007/s00706-019-2351-y

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