Acyclic nucleoside phosphonates containing the amide bond

摘要

AbstractTo study the influence of a linker rigidity and donor–acceptor properties, the P–CH2–>O–CHR– fragment in acyclic nucleoside phosphonates (e.g., acyclovir, tenofovir) was replaced by the P–CH2–>HN–C(O)– residue. The respective phosphonates were synthesized in good yields by coupling the straight chain of ω-aminophosphonates and nucleobase-derived acetic acids with EDC. Based on the ¹H and ¹³C NMR data, the unrestricted rotation within the methylene and 1,2-ethylidene linkers in phosphonates from series >a and >b was confirmed. For phosphonates containing 1,3-propylidene (series >c) fragments, antiperiplanar disposition of the bulky O,O-diethylphosphonate and substituted amidomethyl groups was established. The synthesized ANPs P–X–HNC(O)–CH2B (X = CH2, CH2CH2, CH2CH2CH2, CH2OCH2CH2) appeared inactive in antiviral assays against a wide variety of DNA and RNA viruses at concentrations up to 100 μM while marginal antiproliferative activity (L1210 cells, IC50 = 89 ± 16 μM and HeLa cells, IC50 = 194 ± 19 μM) was noticed for the analog derived from (5-fluorouracyl-1-yl)acetic acid and O,O-diethyl (2-aminoethoxy)methylphosphonate.