Synthesis and antiviral activities of fluorinated acyclic nucleoside phosphonates

Abstract

Novel α-fluoro derivatives of PME and HPMP were synthesized by electrophilic fluorination of 1-tert-butyldimethylsiloxy-2-[(diethoxyphosphoryl)methoxy]ethane 15 and 3-O-benzyl-2-O-[(diethoxyphosphoryl)methyl]-1-O-(tert-butyldimethylsiloxy)glycerol 22, respectively. The first series of acyclic nucleoside phosphonates possessing the α-fluoro(phosphoryl)methoxy group were prepared by coupling of F-PME or F-HPMP derivatives 18, 26, or 27 with the corresponding purine or pyrimidine nucleic bases under either modified Mitsunobu conditions or base-catalyzed alkylation conditions. Treatment of the diesters of F-PMEA 25a–c, F-PMEG 25f and F-PMEC 25g with concentrated aqueous ammonia led to the formation of the corresponding monoammonium salts of monoethyl phosphonate 30a, 30d, 30f and 30g. The synthesized fluorinated acyclic nucleoside phosphonates were tested against herpes viruses, respiratory viruses, hepatitis B virus and HIV. The monoammonium salt of the monoethyl ester of F-PMEA 30a was found to be active against human cytomegalovirus (HCMV), Epstein–Barr virus and measles with EC₅₀ values of 5.6, 1.6 and 32 µg mL^–1, respectively.