Synthesis and antiviral activities of fluorinated acyclic nucleoside phosphonates

Novel alpha-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 alpha-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 EC(50) values of 5.6, 1.6 and 32 mu g mL(-1), respectively.