title: Phosphonoformate and phosphonoacetate derivatives of 5-substituted 2'-deoxyuridines: synthesis and antiviral activity.
abstract: The synthesis of potential "combined prodrugs" wherein phosphonoformate or phosphonoacetate was attached to the 5'-position of 2'-deoxyuridine, 2'-deoxythymidine, 5-iodo-2'-deoxyuridine (IDU), 5-(2-chloroethyl)-2'-deoxyuridine (CEDU), or 5-(2-bromovinyl)-2'-deoxyuridine (BVDU) or to the 3'-position of CEDU is described. The antiviral activities of these derivatives and of reference compounds were compared in Vero, HEp-2, and primary rabbit kidney cells against herpes simplex virus types 1 and 2 (HSV-1 and -2). The CEDU and BVDU analogues were also evaluated against systemic and intracutaneous HSV-1 infection in mice. The nature of the 5-substituent proved critical for antiviral activity, since only the 5-iodo-, 5-(2-bromovinyl)-, and 5-(2-chloroethyl)-substituted derivatives were inhibitory to the herpesviruses. Furthermore, the type specificity is determined by the nature of the 5-substituent: the IDU analogues were similarly inhibitory to HSV-1 and -2 whereas the CEDU and BVDU analogues inhibited HSV-2 replication only at considerably higher concentrations than HSV-1. In vivo, several derivatives were shown to possess significant antiviral activity; however, none surpassed its respective parent compound, CEDU or BVDU, in potency. It seems improbable, therefore, that a synergistic effect between PFA or PAA and the nucleoside analogue occurred. The extent of in vitro and in vivo activity of the CEDU and BVDU 5'-phosphonoformates and 5'-phosphonoacetates is most plausibly explained by the ease by which the "combined prodrugs" are hydrolyzed and the parent compound, CEDU and BVDU, respectively, is released.
authors.affiliation: Institute of Organic Chemistry, Technical University Graz, Austria.
authors.forename: H
authors.initials: H
authors.lastname: Griengl
authors.forename: W
authors.initials: W
authors.lastname: Hayden
authors.forename: G
authors.initials: G
authors.lastname: Penn
authors.forename: E
authors.initials: E
authors.lastname: De Clercq
authors.forename: B
authors.initials: B
authors.lastname: Rosenwirth
mesh_terms: D000818:Animals; D000998:Antiviral Agents; D001973:Bromodeoxyuridine / Q000031:analogs & derivatives / Q000494:pharmacology; D002460:Cell Line; D055598:Chemical Phenomena; D002621:Chemistry; D003857:Deoxyuridine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D017245:Foscarnet; D006561:Herpes Simplex / Q000188:drug therapy; D051379:Mice; D009943:Organophosphorus Compounds / Q000037:antagonists & inhibitors; D004364:Pharmaceutical Preparations / Q000138:chemical synthesis*; D010746:Phosphonoacetic Acid / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors*; D011355:Prodrugs / Q000138:chemical synthesis* / Q000494:pharmacology; D011817:Rabbits; D018139:Simplexvirus / Q000187:drug effects*; D013936:Thymidine / Q000494:pharmacology; D014709:Vero Cells
chemical_list: D000998:Antiviral Agents; D009943:Organophosphorus Compounds; D004364:Pharmaceutical Preparations; D011355:Prodrugs; C020235:brivudine; D017245:Foscarnet; C047370:5-(2-chloroethyl)-2'-deoxyuridine; D001973:Bromodeoxyuridine; D010746:Phosphonoacetic Acid; D013936:Thymidine; D003857:Deoxyuridine