title: Enhanced inhibition of orthopoxvirus replication in vitro by alkoxyalkyl esters of cidofovir and cyclic cidofovir.
abstract: The nucleotide phosphonates cidofovir (CDV) and cyclic cidofovir (cCDV) are potent antiviral compounds when administered parenterally but are not well absorbed orally. These compounds have been reported to have activity against orthopoxvirus replication in vitro and in animal models when administered parenterally or by aerosol. To obtain better oral activity, we synthesized a novel series of analogs of CDV and cCDV by esterification with two long-chain alkoxyalkanols, 3-hexadecyloxy-1-propanol (HDP-CDV; HDP-cCDV) or 3-octadecyloxy-1-ethanol (ODE-CDV; ODE-cCDV). Their activities were evaluated and compared with those of CDV and cCDV in human foreskin fibroblast (HFF) cells infected with vaccinia virus (VV) or cowpox virus (CV) using a plaque reduction assay. The 50% effective concentrations (EC(50)s) against VV in HFF cells for CDV and cCDV were 46.2 and 50.6 microM compared with 0.84 and 3.8 microM for HDP-CDV and HDP-cCDV, respectively. The EC(50)s for ODE-CDV and ODE-cCDV were 0.20 and 1.1 microM, respectively. The HDP analogs were 57- and 13-fold more active than the parent nucleotides, whereas the ODE analogs were 231- and 46-fold more active than the unmodified CDV and cCDV. Similar results were obtained using CV. Cytotoxicity studies indicated that although the analogs were more toxic than the parent nucleotides, the selective index was increased by 4- to 13-fold. These results indicate that the alkoxyalkyl esters of CDV and cCDV have enhanced activity in vitro and need to be evaluated for their oral absorption and efficacy in animal models.
authors.affiliation: University of Alabama School of Medicine, Birmingham, Alabama 35294-2170, USA. Kern@uab.edu
authors.forename: Earl R
authors.initials: ER
authors.lastname: Kern
authors.forename: Caroll
authors.initials: C
authors.lastname: Hartline
authors.forename: Emma
authors.initials: E
authors.lastname: Harden
authors.forename: Kathy
authors.initials: K
authors.lastname: Keith
authors.forename: Natalie
authors.initials: N
authors.lastname: Rodriguez
authors.forename: James R
authors.initials: JR
authors.lastname: Beadle
authors.forename: Karl Y
authors.initials: KY
authors.lastname: Hostetler
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D000077404:Cidofovir; D004396:Coloring Agents; D003500:Cyclization; D003596:Cytosine / Q000031:analogs & derivatives / Q000494:pharmacology*; D004952:Esters / Q000138:chemical synthesis / Q000494:pharmacology; D005347:Fibroblasts / Q000821:virology; D006801:Humans; D007202:Indicators and Reagents; D009499:Neutral Red; D009711:Nucleotides / Q000138:chemical synthesis / Q000494:pharmacology; D063065:Organophosphonates; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D018155:Orthopoxvirus / Q000187:drug effects*; D014709:Vero Cells; D010948:Viral Plaque Assay; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D004396:Coloring Agents; D004952:Esters; D007202:Indicators and Reagents; D009711:Nucleotides; D063065:Organophosphonates; D009943:Organophosphorus Compounds; D009499:Neutral Red; D003596:Cytosine; D000077404:Cidofovir