title: Synthesis and antiviral evaluation of phosphoramidate derivatives of (E)-5-(2-bromovinyl)-2'-deoxyuridine.
abstract: We report the design, synthesis and antiviral evaluation of a number of lipophilic, masked phosphoramidate derivatives of the antiherpetic agent (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU), designed to act as membrane soluble prodrugs of the free nucleotide. The phosphoramidate derivatives of BVDU that contain L-alanine exhibited potent anti herpes simplex virus type 1 and varicella-zoster virus activity but lost marked activity against thymidine kinase-deficient virus strains. The phosphoramidate derivative bearing the amino acid alpha,alpha-dimethylglycine showed poor activity in all cell lines tested. It appears that successful kinase bypass by phosphoramidates is highly dependent on the nucleoside analogue, amino acid and ester structure, as well as the cell line to which the drugs are exposed.
authors.affiliation: Welsh School of Pharmacy, Cardiff University, UK.
authors.forename: S A
authors.initials: SA
authors.lastname: Harris
authors.forename: C
authors.initials: C
authors.lastname: McGuigan
authors.forename: G
authors.initials: G
authors.lastname: Andrei
authors.forename: R
authors.initials: R
authors.lastname: Snoeck
authors.forename: E
authors.initials: E
authors.lastname: De Clercq
authors.forename: J
authors.initials: J
authors.lastname: Balzarini
mesh_terms: D000212:Acyclovir / Q000494:pharmacology; D000577:Amides / Q000737:chemistry*; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001973:Bromodeoxyuridine / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology*; D002460:Cell Line; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D024882:Drug Resistance, Viral; D005347:Fibroblasts; D014645:Herpesvirus 3, Human / Q000187:drug effects; D006801:Humans; D008168:Lung; D015394:Molecular Structure; D010756:Phosphoric Acids / Q000737:chemistry*; D018139:Simplexvirus / Q000187:drug effects; D013329:Structure-Activity Relationship; D014616:Vaccinia virus / Q000187:drug effects; D014721:Vesicular stomatitis Indiana virus / Q000187:drug effects
chemical_list: D000577:Amides; D000998:Antiviral Agents; D010756:Phosphoric Acids; C020235:brivudine; C011067:phosphoramidic acid; D001973:Bromodeoxyuridine; D000212:Acyclovir