title: Structure-activity relationship between (E)-5-(2-bromovinyl)- and 5-vinyl-1-beta-D-arabinofuranosyluracil (BV-araU, V-araU) in inhibition of Epstein-Barr virus replication.
abstract: The structure-activity relationship between (E)-5-(2-bromovinyl)- and 5-vinyl-1-beta-D-arabinofuranosyluracil (BV-araU and V-araU) in inhibition of Epstein-Barr virus (EBV) was evaluated. Both V-araU and BV-araU effectively inhibited EBV replication in virus-producer P3HR-1(LS) cells, as determined by DNA-DNA hybridization. The 50% effective doses (ED50) for viral DNA replication were 0.005 and 0.3 microM for V-araU and BV-araU, respectively. The in vitro therapeutic index was 4000 for V-araU and 1300 for BV-araU. Synthesis of EBV-induced polypeptides with molecular weights of 145,000 (145, 140, 130, and 110 kDa) was significantly inhibited by both drugs. Only V-araU inhibited the synthesis of 85-, 55-, and 32-kDa polypeptides by approx. 50%. Kinetic analysis of inhibition and reversibility of EBV DNA replication after removal of the drugs indicated that BV-araU has a more prolonged inhibitory effect than V-araU. These results indicate that the substitution of H by Br in the 5-vinyl group results in marked reduction in anti-EBV activity while prolonging the drug effect and diminishing cytotoxicity.
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill.
authors.forename: J C
authors.initials: JC
authors.lastname: Lin
authors.forename: J
authors.initials: J
authors.lastname: Reefschläger
authors.forename: G
authors.initials: G
authors.lastname: Herrmann
authors.forename: J S
authors.initials: JS
authors.lastname: Pagano
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D001086:Arabinofuranosyluracil / Q000031:analogs & derivatives* / Q000494:pharmacology; D002051:Burkitt Lymphoma; D004279:DNA, Viral / Q000096:biosynthesis* / Q000737:chemistry / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004854:Herpesvirus 4, Human / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D010455:Peptides / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D014764:Viral Proteins / Q000037:antagonists & inhibitors; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D004279:DNA, Viral; D010455:Peptides; D014764:Viral Proteins; D001086:Arabinofuranosyluracil; C048730:5-vinyl-1-arabinofuranosyluracil; C031368:sorivudine