title: The anti-hepatitis B virus activities, cytotoxicities, and anabolic profiles of the (-) and (+) enantiomers of cis-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine.
abstract: The anti-hepatitis B (anti-HBV) activities of the (-) and (+) enantiomers of cis-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine (2'-deoxy-3'-thia-5-fluorocytosine [FTC]) were studied by using an HBV-transfected cell line (HepG2 derivative 2.2.15, subclone P5A). The (-) isomer was found to be a potent inhibitor of viral replication, with an apparent 50% inhibitory concentration of 10 nM, while the (+) isomer was found to be considerably less active. Both isomers showed minimal toxicity to HepG2 cells (50% inhibitory concentration, > 200 microM) and showed minimal toxicity in the human bone marrow progenitor cell assay. In accord with the cellular antiviral activity data, the 5'-triphosphate of (-)-FTC inhibited viral DNA synthesis in an endogenous HBV DNA polymerase assay, while the 5'-triphosphate of the (+) isomer was inactive. Unphosphorylated (-)-FTC did not inhibit product formation in the endogenous assay, suggesting that the antiviral activity of the compound is dependent on anabolism to the 5'-triphosphate. Both (-)- and (+)-FTC were anabolized to the corresponding 5'-triphosphates in chronically HBV-infected HepG2 cells. The rate of accumulation and the steady-state concentration of the 5'-triphosphate of (-)-FTC were greater. Also, (-)-FTC was not a substrate for cytidine deaminase and, therefore, is not subject to deamination and conversion to an inactive uridine analog. The (+) isomer is, however, a good substrate for cytidine deaminase.
authors.affiliation: Division of Virology, Burroughs Wellcome Co., Research Triangle Park, North Carolina 27709.
authors.forename: P A
authors.initials: PA
authors.lastname: Furman
authors.forename: M
authors.initials: M
authors.lastname: Davis
authors.forename: D C
authors.initials: DC
authors.lastname: Liotta
authors.forename: M
authors.initials: M
authors.lastname: Paff
authors.forename: L W
authors.initials: LW
authors.lastname: Frick
authors.forename: D J
authors.initials: DJ
authors.lastname: Nelson
authors.forename: R E
authors.initials: RE
authors.lastname: Dornsife
authors.forename: J A
authors.initials: JA
authors.lastname: Wurster
authors.forename: L J
authors.initials: LJ
authors.lastname: Wilson
authors.forename: J A
authors.initials: JA
authors.lastname: Fyfe
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology* / Q000633:toxicity; D002470:Cell Survival / Q000187:drug effects; D003564:Cytidine Deaminase / Q000378:metabolism; D004279:DNA, Viral / Q000096:biosynthesis / Q000187:drug effects; D000068679:Emtricitabine / Q000031:analogs & derivatives; D006131:Growth Inhibitors / Q000633:toxicity; D006515:Hepatitis B virus / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D008252:Macaca fascicularis; D010766:Phosphorylation / Q000187:drug effects; D013237:Stereoisomerism; D013379:Substrate Specificity; D016047:Zalcitabine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000633:toxicity
chemical_list: D000998:Antiviral Agents; D004279:DNA, Viral; D006131:Growth Inhibitors; D016047:Zalcitabine; D003564:Cytidine Deaminase; D000068679:Emtricitabine; C075889:Racivir