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.
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.
Furman
P A
PA
Division of Virology, Burroughs Wellcome Co., Research Triangle Park, North Carolina 27709.
Davis
M
M
Liotta
D C
DC
Paff
M
M
Frick
L W
LW
Nelson
D J
DJ
Dornsife
R E
RE
Wurster
J A
JA
Wilson
L J
LJ
Fyfe
J A
JA
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
D000998:Antiviral Agents; D004279:DNA, Viral; D006131:Growth Inhibitors; D016047:Zalcitabine; D003564:Cytidine Deaminase; D000068679:Emtricitabine; C075889:Racivir