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
| Autor: | Donald J. Nelson, P A Furman, R E Dornsife, Lloyd Frick, D C Liotta, M T Paff, J A Wurster, James A. Fyfe, L J Wilson, Michelle G. Davis |
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| Rok vydání: | 1992 |
| Předmět: |
Hepatitis B virus
Cell Survival Stereochemistry Deamination Stereoisomerism Antiviral Agents Substrate Specificity chemistry.chemical_compound Biosynthesis Cytidine Deaminase Animals Emtricitabine Humans Pharmacology (medical) Hydroxymethyl Phosphorylation Pharmacology Zalcitabine Chemistry Biological activity Cytidine deaminase Growth Inhibitors Uridine Macaca fascicularis Infectious Diseases DNA Viral Cytosine Research Article |
| Zdroj: | Antimicrobial Agents and Chemotherapy. 36:2686-2692 |
| ISSN: | 1098-6596 0066-4804 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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