Effect of stereoisomerism on the cellular pharmacology of beta-enantiomers of cytidine analogs in Hep-G2 cells

Biochemical Pharmacology
L T MartinJ P Sommadossi

Abstract

The beta-L enantiomers of 2',3'-dideoxycytidine (beta-L-ddC) and its 5-fuoro derivative, 2',3'-dideoxy-5-fluorocytidine (beta-L-FddC), were demonstrated to be active against human immunodeficiency virus (HIV) and hepatitis B virus (HBV) replication in vitro. In the present study, we investigated the cellular pharmacology of beta-L-ddC and beta-L-FddC and compared it with that of beta-D-2',3'-dideoxy-5-fluorocytidine (beta-D-FddC). Beta-L-FddC (10 microM) was found to be phosphorylated rapidly in Hep-G2 cells to its 5'-mono-, di-, and triphosphate derivatives with intracellular triphosphate levels achieving 26.6 +/- 10.9 pmol/10(6) cells after 72 hr. In contrast, the active 5'-phosphorylated derivative of beta-D-FddC achieved lower levels with triphosphate levels of only 2.3 +/- 0.5 pmol/ (10(6) cells under the same conditions. Beta-L-ddC was also phosphorylated rapidly. A 5'-diphosphocholine (18 +/- 5.8 pmol/10(6) cells) and a 5'-diphosphoethanolamine (13.6 +/- 0.9 pmol/10(6) cells) derivative were detected in beta-D-FddC-treated cells after 72 hr, whereas in beta-L-FddC- and beta-L-ddC-treated cells, only the 5'-diphosphocholine derivative (10.9 +/- 2.8 and 60.4 +/- 5.7 pmol/10(6) cells, respectively) was detected. Beta-L-FddC...Continue Reading

References

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Citations

Apr 4, 2007·Antimicrobial Agents and Chemotherapy·Brenda I Hernandez-SantiagoRaymond F Schinazi
Dec 20, 2000·Antimicrobial Agents and Chemotherapy·M L BryantJ P Sommadossi
Jun 28, 2005·Antimicrobial Agents and Chemotherapy·Brenda I Hernandez-SantiagoRaymond F Schinazi
Sep 21, 2001·Nucleosides, Nucleotides & Nucleic Acids·M L BryantJ P Sommadossi
Aug 27, 1999·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·J Y FengK S Anderson
Jan 20, 2000·Nucleosides & Nucleotides·V BoudouG Gosselin
Apr 2, 1999·Antimicrobial Agents and Chemotherapy·L T MartinJ P Sommadossi
Oct 16, 2004·Clinics in Liver Disease·David J Quan, Marion G Peters

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