Newly synthesized L-enantiomers of 3'-fluoro-modified beta-2'-deoxyribonucleoside 5'-triphosphates inhibit hepatitis B DNA polymerases but not the five cellular DNA polymerases alpha, beta, gamma, delta, and epsilon nor HIV-1 reverse transcriptase

J Med Chem. 1998 Jun 4;41(12):2040-6. doi: 10.1021/jm9704210.

Abstract

Novel beta-L-2',3'-dideoxy-3'-fluoro nucleosides were synthesized and further converted to their 5'-triphosphates. Their inhibitory activities against hepatitis B virus (HBV) and duck hepatitis B virus (DHBV) DNA polymerases, human immunodeficiency virus (HIV) reverse transcriptase (RT), and the cellular DNA polymerases alpha, beta, gamma, delta, and epsilon were investigated and compared with those of the corresponding 3'-fluoro-modified beta-d-analogues. The 5'-triphosphates of 3'-deoxy-3'-fluoro-beta-L-thymidine (beta-L-FTTP), 2',3'-dideoxy-3'-fluoro-beta-L-cytidine (beta-L-FdCTP), and 2',3'-dideoxy-3'-fluoro-beta-l-5-methylcytidine (beta-L-FMetdCTP) emerged as effective inhibitors of HBV/DHBV DNA polymerases (IC50 = 0.25-10.4 microM). They were either equally (FTTP) or less (FMetdCTP, FdCTP) effective than their beta-d-counterparts. Also the 5'-triphosphate of beta-L-thymidine (beta-L-TTP) was shown to be a strong inhibitor of these two viral enzymes (IC50 = 0.46/1.0 microM). However, all beta-L-FdNTPs (also beta-L-TTP) were inactive against HIV-RT, a result which contrasts sharply with the high efficiency of the beta-D- FdNTPs against this polymerase. Between the cellular DNA polymerases only the beta and gamma enzymes displayed a critical susceptibility to beta-D-FdNTPs which is largely abolished by the beta-L-enantiomers. These results recommend beta-L-FTdR, beta-L-FCdR, and beta-L-FMetCdR for further evaluation as selective inhibitors of HBV replication at the cellular level.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Cattle
  • DNA Polymerase I / antagonists & inhibitors
  • DNA Polymerase I / isolation & purification
  • DNA Polymerase II / antagonists & inhibitors
  • DNA Polymerase II / isolation & purification
  • DNA Polymerase III / antagonists & inhibitors
  • DNA Polymerase III / isolation & purification
  • DNA Polymerase beta / antagonists & inhibitors
  • DNA Polymerase beta / isolation & purification
  • DNA Polymerase gamma
  • DNA-Directed DNA Polymerase / isolation & purification
  • Enzyme Inhibitors* / chemical synthesis
  • Enzyme Inhibitors* / chemistry
  • Enzyme Inhibitors* / pharmacology
  • HIV Reverse Transcriptase / antagonists & inhibitors*
  • HIV Reverse Transcriptase / isolation & purification
  • HeLa Cells
  • Hepatitis B / enzymology*
  • Hepatitis B Virus, Duck / enzymology
  • Humans
  • Kinetics
  • Nucleic Acid Synthesis Inhibitors*
  • Organophosphates* / chemical synthesis
  • Organophosphates* / chemistry
  • Organophosphates* / pharmacology
  • Placenta / enzymology
  • Pyrimidine Nucleosides* / chemical synthesis
  • Pyrimidine Nucleosides* / chemistry
  • Pyrimidine Nucleosides* / pharmacology
  • Reverse Transcriptase Inhibitors / chemical synthesis
  • Reverse Transcriptase Inhibitors / chemistry
  • Reverse Transcriptase Inhibitors / pharmacology
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Nucleic Acid Synthesis Inhibitors
  • Organophosphates
  • Pyrimidine Nucleosides
  • Reverse Transcriptase Inhibitors
  • HIV Reverse Transcriptase
  • DNA Polymerase I
  • DNA Polymerase II
  • DNA Polymerase III
  • DNA Polymerase beta
  • DNA Polymerase gamma
  • DNA-Directed DNA Polymerase