Inhibition of HIV-replication by 3'-fluoro-modified nucleosides with low cytotoxicity.
From a series of newly synthesized 3'-fluoro-modified nucleosides the C-5-chloro-substituted derivative of 2',3'-dideoxy-3'-fluorouridine (FddUrd) and the 4-thio analogue of 2',3'-dideoxy-3'-fluorothymidine (FddUrd) emerged as the most efficient and selective anti-HIV agents. Their antiviral doses (ED50) proved to be 700-and 480-fold below their toxic doses (CD50) in MT-4 cells. The 50% inhibitory dose of cell proliferation of the 5-chloro-substituted FddUrd and its parent agent FddUrd was found to be in the millimolar range for various other human cell-lines and for mouse CFU-GM. The 5'-triphosphate of FddUrd as well as of its 5-Chloro derivative are demonstrated to be two of the most active and selective inhibitors of the HIV-reverse transcriptase (IC50 = 0.07 +/- 0.01 and 0.04 +/- 0.006 microM).
Matthes
E
E
Zentralinstitut für Molecularbiologie, Akademe der Wissenchaften der DDR, Berlin-Buch, GDR.
Lehmann
C
C
von Janta-Lipinski
M
M
Scholz
D
D
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002417:Cattle; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects*; D002478:Cells, Cultured; D003114:Colony-Forming Units Assay; D004257:DNA Polymerase II / Q000037:antagonists & inhibitors; D015195:Drug Design; D005461:Fluorine; D006098:Granulocytes / Q000166:cytology; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects; D007700:Kinetics; D008264:Macrophages / Q000166:cytology; D051379:Mice; D009705:Nucleosides / Q000494:pharmacology*; D018894:Reverse Transcriptase Inhibitors; D013329:Structure-Activity Relationship; D013950:Thymus Gland / Q000201:enzymology; D014779:Virus Replication / Q000187:drug effects*
D000998:Antiviral Agents; D009705:Nucleosides; D018894:Reverse Transcriptase Inhibitors; D005461:Fluorine; D004257:DNA Polymerase II