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Inhibition of HIV-replication by 3'-fluoro-modified nucleosides with low cytotoxicity
E Matthes1, C Lehmann, M von Janta-Lipinski
1Zentralinstitut für Molecularbiologie, Akademe der Wissenchaften der DDR, Berlin-Buch, GDR.
Abstract:
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).
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