Inhibition of HIV-replication by 3'-fluoro-modified nucleosides with low cytotoxicity.

Abstract From a series of newly synthesized 3′-fluoro-modified nucleosides the C-5-chloro-substituted derivative of 2′,3′-dideoxy-3′-fluoro-uridine (FddUrd) and the 4-thio analogue of 2′,3′-dideoxy-3′-fluorothymidine (FddThd) ermerged as the most efficient and selective anti-HIV agents. Their antiviral doses (ED 50 ) proved to be 700-and 480-fold below their toxic doses (CD 50 ) 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 (IC 50 = 0.07 ± 0.01 and 0.04 ± 0.006 μM).