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d- and l-2‘,3‘-Didehydro-2‘,3‘-dideoxy-3‘-fluoro-carbocyclic Nucleosides:  Synthesis, Anti-HIV Activity and Mechanism of Resistance

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journal contribution
posted on 19.04.2007, 00:00 by Jianing Wang, Yunho Jin, Kimberly L. Rapp, Raymond F. Schinazi, Chung K. Chu
Introducing 2‘-fluoro substitution on the 2‘,3‘-double bond in carbocyclic nucleosides has provided biologically interesting compounds with potent anti-HIV activity. As an extension of our previous works in the discovery of anti-HIV agents, d- and l-2‘,3‘-unsaturated 3‘-fluoro carbocyclic nucleosides were synthesized and evaluated against HIV-1 in human peripheral blood mononuclear (PBM) cells. Among the synthesized l-series nucleosides, compounds 18, 19, 26 and 28 exhibited moderate antiviral activity (EC50 7.1 μM, 6.4 μM, 10.3 μM, and 20.7 μM, respectively), while among the d-series, the guanosine analogue (35, d-3‘-F-C-d4G) exhibited the most potent anti-HIV activity (EC50 0.4 μM, EC90 2.8 μM). However, the guanosine analogue 35 was cross-resistant to the lamivudine-resistant variants (HIV-1M184V). Molecular modeling studies suggest that hydrophobic interaction as well as hydrogen-bonding stabilize the binding of compound 35 in the active site of wild type HIV reverse transcriptase (HIV-RT). In the case of l-nucleosides, these two effects are opposite which results in a loss of binding affinity. According to the molecular modeling studies, cross-resistance of d-3‘-F-C-d4G (35) to M184V mutant may be caused by the realignment of the primer and template in the HIV-RTM184V interaction, which destabilizes the RT-inhibitor triphosphate complex, resulting in a significant reduction in anti-HIV activity of the d-guanine derivative 35.

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