Synthesis and antiviral activity of 2′-deoxy-2′-fluoro-2′-C-methyl-7-deazapurine nucleosides, their phosphoramidate prodrugs and 5′-triphosphates

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:21

Article

Shi, Junxing²  Zhou, Longhu^1,3  Zhang, Hongwang^1,3  McBrayer, Tamara R.²  Detorio, Mervi A.^1,3  Johns, Melissa^1,3  Bassit, Leda^1,3  Powdrill, Megan H.⁴  Whitaker, Tony²  Coats, Steven J.²  Schinazi, Raymond F.^1,3 

[1] Emory Univ, Sch Med, Dept Pediat, Ctr AIDS Res, Atlanta, GA 30322 USA

[2] RFS Pharma LLC, Tucker, GA 30084 USA

[3] Vet Affairs Med Ctr, Atlanta, GA 30033 USA

[4] McGill Univ, Dept Microbiol & Immunol, Montreal, PQ H3A 2B4, Canada

关键词: HCV;    Antiviral;    7-Deazapurine;    Nucleoside;    Nucleotide;    Prodrug;    Mitsunobu;   

DOI  :  10.1016/j.bmcl.2011.09.089

来源: Elsevier

【 摘 要 】

Thirty novel alpha- and beta-D-2'-deoxy-2'-fluoro-2'-C-methyl-7-deazapurine nucleoside analogs were synthesized and evaluated for in vitro antiviral activity. Several alpha- and beta-7-deazapurine nucleoside analogs exhibited modest anti-HCV activity and cytotoxicity. Four synthesized 7-deazapurine nucleoside phosphoramidate prodrugs (18-21) showed no anti-HCV activity, whereas the nucleoside triphosphates (22-24) demonstrated potent inhibitory effects against both wild-type and S282T mutant HCV polymerases. Cellular pharmacology studies in Huh-7 cells revealed that the 5'-triphosphates were not formed at significant levels from either the nucleoside or the phosphoramidate prodrugs, indicating that insufficient phosphorylation was responsible for the lack of anti-HCV activity. Evaluation of anti-HIV-1 activity revealed that an unusual alpha-form of 7-carbomethoxyvinyl substituted nucleoside (10) had good anti-HIV1 activity (EC(50) = 0.71 +/- 0.25 mu M; EC(90) = 9.5 +/- 3.3 mu M) with no observed cytotoxicity up to 100 mu M in four different cell lines. Published by Elsevier Ltd.

【 授权许可】

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