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Author Notes:

Correspondence: Raymond F. Schinazi, Center for AIDS Research, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia 30322, and Veterans Affairs Medical Center, 1670 Clairmont Road, Decatur, Georgia 30033, USA; Tel.: +1-404-728-7711; Fax: +1-404-417-1535; Email: rschina@emory.edu

Acknowledgments: We thank Emilie Fromentin, Aleksandr Obikhod, Sarah Solomon, and Jason Grier for excellent technical assistance.

Disclosures: Dr. Schinazi is a founder and major shareholder of RFS Pharma, LLC and his laboratory received no funding from RFS Pharma or vice versa.

All other authors have no competing interests.

Subject:

Research Funding:

This work was supported in part by 2P30-AI-050409 (RFS), and the Department of Veterans Affairs (RFS), and by the Cancer Research Society (MG).

Dr. Götte received research grants from Tibotec, Merck, Gilead Sciences, AstraZeneca, Pfizer, and GlaxoSmithKline.

Keywords:

  • HCV
  • antiviral
  • 7-deazapurine
  • nucleoside
  • nucleotide
  • prodrug
  • Mitsunobu

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

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Journal Title:

Bioorganic and Medicinal Chemistry Letters

Volume:

Volume 21, Number 23

Publisher:

, Pages 7094-7098

Type of Work:

Article | Post-print: After Peer Review

Abstract:

Thirty novel α- and β-D-2′-deoxy-2′-fluoro-2′-C-methyl-7-deazapurine nucleoside analogs were synthesized and evaluated for in vitro antiviral activity. Several α- and β-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 α-form of 7-carbomethoxyvinyl substituted nucleoside (10) had good anti-HIV-1 activity (EC50 = 0.71 ± 0.25 μM; EC90 = 9.5 ± 3.3 μM) with no observed cytotoxicity up to 100 μM in four different cell lines.

Copyright information:

© 2011 Elsevier Ltd. All rights reserved.

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommerical-NoDerivs 3.0 Unported License (http://creativecommons.org/licenses/by-nc-nd/3.0/).

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