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Author Notes:

Correspondence: Raymond F. Schinazi, Center for AIDS Research, Department of Pediatrics, Emory University School of Medicine, and the Veterans Affairs Medical Center, Decatur, GA 30033; Tel: +1-404-728-7711; Fax: +1-404-728-7726; Email: rschina@emory.edu

Acknowledgments: Computational modeling was performed with assistance of the Emory School of Medicine Biomolecular Computing Resource (BIMCORE).

Disclosures: RFS is the founder and a major shareholder in RFS Pharma, LLC.

JWM is a consultant to RFS Pharma, LLC, and holds share options in the company.

Subject:

Research Funding:

This work was supported primarily by NIH grant 5R01-AI-071846, and in part by 5R37-AI-025899, 2P30-AI-050409, 5R37-AI-041980, and the Department of Veterans Affairs (to RFS).

Hardware and software was supported in part by Academic Excellence Grants from Sun Microsystems and Accelrys Corporation

Keywords:

  • l-nucleoside analogues
  • antiviral agents
  • HIV
  • HBV
  • 3′-azidopurine nucleosides

Synthesis, antiviral activity, cytotoxicity and cellular pharmacology of l-3′-azido-2′,3′-dideoxypurine nucleosides

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Journal Title:

European Journal of Medicinal Chemistry

Volume:

Volume 46, Number 9

Publisher:

, Pages 3832-3844

Type of Work:

Article | Post-print: After Peer Review

Abstract:

Microwave-assisted optimized transglycosylation reactions were used to prepare eleven modified l-3′-azido-2′,3′-dideoxypurine nucleosides. These l-nucleoside analogs were evaluated against HIV and hepatitis B virus. The l-3′-azido-2′,3′-dideoxypurines nucleosides were metabolized to nucleoside 5′-triphosphates in primary human lymphocytes, but exhibited weak or no antiviral activity against HIV-1. The nucleosides were also inactive against HBV in HepG2 cells. Pre-steady-state kinetic experiments demonstrated that the l-3′-azido-2′,3′-dideoxypurine triphosphates could be incorporated by purified HIV-1 reverse transcriptase, although their catalytic efficiency (kpol/Kd) of incorporation was low. Interestingly, a phosphoramidate prodrug of l-3′-azido-2′,3′-dideoxyadenosine exhibited anti-HIV-1 activity without significant toxicity.

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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