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

• Type of Material: Article
• Authors: HongWang Zhang, Emory University; Mervi Acuzar Detorio, Emory University; Brian D. Herman, University of Pittsburgh; Sarah Solomon, Emory University; Leda C. Bassit, Emory University; James H Nettles, Emory University; Aleksandr Obikhod, Emory University; Si-jia Tao, Emory University; John W. Mellors, University of Pittsburgh; Nicolas Sluis-Cremer, University of Pittsburgh; Raymond F Schinazi, Emory University
• Language: English
• Date: 2011-09
• Publisher: Elsevier
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2011 Elsevier Ltd. All rights reserved.
• License: Creative Commons Attribution-NonCommerical-NoDerivs 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.1016%2Fj.ejmech.2011.05.051
• Title of Journal or Parent Work: European Journal of Medicinal Chemistry
• ISSN: 0223-5234
• Volume: 46
• Issue: 9
• Start Page: 3832
• End Page: 3844
• Grant/Funding Information: Hardware and software was supported in part by Academic Excellence Grants from Sun Microsystems and Accelrys Corporation; 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).
• Keywords: antiviral agents; l-nucleoside analogues; HIV; HBV; 3′-azidopurine nucleosides
• Research Categories: Chemistry, Pharmaceutical

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.