Synthesis, evaluation of anti-HIV-1 and anti-HCV activity of novel 2′,3′-dideoxy-2′,2′-difluoro-4′-azanucleosides

• Type of Material: Article
• Authors: Saul Martinez-Montero, University of California at San Diego; Susana Fernandez, University of Oviedo; Yogesh S. Sanghvi, Rasayan Inc.; Emmanuel A. Theodorakis, University of California at San Diego; Mervi Detorio, Emory University; Tamara Mcbrayer, RFS Pharma LLC; Tony Whitaker, RFS Pharma LLC; Raymond F Schinazi, Emory University; Vicente Gotor, University of Oviedo; Miguel Ferrero, University of Oviedo
• Language: English
• Date: 2012-12-01
• Publisher: Elsevier
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2012 Elsevier Ltd. Published by Elsevier Ltd. All rights reserved.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.bmc.2012.09.026
• Title of Journal or Parent Work: Bioorganic and Medicinal Chemistry
• ISSN: 0968-0896
• Volume: 20
• Issue: 23
• Start Page: 6885
• End Page: 6893
• Grant/Funding Information: We thank the National Science Foundation for instrumentation grants CHE9709183 and CHE0741968.; Financial support of this work by the Spanish Ministerio de Educación y Ciencia (MEC) (Project MEC-CTQ-2007-61126) and PCTI (2006–2009)/FEDER (2007–2013) Asturias (Project EQUIP09-07) are gratefully acknowledged.; We also acknowledge the National Institutes of Health (NIH) for financial support of this work through Grant Number R01 GM081484.; This work was also supported in part by NIH grant 2P30-AI-050409 and the Department of Veterans Affairs
• Keywords: Anti-HCV; Biochemistry & Molecular Biology; HIV ACTIVITY; Chemistry; DERIVATIVES; Science & Technology; Anti-HIV-1; STEREOSELECTIVE-SYNTHESIS; Pharmacology & Pharmacy; Life Sciences & Biomedicine; Chemistry, Organic; Physical Sciences; AZANUCLEOSIDES; CANCER; Synthesis; OLIGONUCLEOTIDE SYNTHESIS; IMMUNODEFICIENCY-VIRUS TYPE-1; NUCLEOSIDES; PYRROLIDINE SUGARS; Azanucleosides; L-Pyroglutamic acid; ANALOGS; Chemistry, Medicinal
• Research Categories: Biology, Molecular; Chemistry, Biochemistry; Health Sciences, Pharmacology

Abstract

A series of 2′,3′-dideoxy-2′,2′-difluoro-4′- azanucleosides of both pyrimidine and purine nucleobases were synthesized in an efficient manner starting from commercially available L-pyroglutamic acid via glycosylation of difluorinated pyrrolidine derivative 15. Several 4′-azanucleosides were prepared as a separable mixture of α- and β-anomers. The 6-chloropurine analogue was obtained as a mixture of N 7 and N 9 regioisomers and their structures were identified based on NOESY and HMBC spectral data. Among the 4′-azanucleosides tested as HIV-1 inhibitors in primary human lymphocytes, four compounds showed modest activity and the 5-fluorouracil analogue (18d) was found to be the most active compound (EC 50 = 36.9 μM) in this series. None of the compounds synthesized in this study demonstrated anti-HCV activity.