☆ 4.7 Article

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

BIOORGANIC & MEDICINAL CHEMISTRY (2012)

Journal

BIOORGANIC & MEDICINAL CHEMISTRY

Volume 20, Issue 23, Pages 6885-6893

Publisher

PERGAMON-ELSEVIER SCIENCE LTD

DOI: 10.1016/j.bmc.2012.09.026

Keywords

Azanucleosides; Synthesis; Anti-HIV-1; Anti-HCV; L-Pyroglutamic acid

Categories

Biochemistry & Molecular Biology Chemistry, Medicinal Chemistry, Organic

Funding

Spanish Ministerio de Educacion y Ciencia (MEC) [MEC-CTQ-2007-61126]
PCTI [EQUIP09-07]
MEC
National Institutes of Health (NIH) [R01 GM081484]
National Science Foundation [CHE9709183, CHE0741968]
NIH [2P30-AI-050409]
Department of Veterans Affairs

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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 alpha- and beta-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 (EC50 = 36.9 mu M) in this series. None of the compounds synthesized in this study demonstrated anti-HCV activity. (C) 2012 Elsevier Ltd. All rights reserved.

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