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Title: Synthesis of an apionucleoside family and discovery of a prodrug with anti-HIV activity
Authors: Toti, Kiran S
Derudas, Marco
Pertusati, Fabrizio
Sinnaeve, Davy
Van den Broeck, Freya
Margamuljana, Lia
Martins, José C
Herdewijn, Piet
Balzarini, Jan
McGuigan, Christopher
Van Calenbergh, Serge # ×
Issue Date: Jun-2014
Publisher: American Chemical Society
Series Title: Journal of Organic Chemistry vol:79 issue:11 pages:5097-112
Article number: 10.1021/jo500659e
Abstract: We report the synthesis of a family of d- and l-furano-d-apionucleosides, their 3'-deoxy, as well as their 2',3'-dideoxy analogues with thymine and adenine nucleobases. Single carbon homologation of 1,2-O-isopropylidene-d-glycero-tetrafuranos-3-ulose (15) and optimized glycosylation conditions involving microwave irradiation were key to the successful synthesis of the target compounds. While all target nucleosides failed to show significant antiviral activity, we demonstrated that the triphosphate of 2',3'-deoxy-d-apio-d-furanoadenosine (1), in contrast to that of its d-apio-l-furanose epimer 2, was readily incorporated into a DNA template by HIV reverse transcriptase to act as a DNA chain terminator. This led us to convert adenine derivative 1 into two phosphoramidate prodrugs. ProTide 9b was found active against HIV-1 and HIV-2 (EC50 = 0.5-1.5 μM), indicating that the lack of activity of the parent nucleoside, and possibly also other members of the d-apio-d-furanose nucleoside family must be sought in the inefficient cellular conversion to the monophosphate.
URI: 
ISSN: 0022-3263
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Laboratory of Virology and Chemotherapy (Rega Institute)
Medicinal Chemistry (Rega Institute)
× corresponding author
# (joint) last author

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