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Synthesis of an apionucleoside family and discovery of a prodrug with anti-HIV activity

Toti, Kiran S., Derudas, Marco, Pertusati, Fabrizio ORCID:, Sinnaeve, Davy, Van den Broeck, Freya, Margamuljana, Lia, Martins, José C., Herdewijn, Piet, Balzarini, Jan, McGuigan, Christopher ORCID: and Van Calenbergh, Serge 2014. Synthesis of an apionucleoside family and discovery of a prodrug with anti-HIV activity. Journal of Organic Chemistry 79 (11) , pp. 5097-5112. 10.1021/jo500659e

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Pharmacy
Systems Immunity Research Institute (SIURI)
Subjects: Q Science > QR Microbiology > QR180 Immunology
Publisher: American Chemical Society
ISSN: 0022-3263
Date of First Compliant Deposit: 30 March 2016
Last Modified: 06 Nov 2023 21:42

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