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

(2014) JOURNAL OF ORGANIC CHEMISTRY. 79(11). p.5097-5112
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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.
Keywords
CHEMISTRY, MECHANISM, INHIBITION, DIDEOXYNUCLEOSIDES, AGENTS, APIOSE, ANALOGS, ACTIVATION PATHWAY, ANTIVIRAL EVALUATION, NUCLEOSIDE PHOSPHONATES

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Citation

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Chicago
Toti, Kiran, Marco Derudas, Davy Sinnaeve, Freya Van den Broeck, Lia Margamuljana, José Martins, Piet Herdewijn, Jan Balzarini, Christopher McGuigan, and Serge Van Calenbergh. 2014. “Synthesis of an Apionucleoside Family and Discovery of a Prodrug with anti-HIV Activity.” Journal of Organic Chemistry 79 (11): 5097–5112.
APA
Toti, K., Derudas, M., Sinnaeve, D., Van den Broeck, F., Margamuljana, L., Martins, J., Herdewijn, P., et al. (2014). Synthesis of an apionucleoside family and discovery of a prodrug with anti-HIV activity. JOURNAL OF ORGANIC CHEMISTRY, 79(11), 5097–5112.
Vancouver
1.
Toti K, Derudas M, Sinnaeve D, Van den Broeck F, Margamuljana L, Martins J, et al. Synthesis of an apionucleoside family and discovery of a prodrug with anti-HIV activity. JOURNAL OF ORGANIC CHEMISTRY. 2014;79(11):5097–112.
MLA
Toti, Kiran, Marco Derudas, Davy Sinnaeve, et al. “Synthesis of an Apionucleoside Family and Discovery of a Prodrug with anti-HIV Activity.” JOURNAL OF ORGANIC CHEMISTRY 79.11 (2014): 5097–5112. Print.
@article{5686691,
  abstract     = {We report the synthesis of a family of d- and l-furano-d-apionucleosides, their 3{\textquotesingle}-deoxy, as well as their 2{\textquotesingle},3{\textquotesingle}-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{\textquotesingle},3{\textquotesingle}-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 \ensuremath{\mu}M), 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.},
  author       = {Toti, Kiran and Derudas, Marco and Sinnaeve, Davy and Van den Broeck, Freya and Margamuljana, Lia and Martins, Jos{\'e} and Herdewijn, Piet and Balzarini, Jan and McGuigan, Christopher and Van Calenbergh, Serge},
  issn         = {0022-3263},
  journal      = {JOURNAL OF ORGANIC CHEMISTRY},
  language     = {eng},
  number       = {11},
  pages        = {5097--5112},
  title        = {Synthesis of an apionucleoside family and discovery of a prodrug with anti-HIV activity},
  url          = {http://dx.doi.org/10.1021/jo500659e},
  volume       = {79},
  year         = {2014},
}

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