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Synlett 2024; 35(06): 703-705
DOI: 10.1055/a-2213-2408
DOI: 10.1055/a-2213-2408
cluster
Special Issue to Celebrate the Centenary Year of Prof. Har Gobind Khorana
Synthesis of 2′-Deoxy-2′-β-fluoro-4′-azido-5-fluorouridine as a Potential Anti-HIV Agent
We thank the Henan Province Epidemic Prevention and Control Emergency Research Project (No. 221111311400), the National Natural Science Foundation of China (Nos. 82130103 and 81773570), and the Young Backbone Teachers Fund of Henan Province (No. 2021GGJS012) for financial support.
Abstract
2′-Deoxy-2′-β-fluoro-4′-azido-5-fluorouridine, a new pyrimidine nucleoside analogue of azvudine (FNC), was designed and synthesized. The synthesis of this nucleoside analogue was achieved by bromination of 1,3,5-O-tribenzoyl-2-deoxy-2-fluoro-d-arabinofuranoside, followed by reaction with silylated 5-fluorouracil and further modifications of the sugar moiety, in a 7.6% overall yield over nine steps. The product exhibited good antiviral activity against HIV-1 infection in HEK293T cells.
Key words
deoxyfluoroazidofluorouridine - nucleoside analogues - medicinal chemistry - anti-HIV-1 activitySupporting Information
- Supporting information for this article is available online at https://doi.org/10.1055/a-2213-2408.
- Supporting Information
Publication History
Received: 29 July 2023
Accepted after revision: 17 November 2023
Accepted Manuscript online:
17 November 2023
Article published online:
21 December 2023
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- 10 2′-Deoxy-2′-β-fluoro-4′-azido-5-fluorouridine (1) A solution of compound 11 (260 mg, 0.474 mmol) in sat. methanolic NH3 (19 mL) was stirred at rt for 20 h, then concentrated and purified by column chromatography [silica gel, MeOH–EtOAc–PE (1:10:10)] to give a white solid; yield: 79 mg (55%); mp 98–100 °C. 1H NMR (400 MHz, CD3OD): δ = 7.89 (dd, J = 6.7, 1.2 Hz, 1 H), 6.35 (ddd, J = 10.0, 5.4, 1.4 Hz, 1 H), 5.13 (dt, J = 53.7, 5.3 Hz, 1 H), 4.43 (dd, J = 22.4, 5.2 Hz, 1 H), 3.76 (t, J = 13.2 Hz, 2 H). 13C NMR (100 MHz, CD3OD): δ = 157.8 (d, J C–F = 26.4 Hz), 149.1, 140.2 (d, J C–F = 233.6 Hz), 125.0 (dd, J C–F = 35.6, 2.1 Hz), 96.9 (d, J C–F = 8.8 Hz), 94.6 (d, J C–F = 194.0 Hz), 82.2 (d, J C–F = 17.1 Hz), 74.3 (d, J C–F = 24.6 Hz), 61.4. HRMS: m/z [M – H]– calcd for C9H8F2N5O5: 304.0499; found: 304.0500.
- 11 The synthesis and anti-HBV activity of 5-halopyrimidine nucleoside analogue II (X = Cl, Br, I) have been described in ref. 6c. In view of the potent anti-HBV activity of compounds IIa and IIc, these two 5-halopyrimidine analogues were selected for anti-HIV-1 and cytotoxicity evaluation in comparison with the target nucleoside 1.