Synthesis of giant globular multivalent glycofullerenes as potent inhibitors in a model of Ebola virus infection

Journal name:
Nature Chemistry
Volume:
8,
Pages:
50–57
Year published:
DOI:
doi:10.1038/nchem.2387
Received
Accepted
Published online

Abstract

The use of multivalent carbohydrate compounds to block cell-surface lectin receptors is a promising strategy to inhibit the entry of pathogens into cells and could lead to the discovery of novel antiviral agents. One of the main problems with this approach, however, is that it is difficult to make compounds of an adequate size and multivalency to mimic natural systems such as viruses. Hexakis adducts of [60]fullerene are useful building blocks in this regard because they maintain a globular shape at the same time as allowing control over the size and multivalency. Here we report water-soluble tridecafullerenes decorated with 120 peripheral carbohydrate subunits, so-called ‘superballs’, that can be synthesized efficiently from hexakis adducts of [60]fullerene in one step by using copper-catalysed azide–alkyne cycloaddition click chemistry. Infection assays show that these superballs are potent inhibitors of cell infection by an artificial Ebola virus with half-maximum inhibitory concentrations in the subnanomolar range.

At a glance

Figures

  1. Synthesis of azide-substituted glycofullerene 9 appended with a long linker and mannose as the carbohydrate unit.
    Figure 1: Synthesis of azide-substituted glycofullerene 9 appended with a long linker and mannose as the carbohydrate unit.

    Five linear steps are required to prepare compound 9 in a 26% overall yield. Reagents and conditions: (i) ethylmalonyl chloride, pyridine, CH2Cl2, 0 to 25 °C, one hour (99%); (ii) C60, I2, DBU, 25 °C, PhMe, 16 hours (49%); (iii) CBr4, DBU, 25 °C, ODCB, 72 hours (67%); (iv) CuSO4·5H2O, sodium ascorbate, THF/H2O, 100 °C (MW), two hours (91%); (v) 8 (19 equiv.), CuSO4·5H2O, sodium ascorbate, TBAF, THF/H2O, 80 °C (MW), 1.5 hours (87%).

  2. Synthetic pathway to azide-substituted glycofullerenes 15a and 15b with a short spacer.
    Figure 2: Synthetic pathway to azide-substituted glycofullerenes 15a and 15b with a short spacer.

    The peripheral glycofullerene units 15a and 15b were prepared using Bingel conditions and CuAAC click chemistry to conjugate the carbohydrate moieties. Reagents and conditions: (i) CBr4, DBU, 20 °C, PhMe, 72 hours (49%); (ii) 2-azidoethyl α-D-mannopyranoside for 14a (or 2-azidoethyl α-D-galactopyranoside for 14b), CuBr·S(CH3)2, sodium ascorbate, Cu0, DMSO, 72 hours (14a, 86%; 14b, 86%); (iii) NaN3, 70 °C (MW), DMSO, three hours (15a, 84%; 15b, 81%).

  3. Syntheses of the tridecafullerenes 17a–17c using CuAAC click chemistry.
    Figure 3: Syntheses of the tridecafullerenes 17a17c using CuAAC click chemistry.

    The core fullerene 16 (endowed with 12 alkyne groups) is joined to the peripheral fullerene-based compounds 9, 15a and 15b by click chemistry. Reagents and conditions: for compounds 17a or 17b (i) 15a or 15b, CuBr·S(CH3)2, sodium ascorbate, Cu(0), DMSO, 25 °C, 48 hours (17a (from 15a), 73%; 17b (from 15b), 79%); for compound 17c (i) 9, CuSO4·5H2O, sodium ascorbate, THF/H2O, 80 °C (MW), two hours (76%).

  4. 13C NMR spectrum of tridecafullerene 17a in DMSO-d6.
    Figure 4: 13C NMR spectrum of tridecafullerene 17a in DMSO-d6.

    The assignments depict the most representative signals. This spectrum is in full agreement with the T-symmetrical structure of the compound and enables confirmation of the complete functionalization of the alkyne moieties in precursor 16 because of the absence of signals that correspond to the sp-hybridized carbons of the alkyne groups.

  5. TEM images and DLS analysis of tridecafullerene 17a.
    Figure 5: TEM images and DLS analysis of tridecafullerene 17a.

    These images show small spherical particles with a diameter of around 4 nm, which corresponds to a single molecule. a, TEM images of compound 17a on deposition of a 0.01 mg ml–1 solution in H2O. b, Detail of a particle that apparently corresponds to one molecule. c, Width profile of the particle shown in b, which has a diameter of ∼4 nm in accordance with the DLS data. a.u., arbitrary units

  6. Biological study of tridecafullerenes 17a–17c.
    Figure 6: Biological study of tridecafullerenes 17a17c.

    The graphic shows the inhibition of infection with EBOV-GP- or VSV-GP-pseudotyped lentiviral particles of Jurkat DC-SIGN+ cells using 17a (blue), 17b (green) and 17c (red). In the cis-infection experiments, 2.5 × 105 Jurkat DC-SIGN+ cells were challenged with 5,000 TCID of recombinant lentiviral particles. The results represent the mean of six independent experiments ± s.e.m. Compounds 17a and 17c show a strong inhibitory activity when EBOV-GP-pseudotyped lentiviral particles are used. No inhibitory activity is detected when VSV-GP-pseudotyped particles (control) are used as the infective agent. Compound 17b (endowed with galactoses as carbohydrate units) does not show inhibitory activity because it is not able to block the DC-SIGN receptor.

Compounds

22 compounds View all compounds
  1. 5-(Trimethylsilyl)pent-4-yn-1-ol
    Compound 1 5-(Trimethylsilyl)pent-4-yn-1-ol
  2. Ethyl (5-(trimethylsilyl)pent-4-yn-1-yl) malonate
    Compound 2 Ethyl (5-(trimethylsilyl)pent-4-yn-1-yl) malonate
  3. 61-Ethyloxycarbonyl-61-[5-(trimethylsilyl)pent-4-yn-1-oxycarbonyl]-1,2-(methano)[60]fullerene
    Compound 3 61-Ethyloxycarbonyl-61-[5-(trimethylsilyl)pent-4-yn-1-oxycarbonyl]-1,2-(methano)[60]fullerene
  4. Bis(3-azidopropyl) malonate
    Compound 4 Bis(3-azidopropyl) malonate
  5. 61-Ethyloxycarbonyl-61-[5-(trimethylsilyl)pent-4-yn-1-oxycarbonyl]-62,62,63,63,64,64,65,65,66,66-deca(3-azidopropyloxycarbonyl)-1,9:16,17:21,40:30,31:44,45:52,60-hexa(methano)[60]fullerene
    Compound 5 61-Ethyloxycarbonyl-61-[5-(trimethylsilyl)pent-4-yn-1-oxycarbonyl]-62,62,63,63,64,64,65,65,66,66-deca(3-azidopropyloxycarbonyl)-1,9:16,17:21,40:30,31:44,45:52,60-hexa(methano)[60]fullerene
  6. (2R,3S,4S,5S,6S)-2-(Hydroxymethyl)-6-(prop-2-yn-1-yloxy)tetrahydro-2H-pyran-3,4,5-triol
    Compound 6 (2R,3S,4S,5S,6S)-2-(Hydroxymethyl)-6-(prop-2-yn-1-yloxy)tetrahydro-2H-pyran-3,4,5-triol
  7. 61-Ethyloxycarbonyl-61-[5-(trimethylsilyl)pent-4-yn-1-oxycarbonyl]-62,62,63,63,64,64,65,65,66,66-deca-{3-[4-(1-α-D-mannopyranosyl-methyl)-1H-1,2,3-triazole-1-yl]-propyl-1-oxycarbonyl}-1,9:16,17:21,40:30,31:44,45:52,60-hexa(methano)[60]fullerene
    Compound 7 61-Ethyloxycarbonyl-61-[5-(trimethylsilyl)pent-4-yn-1-oxycarbonyl]-62,62,63,63,64,64,65,65,66,66-deca-{3-[4-(1-α-D-mannopyranosyl-methyl)-1H-1,2,3-triazole-1-yl]-propyl-1-oxycarbonyl}-1,9:16,17:21,40:30,31:44,45:52,60-hexa(methano)[60]fullerene
  8. 1,23-Diazido-3,6,9,12,15,18,21-heptaoxatricosane
    Compound 8 1,23-Diazido-3,6,9,12,15,18,21-heptaoxatricosane
  9. 61-Ethyloxycarbonyl-61-{3-[1-(20-azido-3,6,9,12,15,18-hexaoxatetradecayl)-1H-1,2,3-triazole-4-yl]-propyl-1-oxycarbonyl}-62,62,63,63,64,64,65,65,66,66-deca-{3-[4-(1-α-D-mannopyranosyl-methyl)-1H-1,2,3-triazole-1-yl]- propyl-1-oxycarbonyl}-1,9:16,17:21,40:30,31:44,45:52,60-hexa(methano)[60]fullerene
    Compound 9 61-Ethyloxycarbonyl-61-{3-[1-(20-azido-3,6,9,12,15,18-hexaoxatetradecayl)-1H-1,2,3-triazole-4-yl]-propyl-1-oxycarbonyl}-62,62,63,63,64,64,65,65,66,66-deca-{3-[4-(1-α-D-mannopyranosyl-methyl)-1H-1,2,3-triazole-1-yl]- propyl-1-oxycarbonyl}-1,9:16,17:21,40:30,31:44,45:52,60-hexa(methano)[60]fullerene
  10. 61-Ethyloxycarbonyl-61-(6-bromohexyl-1-oxycarbonyl)-1,2-(methano)[60]fullerene
    Compound 10 61-Ethyloxycarbonyl-61-(6-bromohexyl-1-oxycarbonyl)-1,2-(methano)[60]fullerene
  11. Di(pent-4-yn-1-yl) malonate
    Compound 11 Di(pent-4-yn-1-yl) malonate
  12. 61-Ethyloxycarbonyl-61-(6-bromohexyl-1-oxycarbonyl)-62,62,63,63,64,64,65,65,66,66-decapent-4-yn-1-oxycarbonyl-1,9:16,17:21,40:30,31:44,45:52,60-hexa(methano)[60]fullerene
    Compound 12 61-Ethyloxycarbonyl-61-(6-bromohexyl-1-oxycarbonyl)-62,62,63,63,64,64,65,65,66,66-decapent-4-yn-1-oxycarbonyl-1,9:16,17:21,40:30,31:44,45:52,60-hexa(methano)[60]fullerene
  13. (2S,3S,4S,5S,6R)-2-(2-Azidoethoxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol
    Compound 13a (2S,3S,4S,5S,6R)-2-(2-Azidoethoxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol
  14. (2R,3R,4S,5R,6R)-2-(2-Azidoethoxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol
    Compound 13b (2R,3R,4S,5R,6R)-2-(2-Azidoethoxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol
  15. 61-Ethyloxycarbonyl-61-(6-bromohexyl-1-oxycarbonyl)-62,62,63,63,64,64,65,65,66,66-deca-{3-[1-(2-α-D-mannopyranosyl-ethyl)-1H-1,2,3-triazole-4-yl]-propyl-1-oxycarbonyl}-1,9:16,17:21,40:30,31:44,45:52,60-hexa(methano)[60]fullerene
    Compound 14a 61-Ethyloxycarbonyl-61-(6-bromohexyl-1-oxycarbonyl)-62,62,63,63,64,64,65,65,66,66-deca-{3-[1-(2-α-D-mannopyranosyl-ethyl)-1H-1,2,3-triazole-4-yl]-propyl-1-oxycarbonyl}-1,9:16,17:21,40:30,31:44,45:52,60-hexa(methano)[60]fullerene
  16. 61-Ethyloxycarbonyl-61-(6-bromohexyl-1-oxycarbonyl)-62,62,63,63,64,64,65,65,66,66-deca-{3-[1-(2-β-D-galactopyranosyl-ethyl)-1H-1,2,3-triazole-4-yl]-propyl-1-oxycarbonyl}-1,9:16,17:21,40:30,31:44,45:52,60-hexa(methano)[60]fullerene
    Compound 14b 61-Ethyloxycarbonyl-61-(6-bromohexyl-1-oxycarbonyl)-62,62,63,63,64,64,65,65,66,66-deca-{3-[1-(2-β-D-galactopyranosyl-ethyl)-1H-1,2,3-triazole-4-yl]-propyl-1-oxycarbonyl}-1,9:16,17:21,40:30,31:44,45:52,60-hexa(methano)[60]fullerene
  17. 61-Ethyloxycarbonyl-61-(6-azidohexyl-1-oxycarbonyl)-62,62,63,63,64,64,65,65,66,66-deca-{3-[1-(2-α-D-mannopyranosyl-ethyl)-1H-1,2,3-triazole-4-yl]-propyl-1-oxycarbonyl}-1,9:16,17:21,40:30,31:44,45:52,60-hexa(methano)[60]fullerene
    Compound 15a 61-Ethyloxycarbonyl-61-(6-azidohexyl-1-oxycarbonyl)-62,62,63,63,64,64,65,65,66,66-deca-{3-[1-(2-α-D-mannopyranosyl-ethyl)-1H-1,2,3-triazole-4-yl]-propyl-1-oxycarbonyl}-1,9:16,17:21,40:30,31:44,45:52,60-hexa(methano)[60]fullerene
  18. 61-Ethyloxycarbonyl-61-(6-azidohexyl-1-oxycarbonyl)-62,62,63,63,64,64,65,65,66,66-deca-{3-[1-(2-β-D-galactopyranosyl-ethyl)-1H-1,2,3-triazole-4-yl]-propyl-1-oxycarbonyl}-1,9:16,17:21,40:30,31:44,45:52,60-hexa(methano)[60]fullerene
    Compound 15b 61-Ethyloxycarbonyl-61-(6-azidohexyl-1-oxycarbonyl)-62,62,63,63,64,64,65,65,66,66-deca-{3-[1-(2-β-D-galactopyranosyl-ethyl)-1H-1,2,3-triazole-4-yl]-propyl-1-oxycarbonyl}-1,9:16,17:21,40:30,31:44,45:52,60-hexa(methano)[60]fullerene
  19. 61,61,62,62,63,63,64,64,65,65,66,66-Dodecapent-4-yn-1-oxycarbonyl-1,9:16,17:21,40:30,31:44,45:52,60-hexa(methano)[60]fullerene
    Compound 16 61,61,62,62,63,63,64,64,65,65,66,66-Dodecapent-4-yn-1-oxycarbonyl-1,9:16,17:21,40:30,31:44,45:52,60-hexa(methano)[60]fullerene
  20. 61,61,62,62,63,63,64,64,65,65,66,66-Dodeca-3-{{1-{61-Ethyloxycarbonyl-62,62,63,63,64,64,65,65,66,66-deca-{[1-(2-α-D-mannopyranosyl-ethyl)-1H-1,2,3-triazole-4-yl]-propyl-1-oxycarbonyl}-1,9:16,17:21,40:30,31:44,45:52,60-hexa(methano)[60]fullerene-61-yl}-6-carbonyloxyhexyl}-1H-1,2,3-triazole-4-yl}-propyl-1-oxycarbonyl-1,9:16,17:21,40:30,31:44,45:52,60-hexa(methano)[60]fullerene
    Compound 17a 61,61,62,62,63,63,64,64,65,65,66,66-Dodeca-3-{{1-{61-Ethyloxycarbonyl-62,62,63,63,64,64,65,65,66,66-deca-{[1-(2-α-D-mannopyranosyl-ethyl)-1H-1,2,3-triazole-4-yl]-propyl-1-oxycarbonyl}-1,9:16,17:21,40:30,31:44,45:52,60-hexa(methano)[60]fullerene-61-yl}-6-carbonyloxyhexyl}-1H-1,2,3-triazole-4-yl}-propyl-1-oxycarbonyl-1,9:16,17:21,40:30,31:44,45:52,60-hexa(methano)[60]fullerene
    View:
  21. 61,61,62,62,63,63,64,64,65,65,66,66-Dodeca-3-{{1-{61-Ethyloxycarbonyl-62,62,63,63,64,64,65,65,66,66-deca-{[1-(2-β-D-galactopyranosyl-ethyl)-1H-1,2,3-triazole-4-yl]-propyl-1-oxycarbonyl}-1,9:16,17:21,40:30,31:44,45:52,60-hexa(methano)[60]fullerene-61-yl}-6-carbonyloxyhexyl}-1H-1,2,3-triazole-4-yl}-propyl-1-oxycarbonyl-1,9:16,17:21,40:30,31:44,45:52,60-hexa(methano)[60]fullerene
    Compound 17b 61,61,62,62,63,63,64,64,65,65,66,66-Dodeca-3-{{1-{61-Ethyloxycarbonyl-62,62,63,63,64,64,65,65,66,66-deca-{[1-(2-β-D-galactopyranosyl-ethyl)-1H-1,2,3-triazole-4-yl]-propyl-1-oxycarbonyl}-1,9:16,17:21,40:30,31:44,45:52,60-hexa(methano)[60]fullerene-61-yl}-6-carbonyloxyhexyl}-1H-1,2,3-triazole-4-yl}-propyl-1-oxycarbonyl-1,9:16,17:21,40:30,31:44,45:52,60-hexa(methano)[60]fullerene
    View:
  22. 61,61,62,62,63,63,64,64,65,65,66,66-Dodeca-3-{{1-{61-Ethyloxycarbonyl-62,62,63,63,64,64,65,65,66,66-deca-{[1-(1-α-D-mannopyranosyl-methyl)-1H-1,2,3-triazole-4-yl]-propyl-1-oxycarbonyl}-1,9:16,17:21,40:30,31:44,45:52,60-hexa(methano)[60]fullerene-61-yl}-20-(3-carbonyloxypropyl-1H-1,2,3-triazole-4-yl)-3,6,9,12,15,18-hexaoxatetradecayl)}-1H-1,2,3-triazole-4-yl}-propyl-1-oxycarbonyl-1,9:16,17:21,40:30,31:44,45:52,60-hexa(methano)[60]fullerene
    Compound 17c 61,61,62,62,63,63,64,64,65,65,66,66-Dodeca-3-{{1-{61-Ethyloxycarbonyl-62,62,63,63,64,64,65,65,66,66-deca-{[1-(1-α-D-mannopyranosyl-methyl)-1H-1,2,3-triazole-4-yl]-propyl-1-oxycarbonyl}-1,9:16,17:21,40:30,31:44,45:52,60-hexa(methano)[60]fullerene-61-yl}-20-(3-carbonyloxypropyl-1H-1,2,3-triazole-4-yl)-3,6,9,12,15,18-hexaoxatetradecayl)}-1H-1,2,3-triazole-4-yl}-propyl-1-oxycarbonyl-1,9:16,17:21,40:30,31:44,45:52,60-hexa(methano)[60]fullerene
    View:

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Author information

Affiliations

  1. Departamento de Química Orgánica, Facultad de Química, Universidad Complutense, Madrid 28040, Spain

    • Antonio Muñoz,
    • Beatriz M. Illescas,
    • Laura Rodríguez-Pérez &
    • Nazario Martín
  2. Laboratory V-SAT (CAMB UMR 7199, CNRS), Labex Medalis, Université de Strasbourg, 74 Route du Rhin, Illkirch-Graffenstaden 67401, France

    • David Sigwalt &
    • Jean-Serge Remy
  3. Laboratoire de Chimie des Matériaux Moléculaires, Université de Strasbourg et CNRS (UMR 7509), Ecole Européenne de Chimie, Polymères et Matériaux, 25 rue Becquerel, Strasbourg 67087, France

    • David Sigwalt,
    • Iwona Nierengarten,
    • Michel Holler &
    • Jean-François Nierengarten
  4. Laboratorio de Microbiología Molecular, Instituto de Investigación Hospital 12 de Octubre (imas12), Madrid 28041, Spain

    • Joanna Luczkowiak &
    • Rafael Delgado
  5. Département de Chimie, Laboratoire de Chimie Bio-Organique, University of Namur (FUNDP), rue de Bruxelles 61, Namur B-5000, Belgium

    • Kevin Buffet &
    • Stéphane P. Vincent
  6. Glycosystems Laboratory, Instituto de Investigaciones Químicas (IIQ), CSIC – Universidad de Sevilla, Av. Américo Vespucio 49, Seville 41092, Spain

    • Javier Rojo
  7. IMDEA-Nanoscience, Campus Cantoblanco, Madrid 28049, Spain

    • Nazario Martín

Contributions

A.M., D.S., I.N., M.H. and K.B. carried out the synthesis and characterization of all the new derivatives. L.R.-P. and J.-S.R. realized and analysed the DLS and TEM. L.R.-P. realized the XPS analyses and contributed to the writing of the paper. J.L. and R.D. realized the biological and cytotoxicity studies. B.M.I., S.P.V., J.R., R.D., J.-F.N. and N.M. designed the project, supervised the work, discussed the data and wrote the manuscript.

Competing financial interests

The authors declare no competing financial interests.

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