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3,4-Dideoxy-3,3,4,4-tetrafluoro- and 4-OH epimeric 3-deoxy-3,3-difluoro-α-GalCer analogues: Synthesis and biological evaluation on human iNKT cells stimulation

3,4-Dideoxy-3,3,4,4-tetrafluoro- and 4-OH epimeric 3-deoxy-3,3-difluoro-α-GalCer analogues: Synthesis and biological evaluation on human iNKT cells stimulation
3,4-Dideoxy-3,3,4,4-tetrafluoro- and 4-OH epimeric 3-deoxy-3,3-difluoro-α-GalCer analogues: Synthesis and biological evaluation on human iNKT cells stimulation
iNKT cells recognize CD1d/-galactosylceramide (-GalCer) complexes via their invariant TCR receptor and stimulate the immune response. Many -GalCer analogues have been investigated to interrogate this interaction. Following our previous work related to the modification of the hydrogen bond network between -GalCer and CD1d, we have now focused our attention on the synthesis of 3-deoxy-3,3-difluoro- and 3,4-dideoxy-3,3,4,4- tetrafluoro-α-GalCer analogues, and studied their ability to stimulate human iNKT cells. In each case, deoxygenation at the indicated positions was accompanied by difluoro introduction in order to evaluate the resulting electronic effect on the stability of the ternary CD1d/Galcer/TCR complex which has been rationalized by modeling study. With deoxy4 difluorination at the 3-position, the two epimeric 4-OH analogues were investigated to establish their capacity to compensate for the lack of the hydrogen bond donating group at the 3-position. The 3,4-dideoxytetrafluoro analogue was of interest to highlight the amide NH-bond hydrogen bond properties.
Fluoro GalCer analogues, iNKT activation, immune response, modeling study
0223-5234
Golten, Samuel
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Patinec, Allan
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Akoumany, Katy
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Rocher, Jézabel
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Graton, Jérôme
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Jacquemin, Denis
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Le Questel, Jean-Yves
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Tessier, Arnaud
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Lebreton, Jacques
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Blot, Virginie
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Pipelier, Muriel
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Douillard, Jean-Yves
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Le Pendu, Jacques
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Linclau, Bruno
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Dubreuila, Didier
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Golten, Samuel
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Patinec, Allan
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Akoumany, Katy
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Rocher, Jézabel
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Graton, Jérôme
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Jacquemin, Denis
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Le Questel, Jean-Yves
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Tessier, Arnaud
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Lebreton, Jacques
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Blot, Virginie
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Pipelier, Muriel
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Douillard, Jean-Yves
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Le Pendu, Jacques
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Linclau, Bruno
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Dubreuila, Didier
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Golten, Samuel, Patinec, Allan, Akoumany, Katy, Rocher, Jézabel, Graton, Jérôme, Jacquemin, Denis, Le Questel, Jean-Yves, Tessier, Arnaud, Lebreton, Jacques, Blot, Virginie, Pipelier, Muriel, Douillard, Jean-Yves, Le Pendu, Jacques, Linclau, Bruno and Dubreuila, Didier (2019) 3,4-Dideoxy-3,3,4,4-tetrafluoro- and 4-OH epimeric 3-deoxy-3,3-difluoro-α-GalCer analogues: Synthesis and biological evaluation on human iNKT cells stimulation. European Journal of Medicinal Chemistry. (doi:10.1016/j.ejmech.2019.05.069).

Record type: Article

Abstract

iNKT cells recognize CD1d/-galactosylceramide (-GalCer) complexes via their invariant TCR receptor and stimulate the immune response. Many -GalCer analogues have been investigated to interrogate this interaction. Following our previous work related to the modification of the hydrogen bond network between -GalCer and CD1d, we have now focused our attention on the synthesis of 3-deoxy-3,3-difluoro- and 3,4-dideoxy-3,3,4,4- tetrafluoro-α-GalCer analogues, and studied their ability to stimulate human iNKT cells. In each case, deoxygenation at the indicated positions was accompanied by difluoro introduction in order to evaluate the resulting electronic effect on the stability of the ternary CD1d/Galcer/TCR complex which has been rationalized by modeling study. With deoxy4 difluorination at the 3-position, the two epimeric 4-OH analogues were investigated to establish their capacity to compensate for the lack of the hydrogen bond donating group at the 3-position. The 3,4-dideoxytetrafluoro analogue was of interest to highlight the amide NH-bond hydrogen bond properties.

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FluoroGalCer_EurmedChem_corrected - Accepted Manuscript
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Accepted/In Press date: 24 May 2019
e-pub ahead of print date: 29 May 2019
Keywords: Fluoro GalCer analogues, iNKT activation, immune response, modeling study

Identifiers

Local EPrints ID: 431398
URI: http://eprints.soton.ac.uk/id/eprint/431398
ISSN: 0223-5234
PURE UUID: f699ee11-1c3f-45f7-9225-d69c151f8adb
ORCID for Bruno Linclau: ORCID iD orcid.org/0000-0001-8762-0170

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Date deposited: 31 May 2019 16:30
Last modified: 26 Nov 2021 05:53

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Contributors

Author: Samuel Golten
Author: Allan Patinec
Author: Katy Akoumany
Author: Jézabel Rocher
Author: Jérôme Graton
Author: Denis Jacquemin
Author: Jean-Yves Le Questel
Author: Arnaud Tessier
Author: Jacques Lebreton
Author: Virginie Blot
Author: Muriel Pipelier
Author: Jean-Yves Douillard
Author: Jacques Le Pendu
Author: Bruno Linclau ORCID iD
Author: Didier Dubreuila

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