3-Fluoro- and 3,3-Difluoro-3,4-dideoxy-KRN7000 Analogues as New Potent Immunostimulator Agents: Total Synthesis and Biological Evaluation in Human Invariant Natural Killer T Cells and Mice - Centre de recherche en cancérologie Nantes-Angers Unité Mixte de Recherche 892 Inserm - 6299 CNRS Access content directly
Journal Articles Journal of Medicinal Chemistry Year : 2012

3-Fluoro- and 3,3-Difluoro-3,4-dideoxy-KRN7000 Analogues as New Potent Immunostimulator Agents: Total Synthesis and Biological Evaluation in Human Invariant Natural Killer T Cells and Mice

Thibauld Oullier

Abstract

We propose here the synthesis and biological evaluation of 3,4-dideoxy-GalCer derivatives. The absence of the 3- and 4-hydroxyls on the sphingoid base is combined with the introduction of mono or difluoro substituent at C3 (analogues 8 and 9, respectively) to evaluate their effect on the stability of the ternary CD1d/GalCer/TCR complex which strongly modulate the immune responses. Biological evaluations were performed in vitro on human cells and in vivo in mice and results discussed with support of modeling studies. The fluoro 3,4-dideoxy-GalCer analogues appears as partial agonists compared to KRN7000 for iNKT cell activation, inducing TH1 or TH2 biases that strongly depend of the mode of antigen presentation, including human vs mouse differences. We evidenced that if a sole fluorine atom is not able to balance the loss of the 3-OH, the presence of a difluorine group at C3 of the sphingosine can significantly restore human iNKT activation.
No file

Dates and versions

hal-00700075 , version 1 (22-05-2012)

Identifiers

Cite

Julie Hunault, Mette Diswall, Jean-Cédric Frison, Virginie Blot, Jézabel Rocher, et al.. 3-Fluoro- and 3,3-Difluoro-3,4-dideoxy-KRN7000 Analogues as New Potent Immunostimulator Agents: Total Synthesis and Biological Evaluation in Human Invariant Natural Killer T Cells and Mice. Journal of Medicinal Chemistry, 2012, 55 (3), pp.1227-1241. ⟨10.1021/jm201368m⟩. ⟨hal-00700075⟩
183 View
0 Download

Altmetric

Share

Gmail Facebook X LinkedIn More