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

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• 作者：Julie Hunault ; Mette Diswall ; Jean-C茅dric Frison ; Virginie Blot ; J茅zabel Rocher ; S茅verine Marionneau-Lambot ; Thibauld Oullier ; Jean-Yves Douillard ; St茅phane Guillarme ; Christine Saluzzo ; Gilles Dujardin ; Denis Jacquemin ; J茅r么me Graton ; Jean-Yves Le Questel ; Michel Evain ; Jacques Lebreton ; Didier Dubreuil ; Jacques Le Pendu ; Muriel Pipelier
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：February 9, 2012
• 年：2012
• 卷：55
• 期：3
• 页码：1227-1241
• 全文大小：580K
• 年卷期：v.55,no.3(February 9, 2012)
• ISSN：1520-4804

文摘

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 T_H1 or T_H2 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.