Université de Nantes, CNRS, Chimie et Interdisciplinarité: Synthèse, Analyse, Modélisation (CEISAM), UMR CNRS 6230, Faculté des Sciences et des Techniques, 2 rue de la Houssinière, BP 92208, 44322 Nantes Cedex 3, France.
J Med Chem. 2012 Feb 9;55(3):1227-41. doi: 10.1021/jm201368m. Epub 2012 Feb 1.
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(H)1 or T(H)2 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.
我们在此提出 3,4-二脱氧半乳糖基-Cer 衍生物的合成和生物学评价。在神经酰胺基底上没有 3-和 4-羟基，同时在 C3 上引入单或双氟取代基（分别为类似物 8 和 9），以评估它们对三元 CD1d/GalCer/TCR 复合物稳定性的影响，该复合物强烈调节免疫反应。在人细胞上进行体外生物学评价，并在小鼠体内进行体内评价，并结合模型研究结果进行讨论。与 KRN7000 相比，氟 3,4-二脱氧 GalCer 类似物作为 iNKT 细胞激活的部分激动剂，诱导 T(H)1 或 T(H)2 偏向，这强烈依赖于抗原呈递的方式，包括人与小鼠的差异。我们证明，如果仅一个氟原子不能平衡 3-OH 的损失，那么在神经酰胺的 C3 上存在双氟基团可以显著恢复人 iNKT 激活。
