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

J Med Chem. 2012 Feb 9;55(3):1227-41. doi: 10.1021/jm201368m. Epub 2012 Feb 1.

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 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adjuvants, Immunologic / chemical synthesis*
  • Adjuvants, Immunologic / chemistry
  • Adjuvants, Immunologic / pharmacology
  • Animals
  • Antigen-Presenting Cells / drug effects
  • Antigen-Presenting Cells / immunology
  • Antigen-Presenting Cells / metabolism
  • Antigens, CD1d / immunology
  • Antigens, CD1d / metabolism
  • Cell Line
  • Female
  • Galactosylceramides / chemical synthesis*
  • Galactosylceramides / chemistry
  • Galactosylceramides / immunology
  • Galactosylceramides / metabolism
  • Galactosylceramides / pharmacology
  • Humans
  • Hydrogen Bonding
  • Mice
  • Mice, Inbred C57BL
  • Models, Molecular
  • Natural Killer T-Cells / drug effects*
  • Natural Killer T-Cells / immunology
  • Natural Killer T-Cells / metabolism
  • Protein Stability
  • Receptors, Antigen, T-Cell / immunology
  • Receptors, Antigen, T-Cell / metabolism
  • Species Specificity
  • Stereoisomerism
  • Structure-Activity Relationship
  • Th1 Cells / drug effects
  • Th1 Cells / immunology
  • Th1 Cells / metabolism
  • Th2 Cells / drug effects
  • Th2 Cells / immunology
  • Th2 Cells / metabolism

Substances

  • 1-O-(galactopyranosyl)-2-hexacosanoylamino-3,3-difluoro-heptadecane
  • 3-fluoro-2-hexacosanoylamino-1-(galactopyranosyl)heptadecane
  • Adjuvants, Immunologic
  • Antigens, CD1d
  • Galactosylceramides
  • Receptors, Antigen, T-Cell
  • KRN 7000