title: 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.
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.
authors.affiliation: 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.
authors.forename: Julie
authors.initials: J
authors.lastname: Hunault
authors.forename: Mette
authors.initials: M
authors.lastname: Diswall
authors.forename: Jean-Cédric
authors.initials: JC
authors.lastname: Frison
authors.forename: Virginie
authors.initials: V
authors.lastname: Blot
authors.forename: Jézabel
authors.initials: J
authors.lastname: Rocher
authors.forename: Séverine
authors.initials: S
authors.lastname: Marionneau-Lambot
authors.forename: Thibauld
authors.initials: T
authors.lastname: Oullier
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Douillard
authors.forename: Stéphane
authors.initials: S
authors.lastname: Guillarme
authors.forename: Christine
authors.initials: C
authors.lastname: Saluzzo
authors.forename: Gilles
authors.initials: G
authors.lastname: Dujardin
authors.forename: Denis
authors.initials: D
authors.lastname: Jacquemin
authors.forename: Jérôme
authors.initials: J
authors.lastname: Graton
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Le Questel
authors.forename: Michel
authors.initials: M
authors.lastname: Evain
authors.forename: Jacques
authors.initials: J
authors.lastname: Lebreton
authors.forename: Didier
authors.initials: D
authors.lastname: Dubreuil
authors.forename: Jacques
authors.initials: J
authors.lastname: Le Pendu
authors.forename: Muriel
authors.initials: M
authors.lastname: Pipelier
mesh_terms: D000276:Adjuvants, Immunologic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000938:Antigen-Presenting Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D055610:Antigens, CD1d / Q000276:immunology / Q000378:metabolism; D002460:Cell Line; D005260:Female; D005699:Galactosylceramides / Q000138:chemical synthesis* / Q000737:chemistry / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D006860:Hydrogen Bonding; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D055611:Natural Killer T-Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D055550:Protein Stability; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism; D013045:Species Specificity; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism
chemical_list: C571530:1-O-(galactopyranosyl)-2-hexacosanoylamino-3,3-difluoro-heptadecane; C571529:3-fluoro-2-hexacosanoylamino-1-(galactopyranosyl)heptadecane; D000276:Adjuvants, Immunologic; D055610:Antigens, CD1d; D005699:Galactosylceramides; D011948:Receptors, Antigen, T-Cell; C103873:KRN 7000