title: Synthesis of C-5″ and C-6″-modified α-GalCer analogues as iNKT-cell agonists.
abstract: Alpha-galactosyl ceramide (α-GalCer) is a prototypical synthetic ligand of invariant natural killer T (iNKT) cells. Upon presentation by the MHC class I-like molecule CD1d, this glycolipid stimulates iNKT cells to secrete a vast amount of both pro-inflammatory Th1 and anti-inflammatory Th2 cytokines. Recently, we discovered that selected 6″-modified α-GalCer analogues may produce markedly Th1-biased responses due to the formation of either an additional anchor with CD1d or by establishing extra interactions with the T-cell receptor of iNKT cells. Here, we report a practical synthesis towards 6″-O-carbamate and galacturonamide analogues of α-GalCer and their evaluation as iNKT cell agonists in mice.
authors.affiliation: Laboratory for Medicinal Chemistry (FFW), Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, B-9000 Gent, Belgium.
authors.forename: Joren
authors.initials: J
authors.lastname: Guillaume
authors.affiliation: Laboratory for Medicinal Chemistry (FFW), Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, B-9000 Gent, Belgium.
authors.forename: Nora
authors.initials: N
authors.lastname: Pauwels
authors.affiliation: Laboratory for Molecular Immunology and Inflammation, Ghent University Hospital, De Pintelaan 185, 9000 Gent, Belgium; Department of Internal Medicine, Faculty of Medicine and Health Sciences, Gent University, 9000 Gent, Belgium.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Aspeslagh
authors.affiliation: Division of Cell Biology, La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, CA 92037, USA; Department of Internal Medicine, Faculty of Medicine and Health Sciences, Gent University, 9000 Gent, Belgium.
authors.forename: Dirk M
authors.initials: DM
authors.lastname: Zajonc
authors.affiliation: Laboratory for Molecular Immunology and Inflammation, Ghent University Hospital, De Pintelaan 185, 9000 Gent, Belgium; VIB Inflammation Research Center, Ghent University, Gent, Belgium.
authors.forename: Dirk
authors.initials: D
authors.lastname: Elewaut
authors.affiliation: Laboratory for Medicinal Chemistry (FFW), Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, B-9000 Gent, Belgium. Electronic address: Serge.vancalenbergh@ugent.be.
authors.forename: Serge
authors.initials: S
authors.lastname: Van Calenbergh
mesh_terms: D000818:Animals; D017951:Antigen Presentation; D055610:Antigens, CD1d / Q000235:genetics / Q000276:immunology; D002219:Carbamates / Q000737:chemistry*; D002240:Carbohydrate Sequence; D018360:Crystallography, X-Ray; D005699:Galactosylceramides / Q000138:chemical synthesis* / Q000494:pharmacology; D015870:Gene Expression; D006603:Hexuronic Acids / Q000737:chemistry*; D007113:Immunity, Innate; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology*; D015847:Interleukin-4 / Q000096:biosynthesis / Q000276:immunology*; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D008969:Molecular Sequence Data; D055611:Natural Killer T-Cells / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D011485:Protein Binding; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology; D013329:Structure-Activity Relationship; D058408:Th1-Th2 Balance / Q000187:drug effects
chemical_list: D055610:Antigens, CD1d; C584692:CD1d antigen, mouse; D002219:Carbamates; D005699:Galactosylceramides; D006603:Hexuronic Acids; D008024:Ligands; D011948:Receptors, Antigen, T-Cell; C493154:alpha-galactosylceramide; D015847:Interleukin-4; D007371:Interferon-gamma
keywords: CD1d; Glycolipids; iNKT-cells; α-GalCer