Structure-activity relationship studies of Bz amide-containing α-GalCer derivatives as natural killer T cell modulators.

Autor: Kishi J; Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Yokohama, Kanagawa 223-8522, Japan., Inuki S; Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Yokohama, Kanagawa 223-8522, Japan; Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-Shimo-Adachi-cho, Sakyo-ku, Kyoto 606-8501, Japan., Hirata N; Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Yokohama, Kanagawa 223-8522, Japan., Kashiwabara E; Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Yokohama, Kanagawa 223-8522, Japan., Yoshidome D; Schrödinger K. K., 1-8-1 Marunouchi Chiyoda-ku, Tokyo 100-0005, Japan., Ichihara O; Schrödinger K. K., 1-8-1 Marunouchi Chiyoda-ku, Tokyo 100-0005, Japan., Fujimoto Y; Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Yokohama, Kanagawa 223-8522, Japan. Electronic address: fujimotoy@chem.keio.ac.jp.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2019 Apr 15; Vol. 29 (8), pp. 970-973. Date of Electronic Publication: 2019 Feb 18.
DOI: 10.1016/j.bmcl.2019.02.018
Abstrakt: CD1d is a non-polymorphic antigen-presenting glycoprotein that recognizes glycolipids as ligands. Ligands bind to the hydrophobic grooves of CD1d, and the resulting ligand-CD1d complexes activate natural killer T (NKT) cells by means of T cell receptor recognition, leading to the secretion of various cytokines. However, details of the ligand recognition mechanism of a large hydrophobic ligand binding pocket and the relationship between cytokine induction and ligand structure are unclear. We report the synthesis of α-GalCer derivatives containing a Bz amide group having various substituting groups in the ceramide moiety, and the analysis of the structure-activity relationships. The assays reveal that the Bz amide-containing CD1d ligands function as NKT cell modulators displaying Th2 cytokine biasing responses. Furthermore, molecular dynamics simulation studies suggest that the phenyl groups can interact with the aromatic amino acid residues in the lipid binding pocket of CD1d.
(Copyright © 2019 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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