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ACS Med Chem Lett. 2017 May 5;8(6):642-647. doi: 10.1021/acsmedchemlett.7b00107. eCollection 2017 Jun 8.

Efficient Divergent Synthesis of New Immunostimulant 4″-Modified α-Galactosylceramide Analogues.

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Laboratory for Medicinal Chemistry, Department of Pharmaceutics (FFW), Ghent University, Ottergemsesteenweg 460, B-9000 Ghent, Belgium.
Laboratory for Organic and Bioorganic Synthesis, Department of Organic and Macromolecular Chemistry, Ghent University, Krijgslaan 281 (S4), B-9000 Ghent, Belgium.
Department of Internal Medicine, Faculty of Medicine and Health Sciences, Ghent University, De Pintelaan 185, B-9000 Ghent, Belgium.
VIB Inflammation Research Center, Ghent University, B-9000 Ghent, Belgium.
Aaron Diamond AIDS Research Center, The Rockefeller University, 1230 York Avenue, New York, New York 10065, United States.
Department of Obstetrics and Gynecology, The Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-ku, Tokyo 105-8461, Japan.


A synthesis strategy for the swift generation of 4″-modified α-galactosylceramide (α-GalCer) analogues is described, establishing a chemical platform to comprehensively investigate the structure-activity relationships (SAR) of this understudied glycolipid part. The strategy relies on a late-stage reductive ring-opening of a p-methoxybenzylidene (PMP) acetal to regioselectively liberate the 4″-OH position. The expediency of this methodology is demonstrated by the synthesis of a small yet diverse set of analogues, which were tested for their ability to stimulate invariant natural killer T-cells (iNKT) in vitro and in vivo. The introduction of a p-chlorobenzyl ether yielded an analogue with promising immunostimulating properties, paving the way for further SAR studies.


CD1d; KRN7000; Th1/Th2; cytokine secretion; immunomodulators; α-Galactosylceramide

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