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

Jonas Janssens; Tine Decruy; Koen Venken; Toshiyuki Seki; Simon Krols; Johan Van der Eycken; Moriya Tsuji; Dirk Elewaut; Serge Van Calenbergh

doi:10.1021/acsmedchemlett.7b00107

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

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

Authors

Jonas Janssens^{1

2}, Tine Decruy^{3

4}, Koen Venken^{3

4}, Toshiyuki Seki^{5

6}, Simon Krols¹, Johan Van der Eycken², Moriya Tsuji⁵, Dirk Elewaut^{3

4}, Serge Van Calenbergh¹

Affiliations

¹ Laboratory for Medicinal Chemistry, Department of Pharmaceutics (FFW), Ghent University, Ottergemsesteenweg 460, B-9000 Ghent, Belgium.
² Laboratory for Organic and Bioorganic Synthesis, Department of Organic and Macromolecular Chemistry, Ghent University, Krijgslaan 281 (S4), B-9000 Ghent, Belgium.
³ Department of Internal Medicine, Faculty of Medicine and Health Sciences, Ghent University, De Pintelaan 185, B-9000 Ghent, Belgium.
⁴ VIB Inflammation Research Center, Ghent University, B-9000 Ghent, Belgium.
⁵ Aaron Diamond AIDS Research Center, The Rockefeller University, 1230 York Avenue, New York, New York 10065, United States.
⁶ Department of Obstetrics and Gynecology, The Jikei University School of Medicine, 3-25-8 Nishi-Shimbashi, Minato-ku, Tokyo 105-8461, Japan.

Abstract

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.

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