Synthesis of C6''-modified α-C-GalCer analogues as mouse and human iNKT cell agonists

Joren Guillaume; Toshiyuki Seki; Tine Decruy; Koen Venken; Dirk Elewaut; Moriya Tsuji; Serge Van Calenbergh

doi:10.1039/c7ob00081b

Synthesis of C6''-modified α-C-GalCer analogues as mouse and human iNKT cell agonists

Org Biomol Chem. 2017 Mar 8;15(10):2217-2225. doi: 10.1039/c7ob00081b.

Authors

Joren Guillaume¹, Toshiyuki Seki², Tine Decruy³, Koen Venken³, Dirk Elewaut³, Moriya Tsuji², Serge Van Calenbergh¹

Affiliations

¹ Laboratory for Medicinal Chemistry (FFW), Faculty of Pharmaceutical Sciences, UGent, Ottergemsesteenweg 460, B-9000 Ghent, Belgium. [email protected].
² Aaron Diamond AIDS Research Center, Affiliate of The Rockefeller University, New York, New York, USA.
³ Department of Internal Medicine, Faculty of Medicine and Health Sciences, Ghent University, B-9000 Ghent, Belgium and VIB Inflammation Research Center, Ghent University, Ghent, Belgium.

PMID: 28221388
DOI: 10.1039/c7ob00081b

Abstract

α-GalCer analogues that combine known Th1 polarizing C6''-modifications with a C-glycosidic linkage were synthesized. We employed a protecting group strategy that allowed the preparation of both saturated and unsaturated derivatives with variable C6''-substituents. Selected analogues demonstrate promising activity in mice. Interestingly, the introduction of a 6''-O-pyridinylcarbamoyl substituent to α-C-GalCer restores its antigenicity in human iNKT cells.

MeSH terms

Animals
Cell Line
Cytokines / biosynthesis
Cytokines / blood
Dose-Response Relationship, Drug
Galactosylceramides / chemical synthesis*
Galactosylceramides / chemistry
Galactosylceramides / pharmacology*
HeLa Cells
Humans
Mice
Mice, Inbred C57BL
Molecular Structure
Natural Killer T-Cells / drug effects*
Natural Killer T-Cells / immunology
Natural Killer T-Cells / metabolism
Structure-Activity Relationship

Substances

C-galactosylceramide
Cytokines
Galactosylceramides