Ligand‐Controlled Stereoselective Synthesis and Biological Activity of 2‐Exomethylene Pseudo‐glycoconjugates: Discovery of Mincle‐Selective Ligands

Author:

Ikazaki Takahiro1,Ishikawa Eri23,Tamashima Hiroto1,Akiyama Hisako45,Kimuro Yusuke1,Yoritate Makoto1,Matoba Hiroaki1,Imamura Akihiro6,Ishida Hideharu6,Yamasaki Sho23,Hirai Go1ORCID

Affiliation:

1. Graduate School of Pharmaceutical Sciences Kyushu University Maidashi Higashi-ku Fukuoka 812-8582 Japan

2. Department of Molecular Immunology Research Institute for Microbial Diseases Osaka University Yamadaoka Suita Osaka 565-0871 Japan

3. Laboratory of Molecular Immunology Immunology Frontier Research Center Osaka University Yamadaoka Suita Osaka 565-0871 Japan

4. Juntendo Advanced Research Institute for Health Science Juntendo University Tokyo 113-8421 Japan

5. RIKEN Center for Brain Science Wako Saitama 351-0198 Japan

6. Department of Applied Bioorganic Chemistry and Institute for Glyco-core Research (iGCORE) Gifu University 1-1 Yanagido Gifu 501-1193 Japan

Abstract

AbstractGlycoconjugate analogues in which the sp3‐hybridized C2 position of the carbohydrate structure (normally bearing a hydroxy group) is converted into a compact sp2‐hybridized exomethylene group are expected to have unique biological activities. We established ligand‐controlled Tsuji–Trost‐type glycosylation methodology to directly prepare a variety of these 2‐exomethylene pseudo‐glycoconjugates, including glucosylceramide analogues, in an α‐ or β‐selective manner. Glucocerebrosidase GBA1 cleaves these synthetic pseudo‐β‐glucosylceramides similarly to native glucosylceramides. The pseudo‐glucosylceramides exhibit selective ligand activity towards macrophage‐inducible C‐type lectin (Mincle), but unlike native glucosylceramides, are inactive towards CD1d.

Funder

Japan Society for the Promotion of Science

Japan Agency for Medical Research and Development

Mizutani Foundation for Glycoscience

Takeda Science Foundation

Publisher

Wiley

Subject

General Medicine

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