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Development of (C-glycoside type) pseudo glycoconjugates that “look exactly same but differ in contents”

January 12, 2024

Establishment of a divergent synthesis method and creation of various analogs with widely altered biological activities

Although development of analog molecules whose structures of natural glycans/glycoconjugate are slightly modified (pseudo glycans/pseudo glycoconjugates) is extremely important in the drug discovery research, only limited investigations have been conducted due to complicatedness of the syntheses and others.

Kyushu University, Setsunan University, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka University, and RIKEN CSRS have devised a novel diversification strategy of C-glycoside type glycoconjugates which cannot be degraded by glycoside hydrolases and have employed light energy and catalytic reactions to develop an efficient divergent synthesis. This method has enabled the divergent synthesis of C-glycoside analogs having three different linkages (CH₂, (R)-CHF, (S)-CHF), leading to the successful syntheses of pseudo isomaltose and pseudo α-galactosylceramide in practice. Furthermore, it has been demonstrated that synthesized CH2-isomaltose shows extremely high amylase inducing activity compared to the natural form and that the (R)-CHF-α-galactosylceramide shows antagonist-like activity of invariant natural killer T cell (iNKT), opposite that of the natural form.

Unique bioactive molecules utilizing glycans/glycoconjugates (such as potential drug seeds that control immune function) are expected to be created in future by a “Linkage-Editing Strategy” as represented by this synthesis method.

Original article
Journal of American Chemical Society doi: 10.1021/jacs.3c12581
T. Moriyama, M. Yoritate, N. Kato, A. Saika, W. Kusuhara, S. Ono, T. Nagatake, H. Koshino, N. Kiya, N. Moritsuka, R. Tanabe, Y. Hidaka, K. Usui, Suzuka Chiba, N. Kudo, R. Nakahashi, K. Igawa, H. Matoba, K. Tomooka, E. Ishikawa, S. Takahashi, J. Kunisawa, S. Yamasaki, G. Hirai,
"Linkage-Editing pseudo-Glycans: A Reductive α-Fluorovinyl-C-Glycosylation Strategy to Create Glycan Analogs with Altered Biological Activities".
Contact
Hiroyuki Koshino; Unit Leader
Molecular Structure Characterization Unit
Shunji Takahashi; Unit Leader
Natural Product Biosynthesis Research Unit