Linkage-Editing Pseudo-Glycans: A Reductive α‑Fluorovinyl‑C‑Glycosylation Strategy to Create Glycan Analogs with Altered Biological Activities

• Published in: Journal of the American Chemical Society 2024-01, Vol.146 (3), p.2237-2247
• Main Authors: Moriyama, Takahiro, Yoritate, Makoto, Kato, Naoki, Saika, Azusa, Kusuhara, Wakana, Ono, Shunsuke, Nagatake, Takahiro, Koshino, Hiroyuki, Kiya, Noriaki, Moritsuka, Natsuho, Tanabe, Riko, Hidaka, Yu, Usui, Kazuteru, Chiba, Suzuka, Kudo, Noyuri, Nakahashi, Rintaro, Igawa, Kazunobu, Matoba, Hiroaki, Tomooka, Katsuhiko, Ishikawa, Eri, Takahashi, Shunji, Kunisawa, Jun, Yamasaki, Sho, Hirai, Go
• Format: Article
• Language: English
• Subjects: Amylases - metabolism; Galactosylceramides; Glycosides; Glycosylation; Polysaccharides - chemistry
• ISSN: 0002-7863; 1520-5126; 1520-5126
• DOI: 10.1021/jacs.3c12581

The acetal (O-glycoside) bonds of glycans and glycoconjugates are chemically and biologically vulnerable, and therefore C-glycosides are of interest as more stable analogs. We hypothesized that, if the O-glycoside linkage plays a vital role in glycan function, the biological activities of C-glycoside analogs would vary depending on their substituents. Based on this idea, we adopted a “linkage-editing strategy” for the creation of glycan analogs (pseudo-glycans). We designed three types of pseudo-glycans with CH2 and CHF linkages, which resemble the O-glycoside linkage in terms of bond lengths, angles, and bulkiness, and synthesized them efficiently by means of fluorovinyl C-glycosylation and selective hydrogenation reactions. Application of this strategy to isomaltose (IM), an inducer of amylase expression, and α-GalCer, which activates iNKT cells, resulted in the discovery of CH2-IM, which shows increased amylase production ability, and CHF-α-GalCer, which shows activity opposite that of native α-GalCer, serving as an antagonist of iNKT cells.