Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
Faculty of Agriculture, Setsunan University, 45-1 Nagaotoge-cho, Hirakata, Osaka 573-0101, Japan.
J Am Chem Soc. 2024 Jan 24;146(3):2237-2247. doi: 10.1021/jacs.3c12581. Epub 2024 Jan 9.
The acetal (-glycoside) bonds of glycans and glycoconjugates are chemically and biologically vulnerable, and therefore -glycosides are of interest as more stable analogs. We hypothesized that, if the -glycoside linkage plays a vital role in glycan function, the biological activities of -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 CH and CHF linkages, which resemble the -glycoside linkage in terms of bond lengths, angles, and bulkiness, and synthesized them efficiently by means of fluorovinyl -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 CH-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.
聚糖和糖缀合物的缩醛（-糖苷）键在化学和生物学上是脆弱的，因此 -糖苷作为更稳定的类似物引起了人们的兴趣。我们假设，如果 -糖苷键在糖的功能中起着至关重要的作用，那么 -糖苷类似物的生物活性将根据它们的取代基而有所不同。基于这一想法，我们采用了一种“键编辑策略”来创建糖类似物（假聚糖）。我们设计了三种具有 CH 和 CHF 键的假聚糖，它们在键长、键角和体积方面与 -糖苷键相似，并通过氟乙烯基 -糖苷化和选择性氢化反应有效地合成了它们。该策略在诱导淀粉酶表达的异麦芽糖（IM）和激活 iNKT 细胞的α-GalCer 上的应用，发现了 CH-IM，其显示出增加的淀粉酶产生能力，以及 CHF-α-GalCer，其显示出与天然α-GalCer 相反的活性，作为 iNKT 细胞的拮抗剂。
