A multi-enzymatic cascade reaction for the synthesis of bioactive C-oligosaccharides

C-oligosaccharides are rare in nature and possess diverse bioactivities. However, their chemical synthesis faces many challenges. In this work, enzymatic introduction of C-linked sugar chains to target aglycones was successfully achieved by multi-enzymatic cascade reactions. A C-glycosyltransferase from Aloe barbadensis was employed to introduce the first C-linked glucose and then a cyclomaltodextrin glucanotransferase from Bacillus licheniformis was used to extend the sugar chain. A total of twenty C-oligosaccharides with 2–6 sugars were synthesized from scale-up reactions and exhibited good water solubility and sodium-dependent glucose transporter 2 (SGLT2) inhibitory activity. Furthermore, a glucoamylase was used to control the length of the sugar chain and the C-maltosides were efficiently synthesized. These findings not only expanded the structural diversity of C-oligosaccharides, but also provided a strategy for the modification of C-glycoside drugs to improve the druggability.