Chemoenzymatic synthesis of remogliflozin etabonate, an antidiabetic agent sodium-glucose cotransporter 2 inhibitor,...

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are antidiabetic drugs developed using phlorizin, a natural glucoside, as the lead compound. Chemical glycosylation requires multi-step reactions involving protection and deprotection steps, posing challenges in terms of regioselectivity and environmental burden due to the use of hazardous reagents and harsh conditions. In contrast, enzymatic glycosylation using UDP-glucosyltransferases (UGTs) enables regio- and stereoselective glycosylation under mild conditions without protection and deprotection steps. In this study, we developed a chemoenzymatic hybrid synthesis method for remogliflozin etabonate, an SGLT2 inhibitor approved in India in 2019, using UGT-catalyzed glucosylation as a key step. Screening plant and bacterial UGTs led to the identification of UGTs from Bacillus that efficiently catalyze the glucosylation of chemically synthesized remogliflozin aglycon. Using this enzyme in combination with a UDP-glucose regeneration system that employs soybean sucrose synthase and cyclodextrin encapsulation to improve substrate solubility, we synthesized remogliflozin at a concentration of approximately 13 g/L with 95 % conversion. These findings highlight the potential of UGT-catalyzed glycosylation as a mild and efficient approach for the synthesis of glycosylated pharmaceutical compounds.