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

Area of Science:

• Biocatalysis
• Organic Synthesis
• Pharmaceutical Chemistry

Background:

• Sodium-glucose cotransporter 2 (SGLT2) inhibitors are crucial antidiabetic drugs.
• Traditional chemical glycosylation methods are complex, regioselectivity-challenging, and environmentally burdensome.
• Enzymatic glycosylation offers a milder, more selective alternative using UDP-glucosyltransferases (UGTs).

Purpose of the Study:

• To develop a chemoenzymatic hybrid synthesis for remogliflozin etabonate, an SGLT2 inhibitor.
• To identify efficient UDP-glucosyltransferases (UGTs) for the key glucosylation step.
• To establish a scalable and sustainable synthesis process.

Main Methods:

• Screening of plant and bacterial UGTs for remogliflozin aglycon glucosylation.
• Development of a UDP-glucose regeneration system using soybean sucrose synthase.
• Utilizing cyclodextrin encapsulation to enhance substrate solubility.
• Chemoenzymatic synthesis of remogliflozin etabonate.

Main Results:

• Identification of efficient UGTs from Bacillus for remogliflozin aglycon glucosylation.
• Successful synthesis of remogliflozin etabonate using a chemoenzymatic approach.
• Achieved a remogliflozin concentration of approximately 13 g/L with 95% conversion.
• Demonstrated a mild and efficient glycosylation process.

Conclusions:

• UGT-catalyzed glycosylation is a potent strategy for synthesizing glycosylated pharmaceuticals.
• The developed chemoenzymatic method offers a sustainable and efficient route for remogliflozin production.
• This approach minimizes hazardous reagents and harsh conditions compared to traditional methods.