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Access to Galectin-3 Inhibitors from Chemoenzymatic Synthons
Christophe Dussouy1, Stéphane Téletchéa1, Annie Lambert1
1Université de Nantes, CNRS, Unité Fonctionnalité et Ingénierie des Protéines (UFIP), UMR 628, F-44000 Nantes, France.
The Journal of Organic Chemistry
|November 17, 2020
Summary
Chemoenzymatic synthesis using a modified enzyme creates novel azide-containing sugar derivatives. These compounds are then used to develop potential galectin-3 inhibitors, showcasing a powerful strategy for creating sugar-based ligands.
Area of Science:
- Carbohydrate Chemistry
- Enzymatic Synthesis
- Medicinal Chemistry
Background:
- Chemoenzymatic strategies offer precise control over regio- and stereoselectivity in synthesizing complex oligosaccharides.
- Bioactive oligosaccharides are crucial in various biological processes and therapeutic applications.
Purpose of the Study:
- To develop a novel chemoenzymatic approach for synthesizing functionalized oligosaccharides.
- To create a library of potential galectin-3 inhibitors using azide-modified sugar derivatives.
Main Methods:
- Utilized a glycosynthase mutant of *Thermus thermophilus* α-glycosidase.
- Employed unnatural glycosides, specifically 6-azido-6-deoxy-d-glucose/glucosamine, as substrates.
- Leveraged the orthogonality of azide and hydroxyl groups for selective functionalization.
Main Results:
- Successfully synthesized β-d-galactopyranosyl-(1→3)-d-glucopyranoside and β-d-galactopyranosyl-(1→3)-2-acetamido-2-deoxy-d-glucopyranoside derivatives with an azide moiety.
- Generated a diverse library of galectin-3 inhibitors through selective modification of the azide group.
- Demonstrated the rapid access to novel sugar-based ligands.
Conclusions:
- The combination of enzyme substrate promiscuity and bioorthogonal chemistry provides an efficient route to complex carbohydrate structures.
- This strategy enables the rapid development of targeted therapeutic agents, such as galectin-3 inhibitors.
- The developed chemoenzymatic method is a powerful tool for synthesizing functionalized sugar ligands.
