Fluoro-labelled sp²-iminoglycolipids with immunomodulatory properties

Area of Science:

• Medicinal Chemistry
• Organic Synthesis
• Glycobiology

Background:

• Fluorine incorporation optimizes drug properties.
• 2-deoxy-2-fluorosugar derivatives are valuable in pharmaceuticals.
• sp2-iminoglycolipids (sp2-IGLs) are immunoregulatory compounds.

Purpose of the Study:

• To synthesize novel 2-deoxy-2-fluoro-sp2-IGLs.
• To evaluate their anti-proliferative and immunomodulatory activities.
• To elucidate their mechanism of action.

Main Methods:

• Sequential Selectfluor-mediated fluorination and thioglycosidation of sp2-iminoglycals.
• Synthesis of two epimeric series of 2-deoxy-2-fluoro-sp2-IGLs.
• In vitro anti-proliferative assays and mechanistic investigations.

Main Results:

• Exclusive formation of the α-anomer due to a strong anomeric effect.
• Compound 11 exhibited potent anti-proliferative activity comparable to Cisplatin with improved selectivity.
• Demonstrated reduction in tumor cell colonies and induced apoptosis.
• Revealed non-canonical activation of the mitogen-activated protein kinase pathway, specifically p38α autoactivation.

Conclusions:

• Novel fluoro-sp2-IGLs are successfully synthesized.
• Compound 11 shows significant therapeutic potential as an anti-cancer agent.
• The compound's mechanism involves p38α activation within the MAPK pathway.