Development of α-Selective Glycosylation for the Synthesis of Deoxyfluorinated T_N Antigen Analogues

Area of Science:

• Carbohydrate Chemistry
• Immunotherapy
• Organic Synthesis

Background:

• The Tn antigen (GalNAcα1-Thr/Ser) is a tumor-associated carbohydrate antigen with potential for cancer immunotherapy.
• Its low immunogenicity limits its therapeutic application, suggesting modification to enhance immune response.

Purpose of the Study:

• To synthesize protected 3- and 4-fluoro analogues of the threonine-containing Tn antigen.
• To evaluate the stereoselectivity of deoxyfluorinated galactosazide thiodonors in glycosylation reactions.

Main Methods:

• Preparation of C3 and C4 deoxyfluorinated galactosazide thiodonors.
• Glycosylation of carbohydrate acceptors and threonine derivatives using these donors.
• Evaluation of stereoselectivity (α/β ratio) under different protection strategies.

Main Results:

• Glycosylation with O-benzylated C4 fluoro donors yielded moderate α-selectivity (α/β = 2.5-3/1).
• Acyl and silyl protection at C4 did not improve selectivity.
• A 4,6-di-tert-butylsilylene protecting group on C3 fluoro donors resulted in exclusive α-selectivity.

Conclusions:

• Deoxyfluorination of the GalNAc moiety is a viable strategy to enhance Tn antigen immunogenicity.
• Specific protecting groups, like the 4,6-di-tert-butylsilylene, are crucial for achieving high α-selectivity in synthesizing fluorinated Tn antigens.
• These findings contribute to the development of more effective antitumor vaccines.