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

0541038 - ÚCHP 2022 RIV US eng J - Journal Article
Kurfiřt, Martin - Červenková Šťastná, Lucie - Cuřínová, Petra - Hamala, Vojtěch - Karban, Jindřich
Development of α-Selective Glycosylation for the Synthesis of Deoxyfluorinated TN Antigen Analogues.
Journal of Organic Chemistry. Roč. 86, č. 7 (2021), s. 5073-5090. ISSN 0022-3263. E-ISSN 1520-6904
R&D Projects: GA ČR(CZ) GA17-18203S
Institutional support: RVO:67985858
Keywords : amino acids * epitopes * stereochemistry
OECD category: Organic chemistry
Impact factor: 4.198, year: 2021
Method of publishing: Open access with time embargo

The Tn antigen (GalNAcα1-Thr/Ser) is abundantly expressed in many tumors but rarely found in healthy tissues, which makes it an attractive epitope for antitumor immunotherapy. The use of the Tn antigen in the development of therapeutic antitumor vaccines is hampered by its low immunogenicity, which may be enhanced by deoxyfluorination of the GalNAc moiety. Here, we report the synthesis of protected 3- and 4-fluoro analogues of the threonine-containing Tn antigen. As the stereoselective synthesis of α-linked fluorinated GalNAc is difficult, we prepared a panel of C3 and C4 deoxyfluorinated galactosazide thiodonors and evaluated their stereoselectivity in the glycosylation of carbohydrate acceptors and threonine derivatives. Glycosylation of threonine derivatives with O-benzylated C4 fluoro donors gave only modest but usable α-selectivity of α/β = 2.5–3/1. The use of acyl and silyl protection at the 3- and 6-positions of the C4 fluoro donors did not enhance the selectivity. Installing a 4,6-di-tert-butylsilylene-protecting group in C3 fluoro donors resulted in exclusive α-selectivity and reaffirmed the strong α-directing effect of this protective group in glycosylation with galacto-configured glycosyl donors.
Permanent Link: http://hdl.handle.net/11104/0318603