Development of α-Selective Glycosylation for the Synthesis of Deoxyfluorinated TN Antigen Analogues.
Development of α-Selective Glycosylation for the Synthesis of Deoxyfluorinated TN Antigen Analogues.
复制标题
用于合成脱氧氟化 TN 抗原类似物的 α-选择性糖基化的开发。
DOI：
10.1021/acs.joc.0c03015
复制
发表时间：
2021
期刊：
影响因子：
--
通讯作者：
J. Karban
中科院分区：
文献类型：
--
作者：
M. Kurfiřt;Červenková Št'astná Lucie;Petra Cuřínová;Vojtěch Hamala;J. Karban
Tn抗原（GalNAcα1-Thr/Ser）在许多肿瘤中大量表达，但在健康组织中很少发现，这使其成为抗肿瘤免疫治疗的一个有吸引力的表位。Tn抗原在治疗性抗肿瘤疫苗开发中的应用受到其低免疫原性的阻碍，这可以通过GalNAc部分的脱氧核糖核酸来增强。在这里，我们报告的合成保护3-和4-氟类似物的苏氨酸含Tn抗原。由于α-连接的氟代GalNAc的立体选择性合成困难，我们制备了一组C3和C4脱氧氟代半乳糖酰肼thiodonors，并评估了它们在糖受体和苏氨酸衍生物的糖基化中的立体选择性。苏氨酸衍生物与O-苄基化C4氟供体的糖基化仅得到适度但可用的α-选择性，α/β = 2.5-3/1。在C4氟供体的3-和6-位使用酰基和甲硅烷基保护并没有提高选择性。在C3氟供体中安装4，6-二叔丁基亚甲硅烷基保护基团导致排他性的α-选择性，并重申了该保护基团在与半乳糖基配置的糖基供体的糖基化中的强α-导向作用。
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.