Hao Tianhui, Mi Tian, Chu Qinyu, Ma Wenjing, Cheng Xi, Zang Yi, Li Jia, Li Tiehai
State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
University of Chinese Academy of Sciences, Beijing 100049, China.
ACS Med Chem Lett. 2024 Jun 5;15(7):1102-1108. doi: 10.1021/acsmedchemlett.4c00199. eCollection 2024 Jul 11.
α-Galactosylceramide (KRN7000 or α-GalCer) analogues terminated with phenyl (Ph) groups at the acyl moiety possess more potency than KRN7000 to activate invariant natural killer T (iNKT) cells for inducing a T helper 1 (Th1)-biased immune response. However, biological activities of phenyl glycolipids with thio-modifications at the acyl moiety remain unknown, and facile approaches for highly stereoselective synthesis of KRN7000 and its analogues are rather scarce. Herein, we exploited 4,6-di---butylsilylene (DTBS)-directed stereospecific galactosylation to efficiently synthesize various α-GalCer analogues bearing thioamide, terminal thiophenyl and dual modifications at the acyl moiety. Biological evaluations suggest that a new analogue S34 featuring a terminal Ph-S-Ph-F group exhibits a more superior Th1-biased immune response in mice. Molecular docking analysis revealed that the introduction of a sulfur atom influences vital hydrogen bonding interactions between glycolipids and the cluster of differentiation 1d (CDld), thus adjusting the stability of the glycolipid-CDld complex.
在酰基部分以苯基（Ph）基团结尾的α-半乳糖神经酰胺（KRN7000或α-GalCer）类似物比KRN7000具有更强的激活不变自然杀伤T（iNKT）细胞以诱导偏向辅助性T细胞1（Th1）免疫反应的能力。然而，在酰基部分具有硫修饰的苯基糖脂的生物学活性仍然未知，并且高效立体选择性合成KRN7000及其类似物的简便方法相当稀少。在此，我们利用4,6-二叔丁基硅撑（DTBS）导向的立体特异性半乳糖基化反应，高效合成了各种在酰基部分带有硫代酰胺、末端硫苯基和双重修饰的α-GalCer类似物。生物学评估表明，一种具有末端Ph-S-Ph-F基团的新类似物S34在小鼠中表现出更优越的偏向Th1的免疫反应。分子对接分析表明，硫原子的引入影响了糖脂与分化簇1d（CD1d）之间至关重要的氢键相互作用，从而调节了糖脂-CD1d复合物的稳定性。
