School of Pharmacy, College of Medicine, National Taiwan University, 1, Jen-Ai Road, Section 1, Taipei 100, Taiwan.
Chembiochem. 2012 Jul 23;13(11):1689-97. doi: 10.1002/cbic.201200004. Epub 2012 Jun 22.
α-GalCer is an immunostimulating glycolipid that binds to CD1d molecules and activates invariant natural killer T (iNKT) cells. Here we report a scaled-up synthesis of α-GalCer analogues with modifications in the acyl side chain and/or at the galactose 6''-position, together with their evaluation in vitro and in vivo. Analogues containing 11-phenylundecanoyl acyl side chains with aromatic substitutions (14, 16-21) and Gal-6''-phenylacetamide-substituted α-GalCer analogues bearing p-nitro- (32), p-tert-butyl (34), or o-, m-, or p-methyl groups (40-42) displayed higher IFN-γ/IL-4 secretion ratios than α-GalCer in vitro. In mice, compound 16, with an 11-(3,4-difluorophenyl)undecanoyl acyl chain, induced significant proliferation of NK and DC cells, which should be beneficial in killing tumors and priming the immune response. These new glycolipids might prove useful as adjuvants or anticancer agents.
α-GalCer 是一种免疫刺激糖脂，可与 CD1d 分子结合并激活不变自然杀伤 T（iNKT）细胞。在这里，我们报告了 α-GalCer 类似物的大规模合成，这些类似物在酰基侧链和/或半乳糖 6''-位进行了修饰，并对其进行了体外和体内评估。含有带有芳香取代基的 11-苯基十一烷酰基侧链的类似物（14、16-21）和带有对硝基（32）、叔丁基（34）或邻、间、或对甲基取代基的 Gal-6''-苯乙酰胺取代的 α-GalCer 类似物（40-42）在体外比 α-GalCer 显示出更高的 IFN-γ/IL-4 分泌比率。在小鼠中，具有 11-(3,4-二氟苯基)十一烷酰基链的化合物 16 诱导 NK 和 DC 细胞的显著增殖，这应该有利于杀死肿瘤和启动免疫反应。这些新的糖脂可能被证明是有用的佐剂或抗癌药物。
