Total enantioselective synthesis and in vivo biological evaluation of a novel fluorescent BODIPY α-galactosylceramide
Total enantioselective synthesis and in vivo biological evaluation of a novel fluorescent BODIPY α-galactosylceramide
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DOI：
10.1002/cbic.200390009
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发表时间：
2003-01-03
期刊：
影响因子：
3.2
通讯作者：
Bonin, M
中科院分区：
文献类型：
--
作者：
Yen, VH;Micouin, L;Bonin, M
自然杀伤T细胞（NKT）是成熟淋巴细胞的一个独特亚群，具有活化和调节性T细胞的特征。α -半乳糖神经酰胺（α - galcers）是唯一能被NKT细胞t细胞受体识别的天然试剂，其合成原型是KRN7000。α - galcer激活的NKT细胞迅速释放ifnγ和IL-4 （IFN =干扰素；IL =白细胞介素），并在数小时内发生凋亡死亡。在小鼠中，活化的NKT细胞负责抗肿瘤活性和对自身免疫性疾病的保护。因此，KRN7000可以被认为是一个新型免疫调节药物家族的根源。为了深入了解α -半乳糖神经酰胺的体内行为，采用聚合合成方案制备了一种原始荧光衍生物。这种策略允许在合成的最后步骤中引入不同的酰基链、碳水化合物残基和各种标签。来自多功能糖脂前体的荧光BODIPY探针在诱导肝脏NKT细胞凋亡方面与KRN7000一样活跃。腹腔巨噬细胞、脾脏抗原呈递细胞、肝脏库普弗样细胞均可见荧光，淋巴细胞未见荧光。
Natural killer T (NKT) cells are a distinct subset of mature lymphocytes endowed with features of activated and regulatory T cells. alpha-Galactosylceramides (alpha-GalCers), the synthetic prototype of which is KRN7000, are the only natural reagents recognised by the T-cell receptor of NKT cells. The alpha-GalCer-activated NKT cells promptly release IFNgamma and IL-4 (IFN = interferon; IL = interleukin) and undergo apoptotic death within hours. In mice, activated NKT cells are responsible for antitumor activity and protection against autoimmune diseases. KRN7000 can thus be considered as the root of a family of novel immunoregulatory drugs. To get insights into the in vivo behaviour of alpha-galactosylceramides, an original fluorescent derivative has been prepared by following a convergent synthetic scheme. This strategy allows the introduction of different acyl chains, carbohydrate residues and various labels in the final steps of the synthesis. The fluorescent BODIPY probe derived from a versatile glycolipid precursor is as active as KRN7000 for inducing apoptosis of liver NKT cells. Fluorescence was detected in peritoneal macrophages and splenic antigen-presenting cells, in Kupffer-like cells in the liver, but not in lymphocytes.