E and Z α-C-galactosylceramides by Julia-Lythgoe-Kocienski chemistry:: A test of the receptor-binding model for glycolipid immunostimulants
E and Z α-C-galactosylceramides by Julia-Lythgoe-Kocienski chemistry:: A test of the receptor-binding model for glycolipid immunostimulants
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DOI：
10.1002/cbic.200500386
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发表时间：
2006-07-01
期刊：
影响因子：
3.2
通讯作者：
Franck, Richard W.
中科院分区：
文献类型：
--
作者：
Chen, Guangwu;Chien, May;Franck, Richard W.
自20世纪90年代Kirin Pharma分离出一组海洋半乳糖基神经酰胺以及随后开发出先导分子α-半乳糖基神经酰胺（1）以来，该家族的强效免疫刺激活性一直是人们非常感兴趣的主题。[1]在生物体水平上，这些分子已被证明对许多疾病具有有效的治疗效果，从癌症到疟疾再到糖尿病。[2]在分子水平上，糖脂1已被证明作为抗原呈递细胞的CD 1d分子呈递给小鼠Va 14受体和自然杀伤T（NKT）细胞的人Va 24受体的连接配体。在CD 1d的背景下识别半乳糖基神经酰胺后，NKT细胞随后被刺激产生干扰素-g（IFN-g）、白细胞介素-4（IL-4）和白细胞介素-2（IL-2）。白细胞介素-12（IL-12）在NKT细胞活化后由抗原呈递细胞（例如树突细胞）分泌。通过对其他先天性和适应性免疫细胞的二次刺激，半乳糖苷-ACHTUNGTRENNUNGamide诱导的NKT细胞活化导致疾病抑制。[3]IFN-γ和IL-4分泌水平之间的平衡可能通过拮抗作用对NKT细胞刺激的最终免疫效果产生重要影响。[4]O-糖苷类似物的发展包括i）在糖中，阿利亚是将半乳糖的6-羟甲基转换为糖醛酸[5]，将3-羟基转换为硫酸盐[6] ii）在脂质链中，改变链长和不饱和度。有趣的是，与亲本1相比，这些变化导致IFN-g和IL-4 ACHTUNGTRENNUNG平衡的相对较小的变化，并且只有一种类似物显示出比亲本更大的前景。[7]当鞘氨醇尾部从14个碳原子缩短至5个碳原子时，观察到O-糖苷系列中最显著的效果;这导致IL-4/IFN-g比率显著增加（由于IFN-g分泌减少）。在小鼠脑脊髓炎疾病模型中，这种变化导致改善的治疗效果。[8]最近，两个独立的报告，X射线晶体ACHTUNGTRENNUNG测定O-半乳糖神经酰胺结合的CD 1d分子已经出现。[9]主要特征包括蛋白质和几个配体位点之间的氢键：半乳糖2和3 OH，侧链3和4 OH，以及糖苷氧。配体的脂质链也具有特征，其被埋在由疏水性氨基酸组成的通道中。与本研究最相关的是，半乳糖和神经酰胺之间的连接区的结合构象揭示了β 1708的“反”二面角。我们的实验室专注于深层结构的变化，C-糖苷的制备。在细胞因子水平上，类似物2引起IFN-g/IL-4比率的增加（由于IL-4分泌的减少），这与报道的所有其他类似物相反;在生物体水平上，类似物2在鼠模型中表现出抑制疟疾和黑素瘤的效力的显著增加。[10]我们之前已经报道了使用Ramberg-Bäcklund方法[11]和烯烃交叉复分解方法合成2和相关材料。[12]在上述X射线报告之前，我们推断具有顺式或反式连接体的C类似物可能为优选的配体结合几何形状提供证据。在这里，我们报告了我们的研究，使用“一锅”版本的朱莉娅烯烃合成，以获得E和Z异构体3和4（方案1），这有助于测试的配体结合模型所建议的X射线数据。同样有趣的是...
Since the isolation of a group of marine galactosyl ceramides in the 1990s by Kirin Pharma, and the subsequent development of the lead molecule a-galactosylceramide (1), the potent immunostimulant activity of this family has been a subject of great interest.[1] At the organism level, these molecules have been shown to have potent therapeutic effects against many diseases, ranging from cancer to malaria to diabetes.[2] At the molecular level, glycolipid 1 has been shown to act as a connecting ligand presented by the CD1d molecule of antigen-presenting cells to the murine Va14 receptor and the human Va24 receptor of natural killer T (NKT) cells. Upon recognition of the galactosyl ceramide in the context of CD1d, the NKT cell then is stimulated to produce interferon-g (IFN-g), interleukin-4 (IL-4), and interleukin-2 (IL-2). Interleukin-12 (IL-12) is secreted by antigen-presenting cells, such as dendritic cells, upon activation of NKT cells. Through secondary stimulation of other innate and adaptive immunocytes, galactosylcer-ACHTUNGTRENNUNGamide-induced NKT cell activation results in disease suppression.[3] The balance between the secreted levels of IFN-g, aTH1 cytokine, and IL-4, a TH2 cytokine, through antagonistic effects, might have an important impact on the ultimate immunotherapeutic effect of NKT cell stimulation.[4] Developments for O-glycoside analogues include i) in the sugar, inter alia, switching the 6-hydroxymethyl of the galactose to an uronic acid [5] and the 3-hydroxyl to sulfate [6] ii) in the lipid chains, varying chain lengths and degrees of unsaturation. Interestingly, these variations result in relatively small changes in the IFN-g and IL-4 ACHTUNGTRENNUNGbalance compared to the parent l, and only one analogue showed greater promise than the parent.[7] The most dramatic effect in the O-glycoside series was seen when the sphingosine tail was shortened from 14 to 5 carbon atoms; this led to a ACHTUNGTRENNUNGsignificant increase in the IL-4/IFN-g ratio (due to a decrease in IFN-g secretion). In the mouse encephalomyelitis disease model, this change results in an improved therapeutic effect.[8] Recently, two independent reports of X-ray crystallographic ACHTUNGTRENNUNGdeterminations of O-galactosylceramides bound to the CD1d molecule have appeared.[9] Key features include hydrogen bonding between the protein and several ligand sites: the gal 2 and 3 OH’s, the side-chain 3 and 4 OH’s, and the glycosidic oxygen. Also featured are the lipid chains of the ligand, which are buried in channels composed of hydrophobic amino acids. Most pertinent to this research, the bound conformation of the linker region between the galactose and the ceramide reveals “anti” dihedral angles of∼ 1708. Our laboratory has focused on a deep-seated structural change, the preparation of C-glycosides. Analogue 2 caused an increase in the IFN-g/IL-4 ratio (due to decreased secretion of IL-4) at the cytokine level, in contrast to all other analogues reported; at the organism level, analogue 2 exhibited a dramatic increase in potency in suppressing malaria and melanoma in murine models.[10] We have previously reported on the syntheses of 2 and related materials using the Ramberg–Bäcklund method [11] and an olefin cross-metathesis approach.[12] Prior to the X-ray reports described above, we reasoned that C analogues with a cis or trans linker might supply evidence for a preferred ligand-binding geometry. Here we report on our studies using the “one-pot” version of the Julia olefin synthesis to obtain both E and Z isomers 3 and 4 (Scheme 1), which serve to test the ligand-binding model suggested by the X-ray data. Also of interest …