The C-glycoside analogue of the immunostimulant alpha-galactosylceramide (KRN7000): synthesis and striking enhancement of activity.
The C-glycoside analogue of the immunostimulant alpha-galactosylceramide (KRN7000): synthesis and striking enhancement of activity.
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DOI：
10.1002/anie.200454215
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发表时间：
2004-07
影响因子：
--
通讯作者：
Guangli Yang;J. Schmieg;M. Tsuji;R. Franck
中科院分区：
文献类型：
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作者：
Guangli Yang;J. Schmieg;M. Tsuji;R. Franck
20世纪90年代初，麒麟制药的一个研究小组报告了他们从冲绳海绵Agelas mauritianus中筛选亲脂性提取物的结果。当他们的提取物在小鼠中进行测试时，而不是在细胞培养中，他们观察到糖脂的有效抗肿瘤活性，他们将其命名为琼脂蛋白（1）。[1]通过合成获得的化合物的结构-活性研究表明，天然琼胶蛋白的一种稍微简单的类似物，一种名为KRN 7000（2）的α半乳糖基神经酰胺，具有测试化合物的最佳活性，并且2的官能团和构型是最佳的。唯一可接受的变量是脂质链的长度、通过酰胺键在脂肪酰胺链末端插入“标记物”、在半乳糖残基的C6处取代、去除植物鞘氨醇部分的C4处的羟基以及脂肪酰胺中是否存在α羟基。[2]自麒麟集团首次披露以来，对KRN 7000生物效应的多方面探索揭示了其对不同疾病的显着活性，例如癌症，包括黑色素瘤，[3]胰腺癌的肝转移，[4]结肠癌的肝转移，[5]和三种不同模型中的原发性肿瘤形成，[6]以及疟疾。[7]青少年糖尿病，[8]肝炎B，[9]和自身免疫性脑脊髓炎，[10]在小鼠/整个动物版本的所有疾病。尽管从未检测到对疾病的细胞培养版本的活性，但可以通过将糖脂与抗原呈递树突状细胞或其分离的CD 1d受体孵育，然后用所得复合物挑战NKT细胞杂交瘤来测量体外活性。[11]研究的爆炸性发展导致了这样的发现：KRN 7000的统一作用机制是其诱导Vα24+ NKT细胞有效扩增的显着能力。事件的顺序是：1）半乳糖基神经酰胺结合抗原呈递细胞的CD 1d受体，然后2）神经酰胺受体复合物结合NKT细胞，其刺激细胞因子级联：导致疾病抑制的过程的信号。[12]目前尚不清楚为什么海洋来源的α-半乳糖神经酰胺会被哺乳动物受体识别并引发惊人的免疫反应。也没有确定是否存在一种内源性哺乳动物物质作为CD 1d受体的“天然”配体。可以说，KRN 7000是开发免疫刺激药物的有效先导化合物。[13个国家]
In the early 1990s a research group at Kirin Pharmaceuticals reported their results from screening lipophilic extracts from the Okinawan sponge Agelas mauritianus. When their extracts were tested in mice, but not in cell culture, they observed potent antitumor activity by glycolipids that they named the agelasphins (1).[1] Structure–activity studies of compounds available through synthesis revealed that a slightly simpler analogue of the natural agelasphins, an αgalactosyl ceramide named KRN7000 (2), had the best activity of the compounds tested, and that the functional groups and configuration of 2 were optimal. The only acceptable variables are the lengths of the lipid chains, the insertion of “taggants” at the terminus of the fatty amide chain through amide linkages, substitution at C6 of the galactose residue, the removal of the hydroxy group at C4 of the phytosphingosine moiety, and the presence or absence of an α hydroxy group in the fatty amide.[2]Since the initial disclosures by the Kirin group, a multifaceted exploration of the biological effects of KRN7000 has unveiled its remarkable activity against a disparate group of diseases, such as cancer, including melanoma,[3] hepatic metastases of pancreatic cancer,[4] hepatic metastases of colon cancer,[5] and primary tumor formation in three different models,[6] as well as malaria,[7] juvenile diabetes,[8] hepatitis B,[9] and autoimmune encephalomyelitis,[10] in murine/whole animal versions of all the diseases. Although no activity against cell-culture versions of the diseases is ever detected, in vitro activity can be measured by incubating the glycolipid with antigen-presenting dendritic cells or their isolated CD1d receptors and then challenging NKT-cell hybridomas with the resulting complex.[11] This explosion of research has led to that finding that the unifying mechanism of action of KRN7000 is its remarkable ability to induce a potent expansion of Vα24+ NKT cells. The sequence of events is: 1) the galactosyl ceramide binds to the CD1d receptor of antigen-presenting cells, then 2) the ceramide receptor complex binds to NKT cells, which stimulate a cascade of cytokines: signals for the processes that result in the suppression of the disease.[12] It is not yet known why an αgalactosyl ceramide of marine origin should be recognized by a mammalian receptor and elicit a spectacular immune response. It has also not been established whether an endogenous mammalian substance exists as the “natural” ligand for the CD1d receptor. Suffice to say that KRN7000 is a potent lead compound for the development of immunostimulant drugs.[13]