Synthesis of pentasaccharides corresponding to the glycoform II of the outer core region of the Pseudomonas aeruginosa lipopolysaccharide
Synthesis of pentasaccharides corresponding to the glycoform II of the outer core region of the Pseudomonas aeruginosa lipopolysaccharide
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DOI：
10.1016/j.carres.2012.07.019
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发表时间：
2012-10-01
影响因子：
3.1
通讯作者：
Nifantiev, Nikolay E.
中科院分区：
文献类型：
--
作者：
Komarova, Bozhena S.;Tsvetkov, Yury E.;Nifantiev, Nikolay E.
囊性纤维化（CF）是一种先天性疾病，由负责合成称为囊性纤维化跨膜传导调节因子（CFTR）的膜蛋白的基因突变引起。对铜绿假单胞菌感染的抗性与CFTR的生物学特性密切相关;然而，这些特性与CFTR作为氯离子和碳酸氢根离子通道的已知作用并没有明确联系。事实上，数据表明CFTR是铜绿假单胞菌的上皮细胞受体，其中CFTR结合细菌脂多糖（LPS）的外核心区域的寡糖，其中已经鉴定出两种不同的糖型。结合导致有效的先天免疫，以清除野生型CFTR个体中的这种病原体。为了揭示通过这种相互作用消除细菌的分子基础，进行了对应于铜绿假单胞菌LPS的外核心区域的两种糖型的五糖的合成。在这里，我们报告的糖型II的合成。与糖型I一样，将其制备为在半乳糖胺部分中带有天然存在的N-丙氨酰和N-乙酰基取代基以及非天然N-乙酰基丙氨酸的三种五糖，以揭示氨基在丙氨酰取代基中的作用。合成的关键特征是两个α-葡糖基化与葡糖基供体轴承α-立体定向酰基在O-6和/或O-3和高产率的叠氮基还原，然后N-酰化和最终的O-脱苄基。(C)2012爱思唯尔有限公司保留所有权利。
Cystic fibrosis (CF) is a congenital disease caused by a mutation in a gene responsible for the synthesis of a membrane protein called the cystic fibrosis transmembrane conductance regulator (CFTR). Resistance to Pseudomonas aeruginosa infection is closely related to the biological properties of CFTR; however, these properties have not been clearly linked to the known role of CFTR as a chloride and bicarbonate ion channel. Indeed, data indicate that CFTR is an epithelial cell receptor for P. aeruginosa, with CFTR binding to the oligosaccharide of the outer core region of the bacterial lipopolysaccharide (LPS), of which two distinct glycoforms have been identified. Binding leads to effective innate immunity to clear this pathogen in individuals with wild-type CFTR. To reveal the molecular basis of elimination of the bacterium through this interaction, the synthesis of pentasaccharides corresponding to both glycoforms of the outer core region of P. aeruginosa LPS was undertaken. Here we report the synthesis of the glycoform II. Like glycoform I, it was prepared as three pentasaccharides bearing naturally occurring N-alanyl and N-acetyl substituents in the galactosamine moiety as well as unnatural N-acetylalanine to reveal the role of the amino group in the alanyl substituent. Key features of the synthesis were two alpha-glucosylations with glucosyl donors bearing alpha-stereodirecting acyl groups at O-6 and/or O-3 and high-yielding reduction of the azido group followed by N-acylation and final O-debenzylation. (C) 2012 Elsevier Ltd. All rights reserved.