Synthesis of N-linked glycopeptides via solid-phase aspartylation
Synthesis of N-linked glycopeptides via solid-phase aspartylation
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DOI：
10.1039/c003673k
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发表时间：
2010-01-01
影响因子：
3.2
通讯作者：
Payne, Richard J.
中科院分区：
文献类型：
--
作者：
Conroy, Trent;Jolliffe, Katrina A.;Payne, Richard J.
描述了一种制备N-连接糖肽的有效策略。该方法依赖于使用天冬氨酸残基上的侧链保护基团，即烯丙基酯和Dmab酯，其与Fmoc策略SPPS中使用的那些是正交的。在肽组装后，选择性地除去这些保护基团，并将所得游离侧链用葡糖胺衍生化，以提供带有天然N-键的树脂结合的糖肽。最初，N-连接的糖肽成功地合成根据这种策略，然而，产量变化很大，这取决于位于邻近（C-末端）的推定的糖基化位点的氨基酸残基的性质。这是由于产生了大量的天冬酰亚胺副产物。天冬酰亚胺的形成是通过在与烯丙基或Dmab保护的天冬氨酸残基相邻的残基上引入2，4-二甲氧基苄基（Dmb）骨架酰胺保护基来克服的。在固相酰化反应后，以优异的产率制备N-连接的糖肽。利用烯丙基和Dmab酯固相方法的实用性和正交性制备具有两个不同碳水化合物部分的N-连接的糖十肽。这举例说明了固相方法用于制备带有各种N-连接聚糖组合的糖肽的效率。
An efficient strategy for the preparation of N-linked glycopeptides is described. The method relies on the use of side chain protecting groups on aspartic acid residues, namely the allyl and Dmab esters, which are orthogonal to those utilised in Fmoc-strategy SPPS. After peptide assembly these protecting groups were selectively removed and the resulting free side chains derivatised with a glycosylamine to afford a resin bound glycopeptide bearing a native N-linkage. Initially, N-linked glycopeptides were successfully synthesised according to this strategy, however, yields varied substantially depending on the nature of the amino acid residue situated adjacent (C-terminal) to the putative glycosylation site. This was due to generation of substantial quantities of aspartimide by-products. Aspartimide formation was overcome by incorporation of a 2,4-dimethoxybenzyl (Dmb) backbone amide protecting group on the residue adjacent to an allyl-or Dmab-protected aspartic acid residue. N-linked glycopeptides were prepared in excellent yield after the solid-phase aspartylation reactions. The utility and orthogonality of the allyl and Dmab ester solid-phase approaches were exploited in the preparation of an N-linked glycodecapeptide bearing two different carbohydrate moieties. This exemplified the efficiency of the solid-phase methodology for the preparation of glycopeptides bearing various combinations of N-linked glycans.