Development of efficient methods for accomplishing cysteine-free peptide and glycopeptide coupling
Development of efficient methods for accomplishing cysteine-free peptide and glycopeptide coupling
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DOI：
10.1002/anie.200702865
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发表时间：
2007-01-01
影响因子：
16.6
通讯作者：
Danishefsky, Samuel J.
中科院分区：
文献类型：
--
作者：
Chen, Gong;Wan, Qian;Danishefsky, Samuel J.
我们目前正在寻求复杂的生物相关糖蛋白的全合成，包含多个低聚糖结构域这个问题的范围和复杂性促使人们产生新的思考和新的实验设计。除了激发创业的学习机会之外，还有具有非凡生物活性和效力的特定糖蛋白，可作为这些研究的目标更广泛地说，从制药的角度来看，潜在的治疗药物要么是“小分子”，要么是“生物制剂”。前者来自化学，而后者被认为完全来自生物手段。因此，从长远的角度来看，我们的目标是通过化学合成来获得重要的“生物”级制剂。如果实现，这种能力将使至少一些“生物制剂”处于药物化学类型优化平台的范围内。趋同合成策略将涉及单个糖肽片段的迭代偶联，每个糖肽片段含有一个或多个碳水化合物单位Kent及其同事在多肽-多肽连接中使用n端半胱氨酸残基作为酰基受体的辉煌进展，是我们研究的起点（方案1a）尽管Kent及其同事使用的天然化学连接（NCL）现在已常规应用于肽和蛋白质的合成，但仍需开发具有o-链和n -链聚糖结构域的糖肽的可靠连接方法。[5]为了进一步推进我们的计划，我们最近设计并实现了一种完成糖肽片段连接的新思路。它是基于在NCL中使用一种相当稳定的具有受保护的邻巯基部分(I)的酚酯来代替传统的巯基酯酰基供体
We are currently pursuing the total synthesis of complex biologically relevant glycoproteins, bearing multiple oligosaccharide domains.[1] The scope and complexity of the problem prompts new thinking and new experimental designs. In addition to the learning opportunities which motivate the venture, there are specific glycoproteins of extraordinary biological activity and potency, which serve as targets for these investigations.[2] More broadly, potential therapeutic agents are viewed in pharma perspectives as either “small molecules” or “biologicals.” The former are derived from chemistry while the latter are seen to emanate exclusively from biological means. Thus, our goal, as seen from a longerrange perspective, is that of reaching important “biologic”-level agents by chemical synthesis. If realizable, such a capability would bring at least some “biologics” under the purview of medicinal chemistry type optimization platforms. A convergent synthetic strategy would involve the iterative coupling of individual glycopeptide fragments, each bearing one or more carbohydrate units.[3] The brilliant advance by Kent and co-workers, in using N-terminal cysteine residues as acyl acceptors in polypeptide–polypeptide ligations, served as the starting point for our studies (Scheme 1 a).[4] Although the native chemical ligation (NCL) used by Kent and co-workers is now routinely applied in the synthesis of peptides and proteins, reliable methods for comparable ligations of glycopeptides bearing complex O-linked and N-linked glycan domains remained to be developed.[5]In furtherance of our program, we recently devised and brought to fruition a new idea to accomplish the ligation of glycopeptide fragments. It is based on the use of a fairly stable phenolic ester bearing a protected ortho-thiol moiety (I) in place of the conventional thiol ester acyl donor in NCL