Department of Pharmacy and Center for Integrated Protein Science, Ludwig-Maximilians-Universität, Butenandtstr. 5-13, 81377, München, Germany.
Angew Chem Int Ed Engl. 2022 Nov 2;61(44):e202211138. doi: 10.1002/anie.202211138. Epub 2022 Sep 29.
Hybrid sequences comprising a peptide with several Cys residues and an aromatic foldamer helix with several chloroacetamide functions at its surface were synthesized. Such products may in principle form numerous macromulticyclic thioether products by intramolecularly combining all Cys residues and all chloroacetamide functions. However, we show that the reactive sites on the structurally defined helix can be placed at such locations that the peptide selectively stitches itself to form a series of different macrocycles within mostly one preferred product. Reactions were monitored by HPLC and products with two, three or four macrocycles were identified using LC-MS and NMR. The series of selective macrocyclizations define a sort of reaction trail where reaction sites otherwise identical are involved successively because of their precise positioning in space. The trails can be predicted to a large extent based on structural considerations and the assumption that smaller macrocycles form faster.
合成了一种含有几个半胱氨酸残基的肽和一种在表面具有几个氯乙酰胺功能的芳香折叠螺旋的混合序列。这些产物原则上可以通过分子内结合所有半胱氨酸残基和所有氯乙酰胺功能形成许多大环多硫醚产物。然而，我们表明，在结构上定义的螺旋上的反应位点可以放置在这样的位置，使得肽选择性地缝合自身以形成一系列不同的大环，主要是在一个首选产物中。通过 HPLC 监测反应，使用 LC-MS 和 NMR 鉴定出具有两个、三个或四个大环的产物。一系列选择性的大环化反应定义了一种反应轨迹，其中由于它们在空间中的精确定位，否则相同的反应位点会相继参与反应。可以在很大程度上基于结构考虑和较小大环形成更快的假设来预测这些轨迹。
