Chiral Propargylamines - Versatile Building Blocks for Peptidomimetics and Foldamers

手性丙炔胺 - 肽模拟物和折叠体的多功能构建模块

• 批准号: 233267300
• 负责人: Professor Dr. Norbert Sewald
• 金额: --
• 依托单位: Arbeitskreis Organische Chemie III
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2012
• 资助国家: 德国
• 起止时间: 2011-12-31 至 2016-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/233267300?language=en
• 关键词: Chiral; Propargylamines; Versatile; Building; Blocks

The proposed project is aiming at the synthesis and structural analysis of new types of peptidomimetics. The stereoselective synthesis of propargylamines as amino acid analogs and their application as versatile building blocks for peptidomimetics will be a key issue. Formally, the carboxy group of an amino acid is replaced by a terminal alkyne in such a building block. The target enantiomerically pure terminal alkynes will be used in copper-catalyzed azide-alkyne cycloadditions (CuAAC) or in the ruthenium-catalyzed correlate (RuAAC) to provide peptide analogs where the peptide bond is replaced by a triazole moiety. Such 1,4- or 1,5-disubstituted 1,2,3-triazoles are considered substitutes of trans- or cis-configured peptide bonds. Special emphasis will initially be placed on derivatives with substituents that resemble the side chains of proteinogenic amino acids. However, one of the strengths of the proposed approach is that it does not rely on the chiral pool like currently employed methods. Along this line, a broad scope of homo-oligomers of triazoles, the so-called triazolamers, formed by CuAAC or RuAAC will become accessible. Above all, triazolamer-peptide hybrids (oligomers composed of alternating 1,4- or 1,5-disubstituted triazole units and amide bonds) will be obtained as promising peptidomimetics. In addition, the terminal alkyne moiety of the key compounds will be coupled to aryl or heteroaryl halides according to Sonogashira to provide peptidomimetic building blocks and even foldamers by solid phase synthesis. The solution structures of the oligomers will be investigated by NMR in combination with MD calculations. With this information, first principles for the quick structural analysis of such foldamers with CD spectroscopy and for the design of secondary structure mimetics will be established. Perspectively, versatile peptidomimetics will then be designed with the different types of foldamers in order to bind proteins and inhibit protein-protein interaction.

本项目的目标是合成和结构分析新型肽模拟物。炔丙胺作为氨基酸类似物的立体选择性合成及其作为肽模拟物的多功能结构单元的应用将是一个关键问题。形式上，在这种结构单元中，氨基酸的羧基被末端炔取代。目标对映体纯的末端炔将用于铜催化的叠氮化物-炔环加成（CuAAC）或铼催化的相关物（RuAAC）中，以提供其中肽键被三唑部分取代的肽类似物。这种1，4-或1，5-二取代的1，2，3-三唑被认为是反式或顺式构型的肽键的取代物。特别强调将首先放在类似于蛋白质氨基酸的侧链的取代基的衍生物。然而，所提出的方法的优点之一是，它不依赖于手性池像目前采用的方法。沿着这条线，由CuAAC或RuAAC形成的广泛范围的三唑均聚物（所谓的三唑异构体）将变得可获得。最重要的是，三唑啉-肽杂合体（由交替的1，4-或1，5-二取代的三唑单元和酰胺键组成的低聚物）将作为有前途的肽模拟物而获得。此外，根据Sonogashira，关键化合物的末端炔部分将偶联至芳基或杂芳基卤化物，以通过固相合成提供拟肽结构单元甚至折叠体。低聚物的溶液结构将通过NMR结合MD计算进行研究。有了这些信息，第一原则的快速结构分析，这样的折叠体与CD光谱和二级结构模拟物的设计将被建立。因此，将用不同类型的折叠体设计通用肽模拟物，以结合蛋白质并抑制蛋白质-蛋白质相互作用。