Chiral Propargylamines - Versatile Building Blocks for Peptidomimetics and Foldamers

拟议的项目旨在合成和结构分析新型多肽类药物。作为氨基酸类似物的炔丙胺的立体选择性合成及其作为多肽模拟物的通用构件的应用将是一个关键问题。形式上，氨基酸的羧基被这种构筑块中的末端炔所取代。目标对映体纯的末端炔烃将用于铜催化的叠氮-炔环加成反应(CuAAC)或Ru催化的相关反应(RuAAC)，以提供多肽类似物，其中多肽键被三唑基团取代。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多肽键的替代品。最初的重点将放在具有类似蛋白质来源氨基酸侧链的取代基的衍生物上。然而，该方法的优点之一是它不像目前使用的方法那样依赖于手性池。沿着这条线，由CuAAC或RuAAC形成的广泛的三唑齐聚物，即所谓的三唑胺，将变得容易获得。最重要的是，三唑胺-多肽杂化化合物(由交替的1，4-或1，5-二取代三氮唑单元和酰胺键组成的低聚物)将是很有前途的肽类药物。此外，根据Sonogashira的说法，关键化合物的末端炔基部分将偶联到芳基或杂芳基卤化物上，通过固相合成提供模拟肽的构建块，甚至是叶酰胺。低聚物的溶液结构将通过核磁共振结合分子动力学计算进行研究。利用这些信息，将建立用CD光谱快速分析这类折叠体的结构和设计二级结构模拟物的第一原理。从长远来看，为了结合蛋白质和抑制蛋白质间的相互作用，将设计出与不同类型的折叠酶结合的多肽模拟物。

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.