設計合成選擇性標定含胍基化合物的化學探針分子

Abstract

胍是一個含多氮的有機化合物，廣泛出現於有機化合物中，精胺酸、胜肽、或是許多天然代謝物都具有胍的官能基，通常它們在生物分子的交互作用上在扮演一定重要角色。因此近年來科學家致力於胍官能基團的標定，同時能應用於精胺酸或是胜肽等生物分子的標記。在本論文中我們開發了一個簡單標定胍官能基團的方法，利用八環具1,2-雙酮的衍生物，在非強鹼溫和的條件下進行縮合及二苯乙醇酸重排反應得到穩定的產物，並且有不錯的產率。另外我們也製備了不同官能基取代的八環1,2-雙酮衍生物與胍進行反應，探討相對的反應活性。我們認為我們開發的方法學能為精胺酸或具有胍官能基團天然代謝物的標定提供一種新的化學方法及分析工具。The development of efficient analytical methods capable of understanding the molecular interaction in biological systems is an important task of chemistry and biology. Biocompatible and bioorthogonal conjugation reactions have proven to be powerful tools in biological research and medicine. Guanidine functional groups can be often as part of several drugs, natural products and metabolites as well as proteins and peptides. In particular, guanidine is an important class of organic molecules, which is larely used in organic synthesis and in medicinal chemistry and have found application in different fields of research. In this thesis, we present an efficient and chemoselective approach based on benzilic acid rearrangement to label a class of guanidine-bearing molecules, which utilizes a dibenzocyclooctadione group on the probe molecule that reacts selectively with 1-methylguanidine. The reaction proceeds in a basic aqueous DMF under mild reaction condition. Importantly, the triazolyl- dibenzocyclooctadione group can be introduced into complex molecules containing azido groups using CuAAC chemistry, providing a robust approach for the generation of dibenzocyclooctadione reactive groups into molecules to be covalently attached onto various guanidine-containing biomolecules. The high reactivity and the biocompatibility of this methodology are key features that make it a powerful tool for the efficient functionization of relevant biomolecules for bottom-up synthetic biology applications.