Diversity-Oriented Synthesis of Macrocyclic Scaffolds Utilizing Organo- and Metal Catalysis

小分子与大分子相互作用并调节其功能的能力已经成为研究生物系统中信号通路的强大工具--这是现代医学中的一个重要领域。在这一背景下，一种系统地获得结构多样化的小分子文库的方法被称为多样性定向合成(DOS)。在概述的研究项目中，我将介绍一种有效的DOS方法来构建大环聚酯和聚酰胺文库，其基础是α，β-不饱和醛和双烯的多效性，以及烯醛和未活化的烯烃或炔烃正交使用的可能性。根据Schreiber的构建/组合/配对算法的建议，我的项目包括三个阶段。首先，我将构建适当数量的预功能化构建块。随后，这些构建块将利用N杂环卡宾催化的反应进行偶联。最后，在配对阶段，构建的区块链将通过Ru催化的烯炔合环歧化反应(RCM)进行环化。为了增加最终文库的整体多样性，所产生的二烯功能将被用作RCM后额外修改的起点。因此，大循环的综合集合将广泛占据化学/生物空间，其中包含多样性的所有四个主要组成部分：附属物多样性、官能团多样性、立体化学多样性和骨架(支架)多样性。我计划用大环文库成员的表型生物活性测试来结束这个项目。在此背景下，我的重点将集中在对不同致病、多药耐药细菌菌株的抗菌活性上。此外，我还将探索合成的大环化合物对与癌细胞增殖过程相关的蛋白质-蛋白质相互作用和多蛋白质复合体的修饰能力。

The ability of small molecules to interact with macromolecules and modulate their function has emerged as a powerful tool for work on signaling pathways in biological systems - an important domain in modern medical sciences. In this context, a systematic approach towards structurally diverse small molecule libraries is called Diversity Oriented Synthesis (DOS).In the outlined research project I will introduce an efficient DOS approach towards a library of macrocyclic polyesters and polyamides, based on the pluripotency of alpha, beta-unsaturated aldehydes and dienes, and the possibility of using enals and unactivated alkenes or alkynes orthogonally. In line with the recommendations of the Schreiber's build/couple/pair algorithm, my project consists of three stages. First, I will build an appropriate number of pre-functionalized building blocks. Subsequently, these building blocks will be coupled utilizing N heterocyclic carbene catalyzed reactions. Finally, in the pairing phase the building block chain will be cyclized via ruthenium catalyzed enyne-ring-closing metathesis (RCM). In order to increase the overall diversity of the final library, the resulted diene functionality will be used as a starting point for additional post-RCM modifications. As a result, the synthesized collection of macrocycles will broadly occupy the chemical/biological space containing all four principle components of diversity: appendage diversity, functional group diversity, stereochemical diversity and skeletal (scaffold) diversity. I plan to conclude this project with phenotypic bioactivity tests of the macrocyclic library members. In this context, my focus will lie on the antibacterial activity against different pathogenic, multidrug-resistant bacterial strains. Furthermore, I will explore the ability of the synthesized macrocyclic compounds to modify protein-protein interactions and multi-protein complexes relevant in the process of cancer cell proliferation.