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

利用有机和金属催化的大环支架的多样性合成

• 批准号: 245388588
• 负责人: Dr. André Grossmann
• 金额: --
• 依托单位: Yusuf Hamied Department of Chemistry
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2013
• 资助国家: 德国
• 起止时间: 2012-12-31 至 2014-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/245388588?language=en
• 关键词: Diversity; Oriented; Synthesis; Macrocyclic; Scaffolds

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.

小分子与大分子相互作用并调节其功能的能力已成为研究生物系统信号通路的有力工具，这是现代医学科学的一个重要领域。在这种情况下，一种结构多样的小分子文库的系统方法被称为多样性定向合成（DOS）。在概述的研究项目中，我将基于α、β -不饱和醛和二烯的多能性，以及烯醛和未活化的烯烃或炔正交使用的可能性，介绍一种高效的DOS方法来构建大环聚酯和聚酰胺库。根据Schreiber的构建/配对/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杂环碳催化反应偶联。最后，在配对阶段，构建链将通过钌催化的炔合环复分解（RCM）进行环化。为了增加最终库的整体多样性，生成的diene功能将被用作rcm后附加修改的起点。因此，合成的大环将广泛地占据包含多样性的所有四个主要组成部分的化学/生物空间：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。在这种情况下，我的重点将放在抗菌活性对不同致病性，多重耐药菌株。此外，我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复合物的修饰能力。