Ruthenium catalysed C-H functionalization for the construction of DNA-Encoded Libraries

钌催化的 C-H 功能化用于构建 DNA 编码文库

• 批准号: EP/Z001404/1
• 负责人: Cassandre Bories
• 金额: $ 24.5万
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FZ001404%2F1
• 关键词: Ruthenium; catalysed; functionalization; construction; DNA

DNA-encoded libraries (DELs) have emerged in recent years as a powerful approach for lead compound screening in drug discovery. Indeed, the combination of organic molecules and genetic encoding have unlocked a methodology where billions of compounds can be simultaneously tested in one vessel, decreasing both the cost and the amount of material needed in comparison to classic high throughput screening. This approach has already shown success and led to the discovery of several hit molecules by pharmaceutical companies. However, the current limitation of DELs lie in the development of chemical synthesis tools compatible with DNA to ensure the diversity of these compound libraires. In this proposal, we aim to address the unmet challenge of developing both C H arylation and alkylation on substrates linked to DNA sequences to expand the chemical space of DELs by applying the host group's expertise in Ru catalysis. We envisage that by tuning the Ru catalyst and the other reaction parameters, highly selective methodologies for C H activation of DNA-linked molecules may be at hand. Indeed, Ru catalysts from the host group have previously been shown to achieve C H activation under very mild conditions, in line with key requirements for on-DNA chemistry. Finally, we expect the methodologies developed in this project to be applicable in an iterative way in order to construct a DEL of various functionalised molecules starting from readily available building blocks. Success will push the boundaries of the state of the art in DNA compatible chemistry and the construction of DELs.

DNA编码文库（DELs）是近年来出现的一种筛选药物先导化合物的有效方法。事实上，有机分子和遗传编码的组合已经解锁了一种方法，其中可以在一个容器中同时测试数十亿种化合物，与经典的高通量筛选相比，降低了成本和所需材料的量。这种方法已经取得了成功，并导致制药公司发现了几种热门分子。然而，目前DELs的局限性在于开发与DNA相容的化学合成工具，以确保这些化合物库的多样性。在这项提案中，我们的目标是解决未满足的挑战，开发两个C H芳基化和烷基化的基板连接到DNA序列，以扩大化学空间的DEL通过应用主机组的专业知识在Ru催化。我们设想，通过调整钌催化剂和其他反应参数，高选择性的方法C H激活的DNA连接的分子可能在手。事实上，来自主体基团的Ru催化剂先前已经显示出在非常温和的条件下实现CH活化，这符合DNA上化学的关键要求。最后，我们希望在这个项目中开发的方法是适用的，以迭代的方式，以构建一个DEL的各种功能化的分子从现成的积木开始。成功将推动DNA相容化学和DEL构建的最新技术水平的界限。