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

DNA编码库(DELs)是近年来在药物开发中筛选先导化合物的一种有效方法。事实上，有机分子和遗传编码的结合开启了一种方法，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数量。这种方法已经取得了成功，并导致制药公司发现了几个热门分子。然而，目前DELS的局限性在于开发与DNA兼容的化学合成工具，以确保这些化合物的多样性。在这项建议中，我们的目标是通过应用主体组在Ru催化方面的专业知识来解决尚未解决的挑战，即在与DNA序列相连的底物上发展C-H芳基化和烷基化，以扩大DELS的化学空间。我们设想，通过调整Ru催化剂和其他反应参数，高选择性的DNA连接分子的C-H活化方法可能近在咫尺。事实上，来自主基的Ru催化剂之前已经被证明在非常温和的条件下实现了C-H活化，这与DNA上化学的关键要求是一致的。最后，我们希望在这个项目中开发的方法能够以迭代的方式应用，以便从现成的构建块开始构建各种官能化分子的DEL。成功将推动DNA兼容化学和DELs构建的最先进水平。

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.