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

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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.