Copper(II)-Catalyzed Atom and Step Economical Late Stage Functionalisation of Bioactive Compounds

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Synthetic chemists have always been fascinated with creating molecular complexity from readilyavailable starting materials.The typical cost of developing a drug is over 2 billion USD,and the timerequired to reach the market is approximately 14 years. With a very high attrition rate, faster, moreeconomical processes for creating these entities are welcome. Selective processes that lead to thecorrect shape of the drug ensure that it fits correctly in its 3D-biological chiral protein target. Moreover,drugs need to be made on a large scale.We have recently described a series of metal catalysedmulticomponent reactions that are "atom economical", using all atoms to create complicatedarchitectures with 3D shapes, to complement the complexity of protein targets.Moreover, the catalyticnature ensures that energy use, waste production, solvent use are minimal, so have the potential forlargescale production. Also, the catalysts are very easy to make and are stable in air, making themreadily available and scalable, and the fact that we can monitor and optimise new reactions withoutrequiring expensive inert gases. We aim to demonstrate that these catalytic reactions have real-worldapplications as in the design of PROTAC (proteolysis targeting chimeras) molecules for targeted proteindegradation, an area of intense current academic and commercial interest. PROTACs induce theubiquitination machinery to tag a protein for recycling by the proteasome. Structurally guided drug designand biological assays can form a feedback loop to our synthetic chemistry where we can optimise thePROTACs to improve their selectivity and properties, such as solubility, permeability,and stability.Thesefindings will profoundly influence the design and optimisation of PROTACs andlinker chemistry ingeneral, and the combination of academic groups with leading UK industrial partners will enable us toattain our goals.