Deliberately Losing Control of C−H Activation Processes in the Design of Small‐Molecule‐Fragment Arrays Targeting Peroxisomal Metabolism

• DOI: 10.1002/cmdc.202000543
• Publication Date: 2020-08-28T06:24:40Z
• Authors: Raysa Khan Tareque; Storm Hassell‐Hart; Tobias Krojer; Anthony Bradley; Srikannathasan Ve...; Romain Talon; Michael Fairhead; Iain J. Day; Kamlesh Bala; Robert Felix; Paul D. Kemmitt; Paul Brennan; Frank von Delft; Laura Díaz Sáez; Kilian Huber; John Spencer
• Keywords: 0301 basic medicine; Pyridines; Nudix Hydrolases; Chemistry Techniques, Synthetic; Crystallography, X-Ray; Proof of Concept Study; Catalysis; Pyrrolidinones; Small Molecule Libraries; 03 medical and health sciences; Coordination Complexes; Drug Design; Benzene Derivatives; Feasibility Studies; Humans; Enzyme Inhibitors; Pyrophosphatases; Palladium; Protein Binding

AbstractCombined photochemical arylation, “nuisance effect” (SNAr) reaction sequences have been employed in the design of small arrays for immediate deployment in medium‐throughput X‐ray protein–ligand structure determination. Reactions were deliberately allowed to run “out of control” in terms of selectivity; for example the ortho‐arylation of 2‐phenylpyridine gave five products resulting from mono‐ and bisarylations combined with SNAr processes. As a result, a number of crystallographic hits against NUDT7, a key peroxisomal CoA ester hydrolase, have been identified.