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

Khan Tareque R., Hassell-Hart S., Krojer T., Bradley A., Velupillai S., Talon R., Fairhead M., Day IJ., Bala K., Felix R., Kemmitt PD., Brennan P., von Delft F., Díaz Sáez L., Huber K., Spencer J.

Combined photochemical arylation, "nuisance effect" (SN Ar) 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 SN Ar processes. As a result, a number of crystallographic hits against NUDT7, a key peroxisomal CoA ester hydrolase, have been identified.

DOI

10.1002/cmdc.202000543

Type

Journal article

Journal

ChemMedChem

Publication Date

15/12/2020

Volume

15

Pages

2513 - 2520

Keywords

Benzene Derivatives, Catalysis, Chemistry Techniques, Synthetic, Coordination Complexes, Crystallography, X-Ray, Drug Design, Enzyme Inhibitors, Feasibility Studies, Humans, Palladium, Proof of Concept Study, Protein Binding, Pyridines, Pyrophosphatases, Pyrrolidinones, Small Molecule Libraries

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