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Deliberately Losing Control of C?H Activation Processes in the Design of Small-Molecule-Fragment Arrays Targeting Peroxisomal Metabolism |
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| Authors: | Dr Raysa Khan Tareque Dr Storm Hassell-Hart Dr Tobias Krojer Dr Anthony Bradley Dr Srikannathasan Velupillai Dr Romain Talon Dr Michael Fairhead Dr Iain J Day Kamlesh Bala Dr Robert Felix Dr Paul D Kemmitt Prof Paul Brennan Prof Frank von Delft Dr Laura Díaz Sáez Prof Kilian Huber Prof John Spencer |
| Affiliation: | 1. Chemistry Deparment, University of Sussex, Falmer, East Sussex, BN1 9QJ UK;2. Structural Genomics Consortium (SGC), Nuffield Department of Medicine, University of Oxford, Oxford, OX3 7DQ UK;3. Bio-Techne (Tocris Bioscience), The Watkins Building, Atlantic Road Avonmouth, Bristol, BS11 9QD UK;4. Medicinal Chemistry, Oncology R&D, AstraZeneca, Cambridge, CB10 1XL UK;5. Structural Genomics Consortium (SGC), Nuffield Department of Medicine, University of Oxford, Oxford, OX3 7DQ UK
Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford, OX3 7FZ UK |
| Abstract: | Combined 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. |
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