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

ChemMedChem. 2020 Dec 15;15(24):2513-2520. doi: 10.1002/cmdc.202000543. Epub 2020 Sep 28.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Benzene Derivatives / chemical synthesis*
  • Benzene Derivatives / metabolism
  • Catalysis
  • Chemistry Techniques, Synthetic / methods
  • Coordination Complexes / chemistry
  • Crystallography, X-Ray
  • Drug Design
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / metabolism
  • Feasibility Studies
  • Humans
  • Nudix Hydrolases
  • Palladium / chemistry
  • Proof of Concept Study
  • Protein Binding
  • Pyridines / chemical synthesis
  • Pyridines / metabolism
  • Pyrophosphatases / metabolism
  • Pyrrolidinones / chemical synthesis
  • Pyrrolidinones / metabolism
  • Small Molecule Libraries / chemical synthesis*
  • Small Molecule Libraries / metabolism

Substances

  • Benzene Derivatives
  • Coordination Complexes
  • Enzyme Inhibitors
  • Pyridines
  • Pyrrolidinones
  • Small Molecule Libraries
  • Palladium
  • Pyrophosphatases