Design, synthesis and biological evaluation of isoxazole-based CK1 inhibitors modified with chiral pyrrolidine scaffolds

Andreas Luxenburger, Dorian Schmidt, Chiara Ianes, Christian Pichlo, Marc Krüger, Thorsten von Drathen, Elena Brunstein, Graeme J. Gainsford, Ulrich Baumann, Uwe Knippschild, Christian Peifer

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

In this study, we report on the modification of a 3,4-diaryl-isoxazole-based CK1 inhibitor with chiral pyrrolidine scaffolds to develop potent and selective CK1 inhibitors. The pharmacophore of the lead structure was extended towards the ribose pocket of the adenosine triphosphate (ATP) binding site driven by structure-based drug design. For an upscale compatible multigram synthesis of the functionalized pyrrolidine scaffolds, we used a chiral pool synthetic route starting from methionine. Biological evaluation of key compounds in kinase and cellular assays revealed significant effects of the scaffolds towards activity and selectivity, however, the absolute configuration of the chiral moieties only exhibited a limited effect on inhibitory activity. X-ray crystallographic analysis of ligand-CK1δ complexes confirmed the expected binding mode of the 3,4-diaryl-isoxazole inhibitors. Surprisingly, the original compounds underwent spontaneous Pictet-Spengler cyclization with traces of formaldehyde during the co-crystallization process to form highly potent new ligands. Our data suggests chiral “ribose-like” pyrrolidine scaffolds have interesting potential for modifications of pharmacologically active compounds.

Original languageEnglish
Article number873
JournalMolecules
Volume24
Issue number5
DOIs
StatePublished - 2019
Externally publishedYes

Keywords

  • 3,4-diaryl-isoxazole
  • Chiral kinase inhibitors
  • Formerly known as casein kinase 1
  • Iminoribitol
  • Pictet-Spengler cyclization
  • Protein kinase CK1
  • Ribose pocket

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