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Open AccessArticle

Design, Synthesis and Biological Evaluation of Isoxazole-Based CK1 Inhibitors Modified with Chiral Pyrrolidine Scaffolds

1
Ferrier Research Institute, Victoria University of Wellington, 69 Gracefield Rd, Lower Hutt 5040, New Zealand
2
Institute of Pharmacy, Christian-Albrechts-University of Kiel, Gutenbergstraße 76, D-24116 Kiel, Germany
3
Department of General and Visceral Surgery, Ulm University Hospital, Albert-Einstein-Allee 23, D-89081 Ulm, Germany
4
Institute of Biochemistry, University of Cologne, Zuelpicher Str. 47, D-50674 Cologne, Germany
*
Authors to whom correspondence should be addressed.
These two authors contribute equally to this work.
Academic Editor: Derek J. McPhee
Molecules 2019, 24(5), 873; https://doi.org/10.3390/molecules24050873
Received: 12 December 2018 / Revised: 23 February 2019 / Accepted: 27 February 2019 / Published: 1 March 2019
(This article belongs to the Special Issue Kinase Inhibitors II)
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. View Full-Text
Keywords: protein kinase CK1; formerly known as casein kinase 1; chiral kinase inhibitors; iminoribitol; ribose pocket; 3,4-diaryl-isoxazole; Pictet-Spengler cyclization protein kinase CK1; formerly known as casein kinase 1; chiral kinase inhibitors; iminoribitol; ribose pocket; 3,4-diaryl-isoxazole; Pictet-Spengler cyclization
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MDPI and ACS Style

Luxenburger, A.; Schmidt, D.; Ianes, C.; Pichlo, C.; Krüger, M.; von Drathen, T.; Brunstein, E.; Gainsford, G.J.; Baumann, U.; Knippschild, U.; Peifer, C. Design, Synthesis and Biological Evaluation of Isoxazole-Based CK1 Inhibitors Modified with Chiral Pyrrolidine Scaffolds. Molecules 2019, 24, 873.

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