Design, Synthesis and Biological Evaluation of Isoxazole-Based CK1 Inhibitors Modified with Chiral Pyrrolidine Scaffolds
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...
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| Format: | Article |
| Language: | English |
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MDPI AG
2019-03-01
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| Series: | Molecules |
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| Online Access: | http://www.mdpi.com/1420-3049/24/5/873 |
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| author | Andreas Luxenburger Dorian Schmidt Chiara Ianes Christian Pichlo Marc Krüger Thorsten von Drathen Elena Brunstein Graeme J. Gainsford Ulrich Baumann Uwe Knippschild Christian Peifer |
| author_facet | Andreas Luxenburger Dorian Schmidt Chiara Ianes Christian Pichlo Marc Krüger Thorsten von Drathen Elena Brunstein Graeme J. Gainsford Ulrich Baumann Uwe Knippschild Christian Peifer |
| author_sort | Andreas Luxenburger |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-14T01:07:39Z |
| format | Article |
| id | doaj.art-d440f729899d4674be885230fa1ca581 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-04-14T01:07:39Z |
| publishDate | 2019-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-d440f729899d4674be885230fa1ca5812022-12-22T02:21:11ZengMDPI AGMolecules1420-30492019-03-0124587310.3390/molecules24050873molecules24050873Design, Synthesis and Biological Evaluation of Isoxazole-Based CK1 Inhibitors Modified with Chiral Pyrrolidine ScaffoldsAndreas Luxenburger0Dorian Schmidt1Chiara Ianes2Christian Pichlo3Marc Krüger4Thorsten von Drathen5Elena Brunstein6Graeme J. Gainsford7Ulrich Baumann8Uwe Knippschild9Christian Peifer10Ferrier Research Institute, Victoria University of Wellington, 69 Gracefield Rd, Lower Hutt 5040, New ZealandInstitute of Pharmacy, Christian-Albrechts-University of Kiel, Gutenbergstraße 76, D-24116 Kiel, GermanyDepartment of General and Visceral Surgery, Ulm University Hospital, Albert-Einstein-Allee 23, D-89081 Ulm, GermanyInstitute of Biochemistry, University of Cologne, Zuelpicher Str. 47, D-50674 Cologne, GermanyDepartment of General and Visceral Surgery, Ulm University Hospital, Albert-Einstein-Allee 23, D-89081 Ulm, GermanyInstitute of Pharmacy, Christian-Albrechts-University of Kiel, Gutenbergstraße 76, D-24116 Kiel, GermanyInstitute of Biochemistry, University of Cologne, Zuelpicher Str. 47, D-50674 Cologne, GermanyFerrier Research Institute, Victoria University of Wellington, 69 Gracefield Rd, Lower Hutt 5040, New ZealandInstitute of Biochemistry, University of Cologne, Zuelpicher Str. 47, D-50674 Cologne, GermanyDepartment of General and Visceral Surgery, Ulm University Hospital, Albert-Einstein-Allee 23, D-89081 Ulm, GermanyInstitute of Pharmacy, Christian-Albrechts-University of Kiel, Gutenbergstraße 76, D-24116 Kiel, GermanyIn 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.http://www.mdpi.com/1420-3049/24/5/873protein kinase CK1formerly known as casein kinase 1chiral kinase inhibitorsiminoribitolribose pocket3,4-diaryl-isoxazolePictet-Spengler cyclization |
| spellingShingle | Andreas Luxenburger Dorian Schmidt Chiara Ianes Christian Pichlo Marc Krüger Thorsten von Drathen Elena Brunstein Graeme J. Gainsford Ulrich Baumann Uwe Knippschild Christian Peifer Design, Synthesis and Biological Evaluation of Isoxazole-Based CK1 Inhibitors Modified with Chiral Pyrrolidine Scaffolds Molecules protein kinase CK1 formerly known as casein kinase 1 chiral kinase inhibitors iminoribitol ribose pocket 3,4-diaryl-isoxazole Pictet-Spengler cyclization |
| title | Design, Synthesis and Biological Evaluation of Isoxazole-Based CK1 Inhibitors Modified with Chiral Pyrrolidine Scaffolds |
| title_full | Design, Synthesis and Biological Evaluation of Isoxazole-Based CK1 Inhibitors Modified with Chiral Pyrrolidine Scaffolds |
| title_fullStr | Design, Synthesis and Biological Evaluation of Isoxazole-Based CK1 Inhibitors Modified with Chiral Pyrrolidine Scaffolds |
| title_full_unstemmed | Design, Synthesis and Biological Evaluation of Isoxazole-Based CK1 Inhibitors Modified with Chiral Pyrrolidine Scaffolds |
| title_short | Design, Synthesis and Biological Evaluation of Isoxazole-Based CK1 Inhibitors Modified with Chiral Pyrrolidine Scaffolds |
| title_sort | design synthesis and biological evaluation of isoxazole based ck1 inhibitors modified with chiral pyrrolidine scaffolds |
| topic | protein kinase CK1 formerly known as casein kinase 1 chiral kinase inhibitors iminoribitol ribose pocket 3,4-diaryl-isoxazole Pictet-Spengler cyclization |
| url | http://www.mdpi.com/1420-3049/24/5/873 |
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