Luxenburger, Andreas ORCID: 0000-0002-7574-8027, Schmidt, Dorian, Ianes, Chiara, Pichlo, Christian ORCID: 0000-0002-3156-5667, Krueger, Marc, von Drathen, Thorsten, Brunstein, Elena, Gainsford, Graeme J., Baumann, Ulrich, Knippschild, Uwe and Peifer, Christian (2019). Design, Synthesis and Biological Evaluation of Isoxazole-Based CK1 Inhibitors Modified with Chiral Pyrrolidine Scaffolds. Molecules, 24 (5). BASEL: MDPI. ISSN 1420-3049

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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-CK1 delta 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Luxenburger, AndreasUNSPECIFIEDorcid.org/0000-0002-7574-8027UNSPECIFIED
Schmidt, DorianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ianes, ChiaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pichlo, ChristianUNSPECIFIEDorcid.org/0000-0002-3156-5667UNSPECIFIED
Krueger, MarcUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
von Drathen, ThorstenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brunstein, ElenaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gainsford, Graeme J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Baumann, UlrichUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Knippschild, UweUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Peifer, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-154923
DOI: 10.3390/molecules24050873
Journal or Publication Title: Molecules
Volume: 24
Number: 5
Date: 2019
Publisher: MDPI
Place of Publication: BASEL
ISSN: 1420-3049
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
CASEIN KINASE 1; ENANTIOSELECTIVE SYNTHESIS; POTENT INHIBITORS; 3-DIMENSIONAL STRUCTURE; EFFICIENT SYNTHESIS; ACCURATE DOCKING; TYROSINE KINASE; AMINO-ACIDS; PROTEIN; CANCERMultiple languages
Biochemistry & Molecular Biology; Chemistry, MultidisciplinaryMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/15492

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