Universität zu Köln

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:	Creators Email ORCID ORCID Put Code Luxenburger, Andreas UNSPECIFIED orcid.org/0000-0002-7574-8027 UNSPECIFIED Schmidt, Dorian UNSPECIFIED UNSPECIFIED UNSPECIFIED Ianes, Chiara UNSPECIFIED UNSPECIFIED UNSPECIFIED Pichlo, Christian UNSPECIFIED orcid.org/0000-0002-3156-5667 UNSPECIFIED Krueger, Marc UNSPECIFIED UNSPECIFIED UNSPECIFIED von Drathen, Thorsten UNSPECIFIED UNSPECIFIED UNSPECIFIED Brunstein, Elena UNSPECIFIED UNSPECIFIED UNSPECIFIED Gainsford, Graeme J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Baumann, Ulrich UNSPECIFIED UNSPECIFIED UNSPECIFIED Knippschild, Uwe UNSPECIFIED UNSPECIFIED UNSPECIFIED Peifer, Christian UNSPECIFIED UNSPECIFIED UNSPECIFIED
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:	Faculty of Mathematics and Natural Sciences
Divisions:	Faculty of Mathematics and Natural Sciences > Department of Chemistry > Institute of Biochemistry
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language CASEIN KINASE 1; ENANTIOSELECTIVE SYNTHESIS; POTENT INHIBITORS; 3-DIMENSIONAL STRUCTURE; EFFICIENT SYNTHESIS; ACCURATE DOCKING; TYROSINE KINASE; AMINO-ACIDS; PROTEIN; CANCER Multiple languages Biochemistry & Molecular Biology; Chemistry, Multidisciplinary Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/15492