{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T02:09:28Z","timestamp":1773108568621,"version":"3.50.1"},"reference-count":92,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2019,3,1]],"date-time":"2019-03-01T00:00:00Z","timestamp":1551398400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"iNEXT initiative proposal 1859, EU program Horizon 2020","award":["proposal 1859, EU program Horizon 2020"],"award-info":[{"award-number":["proposal 1859, EU program Horizon 2020"]}]},{"name":"NZP) and the Ministry of Business, Innovation and Employment","award":["MBIE; C08X0711"],"award-info":[{"award-number":["MBIE; C08X0711"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>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\u03b4 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 \u201cribose-like\u201d pyrrolidine scaffolds have interesting potential for modifications of pharmacologically active compounds.<\/jats:p>","DOI":"10.3390\/molecules24050873","type":"journal-article","created":{"date-parts":[[2019,3,4]],"date-time":"2019-03-04T05:45:36Z","timestamp":1551678336000},"page":"873","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Design, Synthesis and Biological Evaluation of Isoxazole-Based CK1 Inhibitors Modified with Chiral Pyrrolidine Scaffolds"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7574-8027","authenticated-orcid":false,"given":"Andreas","family":"Luxenburger","sequence":"first","affiliation":[{"name":"Ferrier Research Institute, Victoria University of Wellington, 69 Gracefield Rd, Lower Hutt 5040, New Zealand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dorian","family":"Schmidt","sequence":"additional","affiliation":[{"name":"Institute of Pharmacy, Christian-Albrechts-University of Kiel, Gutenbergstra\u00dfe 76, D-24116 Kiel, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chiara","family":"Ianes","sequence":"additional","affiliation":[{"name":"Department of General and Visceral Surgery, Ulm University Hospital, Albert-Einstein-Allee 23, D-89081 Ulm, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3156-5667","authenticated-orcid":false,"given":"Christian","family":"Pichlo","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry, University of Cologne, Zuelpicher Str. 47, D-50674 Cologne, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marc","family":"Kr\u00fcger","sequence":"additional","affiliation":[{"name":"Department of General and Visceral Surgery, Ulm University Hospital, Albert-Einstein-Allee 23, D-89081 Ulm, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thorsten","family":"von Drathen","sequence":"additional","affiliation":[{"name":"Institute of Pharmacy, Christian-Albrechts-University of Kiel, Gutenbergstra\u00dfe 76, D-24116 Kiel, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elena","family":"Brunstein","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry, University of Cologne, Zuelpicher Str. 47, D-50674 Cologne, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Graeme J.","family":"Gainsford","sequence":"additional","affiliation":[{"name":"Ferrier Research Institute, Victoria University of Wellington, 69 Gracefield Rd, Lower Hutt 5040, New Zealand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0383-0168","authenticated-orcid":false,"given":"Ulrich","family":"Baumann","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry, University of Cologne, Zuelpicher Str. 47, D-50674 Cologne, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Uwe","family":"Knippschild","sequence":"additional","affiliation":[{"name":"Department of General and Visceral Surgery, Ulm University Hospital, Albert-Einstein-Allee 23, D-89081 Ulm, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christian","family":"Peifer","sequence":"additional","affiliation":[{"name":"Institute of Pharmacy, Christian-Albrechts-University of Kiel, Gutenbergstra\u00dfe 76, D-24116 Kiel, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2019,3,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3451","DOI":"10.1021\/jm200187y","article-title":"The Medicinal Chemist\u2019s Toolbox: An Analysis of Reactions Used in the Pursuit of Drug Candidates","volume":"54","author":"Roughley","year":"2011","journal-title":"J. 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