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

被引：11

作者：

Luxenburger, Andreas ^{[1
]}

Schmidt, Dorian ^{[2
]}

Ianes, Chiara ^{[3
]}

Pichlo, Christian ^{[4
]}

Krueger, Marc ^{[3
]}

von Drathen, Thorsten ^{[2
]}

Brunstein, Elena ^{[4
]}

Gainsford, Graeme J. ^{[1
]}

Baumann, Ulrich ^{[4
]}

Knippschild, Uwe ^{[3
]}

Peifer, Christian ^{[2
]}

机构：

[1] Victoria Univ Wellington, Ferrier Res Inst, 69 Gracefield Rd, Lower Hutt 5040, New Zealand

[2] Christian Albrechts Univ Kiel, Inst Pharm, Gutenbergstr 76, D-24116 Kiel, Germany

[3] Ulm Univ Hosp, Dept Gen & Visceral Surg, Albert Einstein Allee 23, D-89081 Ulm, Germany

[4] Univ Cologne, Inst Biochem, Zuelpicher Str 47, D-50674 Cologne, Germany

来源：

MOLECULES | 2019年 / 24卷 / 05期

关键词：

protein kinase CK1; formerly known as casein kinase 1; chiral kinase inhibitors; iminoribitol; ribose pocket; 3,4-diaryl-isoxazole; Pictet-Spengler cyclization; CASEIN KINASE 1; ENANTIOSELECTIVE SYNTHESIS; POTENT INHIBITORS; 3-DIMENSIONAL STRUCTURE; EFFICIENT SYNTHESIS; ACCURATE DOCKING; TYROSINE KINASE; AMINO-ACIDS; PROTEIN; CANCER;

D O I：

10.3390/molecules24050873

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页数：34

共 92 条

[1] Pyrimidinylimidazole inhibitors of p38: Cyclic N-1 imidazole substituents enhance p38 kinase inhibition and oral activity [J].