期刊
INORGANICA CHIMICA ACTA
卷 393, 期 -, 页码 261-268出版社
ELSEVIER SCIENCE SA
DOI: 10.1016/j.ica.2012.04.035
关键词
Rhodium; Cyclometalation; Kinase inhibitors; Chiral ligand; Asymmetric synthesis
资金
- German Research Foundation (DFG) [ME 1805/2-1]
- National Institutes of Health USA [CA114046]
- Fonds der Chemischen Industrie
A new metal-containing scaffold for the generation of rhodium(III)-based protein kinase inhibitors is introduced in which the pharmacophore ligand 4-phenylpyrrolo[3,4-c]quinoline-1,3(2H)-dione is designed to form two hydrogen bonds with the hinge region of the ATP-binding site. The phenylquinoline ligand binds to rhodium(III) in a cyclometalated fashion by coordinating to the quinoline nitrogen and forming a covalent bond to a carbon atom of the phenyl substituent. Additional acyclic tridentate ligands were used to control the relative stereochemistry, whereas a chiral proline-derived tridentate ligand was employed for the asymmetric synthesis of single enantiomers. Finally, protein kinase profiling and inhibition data confirmed that the new rhodium(III)-phenylquinoline scaffold is suitable for the generation of selective protein kinase inhibitors. (C) 2012 Elsevier B.V. All rights reserved.
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