title: Rational Design of Coumarin Derivatives as CK2 Inhibitors by Improving the Interaction with the Hinge Region.
abstract: Design of novel coumarin derivatives as CK2 inhibitors were attempted by targeting the interaction with the hinge region. A set of substituents capable of forming a hydrogen bond or halogen bond with the hinge region were screened in silico, and trifluoromethyl emerges as a promising motif by forming favorable electrostatic interaction and a presumable halogen bond with the hinge region. As proof of concept, three trifluoromethyl derivatives of coumarin were synthesized and tested in vitro. The results indicated that replacement of methyl by trifluoromethyl leads to a modest 5-fold improvement in potency, with the most active compound being 0.4 µM. The newly designed compounds were further screened on one lung cancer cell line A549, showing low micromolar anti-proliferative activity.
authors: College of Life Science and Bioengineering, Beijing University of Technology, Beijing 100124, China, Phone: +86-10-67391667. nanatonglei@bjut.edu.cn.
authors: Na
authors: N
authors: Zhang
authors: College of Life Science and Bioengineering, Beijing University of Technology, Beijing 100124, China, Phone: +86-10-67391667.
authors: Wen-Juan
authors: WJ
authors: Chen
authors: College of Life Science and Bioengineering, Beijing University of Technology, Beijing 100124, China, Phone: +86-10-67391667.
authors: Yue
authors: Y
authors: Zhou
authors: Lephar Research, Rindögatan 21, 11558 Stockholm, Sweden.
authors: Hongtao
authors: H
authors: Zhao
authors: College of Life Science and Bioengineering, Beijing University of Technology, Beijing 100124, China, Phone: +86-10-67391667.
authors: Ru-Gang
authors: RG
authors: Zhong
mesh_terms: D000072283:A549 Cells; D047390:Casein Kinase II / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D003374:Coumarins / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D006860:Hydrogen Bonding; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D000072417:Protein Domains; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D003374:Coumarins; D047428:Protein Kinase Inhibitors; D047390:Casein Kinase II
keywords: Protein kinase CK2; cancer; hinge region; molecular docking