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学科主题: 基础医学
题名:
Design and Synthesis of Tri-substituted Chiral Pyrrolidin-2-one Derivatives as CCR4 Antagonists
作者: Sun, Wei1; Tian, Linjie3; Qi, Hui3; Jiang, Dan2; Wang, Ying3; Li, Song2; Xiao, Junhai2; Yang, Xiaohong1
关键词: CCR4 antagonists ; tri-substituted chiral pyrrolidin-2-one derivatives ; synthesis
刊名: CHINESE JOURNAL OF CHEMISTRY
发表日期: 2013-09-01
DOI: 10.1002/cjoc.201300363
卷: 31, 期:9, 页:1144-1152
收录类别: SCI ; IC
文章类型: Article
WOS标题词: Science & Technology
类目[WOS]: Chemistry, Multidisciplinary
研究领域[WOS]: Chemistry
关键词[WOS]: CHEMOKINE-LIKE FACTOR-1 ; MOLECULAR-CLONING ; FUNCTIONAL LIGAND ; RECEPTOR 4 ; T-CELLS ; EXPRESSION ; TARC
英文摘要:

A series of tri-substituted chiral pyrrolidin-2-one derivatives have been designed and synthesized as CC chemokine receptor 4 (CCR4) antagonists. The structure of CCR4 was built by homology modeling. Asymmetric synthesis was applied to synthesize the R,R configuration chiral pyrrolidin-2-one scaffold. The stereoisomeric configurations of the compounds were identified by 2D H-1-H-1 COSY spectroscopy and 1D NOESY spectroscopy. This method was more economical and convenient than traditional X-ray single crystal diffraction. In addition, the interactions between these compounds and the N-terminal extracellular tail of CCR4 were studied using capillary zone electrophoresis. The CCR4 chemotaxis inhibition effect was tested in CCR4-transfected HEK293 cells. Several compounds showed potent activities as CCR4 antagonists. Among these compounds, 1c is the most active one. Its apparent binding constant of CZE experiment result is (1.569 +/- 0.11)x10(5) Lmol(-1), and its percentage inhibition of the HEK293/CCR4 cells migration with the concentration of 1 mu molL-1 in DMSO is 59%. And compound 1f has slightly higher affinity to N-terminal of CCR4 according to its apparent binding constant than 1b because of the introduced ester linkage. Further studies on the mechanism of these compounds are in progress.

语种: 英语
所属项目编号: 30472093 ; 30872292 ; 90813025 ; 2009ZX09103-024 ; 201201020
项目资助者: National Natural Science Foundation of China ; National Major Science & ; Technology Specific Project ; Young Scientific Research Fund Project for Department of Science and Technology of Jilin Province
WOS记录号: WOS:000327882900005
Citation statistics:
内容类型: 期刊论文
版本: 出版稿
URI标识: http://ir.bjmu.edu.cn/handle/400002259/65489
Appears in Collections:基础医学院_北京大学人类疾病基因研究中心_期刊论文

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作者单位: 1.Jilin Univ, Sch Pharmaceut Sci, Changchun 130021, Jilin, Peoples R China
2.Beijing Inst Pharmacol & Toxicol, Lab Computer Aided Drug Design & Discovery, Beijing 100850, Peoples R China
3.Peking Univ, Ctr Human Dis Genom, Beijing 100083, Peoples R China

Recommended Citation:
Sun, Wei,Tian, Linjie,Qi, Hui,et al. Design and Synthesis of Tri-substituted Chiral Pyrrolidin-2-one Derivatives as CCR4 Antagonists[J]. CHINESE JOURNAL OF CHEMISTRY,2013,31(9):1144-1152.
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