Design, Synthesis, and Pharmacological Evaluation of 2-(2,5-Dimethyl-5,6,7,8-tetrahydroquinolin-8-yl)-N-aryl Propanamides as Novel Smoothened (Smo) Antagonists
2016-12-22
发表期刊JOURNAL OF MEDICINAL CHEMISTRY (IF:6.8[JCR-2023],7.1[5-Year])
ISSN0022-2623
卷号59期号:24页码:11050-11068
发表状态已发表
DOI10.1021/acs.jmedchem.6b01247
摘要A series of novel Smo antagonists were developed either by directly incorporating the basic skeleton of the natural product artemisinin or by first breaking artemisinin into structurally simpler and stable intermediates and then reconstructing into diversified heterocyclic derivatives, equipped with a Smo-targeting bullet. 2-(2,5-Dimethy1-5,6,7,8-tetrahydroquinolin-8-yl)-N-arylpropanamide 65 was identified as the most potent, with an IC50 value of 9.53 nM against the Hh signaling pathway. Complementary mechanism studies confirmed that 65 inhibits Hh signaling pathway by targeting Smo and shares the same binding site as that of the tool drug cyclopamine. Meanwhile, 65 has a good plasma exposure and an acceptable oral bioavailability. Dose-dependent antiproliferative effects were observed in ptch+/;p53-/- medulloblastoma cells, and significant tumor growth inhibitions were achieved for 65 in the ptch+/-;p53-/- medulloblastoma allograft model.
收录类别SCI ; IC
语种英语
资助项目CAS Key Laboratory of Receptor Research of SIMM[SIMM1606YKF-08] ; CAS Key Laboratory of Receptor Research of SIMM[SIMM1606YZZ-06]
WOS研究方向Pharmacology & Pharmacy
WOS类目Chemistry, Medicinal
WOS记录号WOS:000390735500015
出版者AMER CHEMICAL SOC
WOS关键词HEDGEHOG SIGNALING PATHWAY ; BASAL-CELL CARCINOMA ; DIHYDROARTEMISINIC ACID ; PLASMODIUM-FALCIPARUM ; BIOLOGICAL EVALUATION ; ANTICANCER AGENTS ; CANCER-THERAPY ; ARTEMISININ ; INHIBITORS ; DERIVATIVES
原始文献类型Article
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文献类型期刊论文
条目标识符https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/1596
专题生命科学与技术学院
生命科学与技术学院_特聘教授组_张翱组
生命科学与技术学院_博士生
通讯作者Long, Ya-Qiu; Tan, Wenfu; Zhang, Ao
作者单位
1.Univ Chinese Acad Sci, SIMM, CAS Key Lab Receptor Res, 555 Zuchongzhi Lu,Bldg 3,Room 426, Shanghai 201203, Peoples R China
2.Fudan Univ, Sch Pharm, Dept Pharmacol, Shanghai 201203, Peoples R China
3.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China
通讯作者单位生命科学与技术学院
推荐引用方式
GB/T 7714
Liu, Gang,Xue, Ding,Yang, Jun,et al. Design, Synthesis, and Pharmacological Evaluation of 2-(2,5-Dimethyl-5,6,7,8-tetrahydroquinolin-8-yl)-N-aryl Propanamides as Novel Smoothened (Smo) Antagonists[J]. JOURNAL OF MEDICINAL CHEMISTRY,2016,59(24):11050-11068.
APA Liu, Gang.,Xue, Ding.,Yang, Jun.,Wan, Juan.,Liu, Xiaohua.,...&Zhang, Ao.(2016).Design, Synthesis, and Pharmacological Evaluation of 2-(2,5-Dimethyl-5,6,7,8-tetrahydroquinolin-8-yl)-N-aryl Propanamides as Novel Smoothened (Smo) Antagonists.JOURNAL OF MEDICINAL CHEMISTRY,59(24),11050-11068.
MLA Liu, Gang,et al."Design, Synthesis, and Pharmacological Evaluation of 2-(2,5-Dimethyl-5,6,7,8-tetrahydroquinolin-8-yl)-N-aryl Propanamides as Novel Smoothened (Smo) Antagonists".JOURNAL OF MEDICINAL CHEMISTRY 59.24(2016):11050-11068.
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