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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]) |
ISSN | 0022-2623 |
卷号 | 59期号:24页码:11050-11068 |
发表状态 | 已发表 |
DOI | 10.1021/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 |
引用统计 | 正在获取...
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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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