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

doi:10.1021/acs.jmedchem.6b01247

	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
	Liu, Gang 1; Xue, Ding 1; Yang, Jun 2; Wan, Juan 2; Liu, Xiaohua 1; Huang, Wenjing 2; Li, Jie3 ; Long, Ya-Qiu 1; Tan, Wenfu 2; Zhang, Ao1,3
	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...
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.