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
文献类型：期刊论文
| 作者 | Liu, Gang1; Xue, Ding1; Yang, Jun3; Wan, Juan3; Liu, Xiaohua1; Huang, Wenjing3; Li, Jie2; Long, Ya-Qiu1; Tan, Wenfu3; Zhang, Ao1,2
|
| 刊名 | JOURNAL OF MEDICINAL CHEMISTRY
 |
| 出版日期 | 2016-12-22 |
| 卷号 | 59期号:24页码:11050-11068 |
| ISSN号 | 0022-2623 |
| DOI | 10.1021/acs.jmedchem.6b01247 |
| 文献子类 | Article |
| 英文摘要 | 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. |
| WOS关键词 | HEDGEHOG SIGNALING PATHWAY ; BASAL-CELL CARCINOMA ; DIHYDROARTEMISINIC ACID ; PLASMODIUM-FALCIPARUM ; BIOLOGICAL EVALUATION ; ANTICANCER AGENTS ; CANCER-THERAPY ; ARTEMISININ ; INHIBITORS ; DERIVATIVES |
| 资助项目 | Chinese NSF[81430080] ; Chinese NSF[81325020] ; Chinese NSF[81321092] ; Chinese NSF[81373277] ; National Program on Key Basic Research Project of China[2015CB910603] ; International Cooperative Program[GJHZ1622] ; Key Program of the Frontier Science of the Chinese Academy of Sciences[160621] ; Shanghai Commission of Science and Technology[16XD1404600] ; Shanghai Commission of Science and Technology[14431905300] ; Shanghai Commission of Science and Technology[14431900400] ; 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 |
| 语种 | 英语 |
| 出版者 | AMER CHEMICAL SOC |
| WOS记录号 | WOS:000390735500015 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/275761]  |
| 专题 | 药理学第一研究室 药物化学研究室 |
| 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.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China 3.Fudan Univ, Sch Pharm, Dept Pharmacol, Shanghai 201203, Peoples R China; |
| 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. |
入库方式： OAI收割
来源：上海药物研究所
浏览0
下载0
收藏0
其他版本
除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。