title: 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.
abstract: 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-Dimethyl-5,6,7,8-tetrahydroquinolin-8-yl)-N-arylpropanamide 65 was identified as the most potent, with an IC50value 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.
authors.affiliation: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica (SIMM), University of Chinese Academy of Sciences , 555 Zuchongzhi Lu, Building 3, Room 426, Shanghai 201203, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Liu
authors.affiliation: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica (SIMM), University of Chinese Academy of Sciences , 555 Zuchongzhi Lu, Building 3, Room 426, Shanghai 201203, China.
authors.forename: Ding
authors.initials: D
authors.lastname: Xue
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fudan University , Shanghai 201203, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fudan University , Shanghai 201203, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Wang
authors.affiliation: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica (SIMM), University of Chinese Academy of Sciences , 555 Zuchongzhi Lu, Building 3, Room 426, Shanghai 201203, China.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fudan University , Shanghai 201203, China.
authors.forename: Wenjing
authors.initials: W
authors.lastname: Huang
authors.affiliation: School of Life Science and Technology, ShanghaiTech University , Shanghai 201210, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.affiliation: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica (SIMM), University of Chinese Academy of Sciences , 555 Zuchongzhi Lu, Building 3, Room 426, Shanghai 201203, China.
authors.forename: Ya-Qiu
authors.initials: YQ
authors.lastname: Long
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fudan University , Shanghai 201203, China.
authors.forename: Wenfu
authors.initials: W
authors.lastname: Tan
authors.affiliation: CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica (SIMM), University of Chinese Academy of Sciences , 555 Zuchongzhi Lu, Building 3, Room 426, Shanghai 201203, China.|School of Life Science and Technology, ShanghaiTech University , Shanghai 201210, China.
authors.forename: Ao
authors.initials: A
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D057809:HEK293 Cells; D006801:Humans; D007624:KB Cells; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000072086:Smoothened Receptor / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D011804:Quinolines; C491023:SMO protein, human; D000072086:Smoothened Receptor