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
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
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DOI：
10.1021/acs.jmedchem.6b01247
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发表时间：
2016-12-22
影响因子：
7.3
通讯作者：
Zhang, Ao
中科院分区：
文献类型：
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作者：
Liu, Gang;Xue, Ding;Zhang, Ao
通过直接结合天然产物青蒿素的基本骨架，或首先将青蒿素分解成结构更简单且稳定的中间体，然后重建成多样化的杂环衍生物，并配备Smo靶向子弹，开发了一系列新型Smo拮抗剂。2-（2，5-二甲基-5，6，7，8-四氢喹啉-8-基）-N-芳基丙酰胺65被鉴定为最有效的，对Hh信号传导途径的IC 50值为9.53 nM。补充机制研究证实，65通过靶向Smo抑制Hh信号通路，并且与工具药物环巴胺具有相同的结合位点。同时，65具有良好的血浆暴露和可接受的口服生物利用度。在ptch+/;p53-/-髓母细胞瘤细胞中观察到剂量依赖性抗增殖作用，并且在ptch+/-;p53-/-髓母细胞瘤同种异体移植物模型中，65达到了显著的肿瘤生长抑制。
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.