Synthesis and c-Met kinase inhibition of 3,5-disubstituted and 3,5,7-trisubstituted quinolines: identification of 3-(4-acetylpiperazin-1-yl)-5-(3-nitrobenzylamino)-7- (trifluoromethyl)quinoline as a novel anticancer agent.
Synthesis and c-Met kinase inhibition of 3,5-disubstituted and 3,5,7-trisubstituted quinolines: identification of 3-(4-acetylpiperazin-1-yl)-5-(3-nitrobenzylamino)-7- (trifluoromethyl)quinoline as a novel anticancer agent.
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DOI：
10.1021/jm101340q
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发表时间：
2011-03
影响因子：
7.3
通讯作者：
Yuanxiang Wang;Jing Ai;Ying Wang;Yi Chen;Lu Wang;Gang Liu;M. Geng;Ao Zhang
中科院分区：
文献类型：
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作者：
Yuanxiang Wang;Jing Ai;Ying Wang;Yi Chen;Lu Wang;Gang Liu;M. Geng;Ao Zhang
采用改进的合成策略，合成了一系列3，5-二取代和3，5，7-三取代喹啉。3，5，7-三取代喹啉21a-c、21L和27a-c被鉴定为最有效的c-Met抑制剂，其IC(50)小于1.0 nM。化合物21b对c-Met家族成员RON和其他12种酪氨酸激酶具有很高的效力和极高的选择性，显示出最有希望的整体PK谱。它对c-Met依赖细胞系的c-Met磷酸化产生结构性抑制。在100 mg/kg剂量下，化合物21b对NIH-3T3-TPR-Met和U-87 MG人胶质母细胞瘤移植瘤模型均有显著的肿瘤生长抑制作用(68-69%)。这些结果清楚地表明，化合物21b是一种有效的、高选择性的c-Met抑制剂。其良好的体外和体内图谱值得进一步研究。
By use of an improved synthetic strategy, a series of 3,5-disubstituted and 3,5,7-trisubstituted quinolines were readily prepared. 3,5,7-Trisubstituted quinolines 21a-c, 21l, and 27a-c were identified as the most potent c-Met inhibitors with IC(50) of less than 1.0 nM. Compound 21b showed the most promising overall PK profile and has high potency and extraordinary selectivity to c-Met against c-Met family member Ron and 12 other tyrosine kinases. It produced constitutive inhibition of c-Met phosphorylation in c-Met dependent cell lines. At doses of 100 mg/kg, compound 21b showed statistically significant tumor growth inhibition (68-69%) in both NIH-3T3-TPR-Met and U-87 MG human gliobastoma xenograft models. These results clearly indicated that compound 21b is a potent and highly selective c-Met inhibitor. Its favorable in vitro and in vivo profiles warrant further investigation.