Discovery of novel quinoline-based mTOR inhibitors via introducing intra-molecular hydrogen bonding scaffold (iMHBS): The design, synthesis and biological evaluation

Ma Xiaodong; Lv Xiaoqing; Qiu NiYang BoHe QiaojunHu Yongzhou

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Discovery of novel quinoline-based mTOR inhibitors via introducing intra-molecular hydrogen bonding scaffold (iMHBS): The design, synthesis and biological evaluation

机译：Discovery of novel quinoline-based mTOR inhibitors via introducing intra-molecular hydrogen bonding scaffold (iMHBS): The design, synthesis and biological evaluation

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A series of quinoline derivatives featuring the novelty of introducing intra-molecular hydrogen bonding scaffold (iMHBS) were designed, synthesized and biologically evaluated for their mTOR inhibitory activity, as well as anti-proliferative efficacies against HCT-116, PC-3 and MCF-7 cell lines. As a result, six compounds exhibited significant inhibition against mTOR with IC50 values below 35 nM. Compound 15a, the most potent mTOR inhibitor reported herein (IC50 = 14 nM), also displayed the most favorable cellular activities, with the IC50 values of 0.46, 0.61 and 0.24 mu M against HCT-116, PC-3 and MCF-7, respectively. Besides, several compounds in this series were identified to be selective over class I PI3Ks. Further western blot analysis of 16b, a representative compound in this series, highlighted their advantage in surmounting the S6K/IRS1/PI3K negative feedback loop upon dual inhibition of mTORC1 and mTORC2. In addition to the remarkable activity, 15a demonstrated acceptable stability in simulated gastric fluid (SGF), simulated intestinal fluid (SIF) and liver microsome, thereby being valuable for extensive in vivo investigation. (c) 2015 Elsevier Ltd. All rights reserved.

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《Bioorganic and medicinal chemistry》 |2015年第24期|7585-7596|共12页
作者
Ma Xiaodong; Lv Xiaoqing; Qiu NiYang BoHe QiaojunHu Yongzhou;
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作者单位

Zhejiang Univ, Coll Pharmaceut Sci, Zhejiang Prov Key Lab Anticanc Drug Res, Hangzhou 310058;

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正文语种英语
中图分类药学;
关键词
Quinoline derivatives; mTOR inhibitor; Anti-proliferative efficacy; Selectivity; Negative feedback loop; Stability;

Discovery of novel quinoline-based mTOR inhibitors via introducing intra-molecular hydrogen bonding scaffold (iMHBS): The design, synthesis and biological evaluation

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