title: Discovery of novel quinoline-based mTOR inhibitors via introducing intra-molecular hydrogen bonding scaffold (iMHBS): The design, synthesis and biological evaluation.
abstract: 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 35nM. Compound 15a, the most potent mTOR inhibitor reported herein (IC50=14nM), also displayed the most favorable cellular activities, with the IC50 values of 0.46, 0.61 and 0.24μM 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.
authors.affiliation: Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Ma
authors.affiliation: Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Lv
authors.affiliation: Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Ni
authors.initials: N
authors.lastname: Qiu
authors.affiliation: Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Yang
authors.affiliation: Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Qiaojun
authors.initials: Q
authors.lastname: He
authors.affiliation: Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China. Electronic address: huyz@zju.edu.cn.
authors.forename: Yongzhou
authors.initials: Y
authors.lastname: Hu
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D045325:HCT116 Cells; D006801:Humans; D006860:Hydrogen Bonding; D061986:MCF-7 Cells; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D062105:Molecular Docking Simulation; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D011804:Quinolines / Q000737:chemistry* / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D046912:Multiprotein Complexes; D019869:Phosphatidylinositol 3-Kinases; D047428:Protein Kinase Inhibitors; D011804:Quinolines; D058570:TOR Serine-Threonine Kinases; C037219:quinoline; C546842:MTOR protein, human
keywords: Anti-proliferative efficacy; Negative feedback loop; Quinoline derivatives; Selectivity; Stability; mTOR inhibitor