title: Design, synthesis and biological evaluation of novel 4-alkynyl-quinoline derivatives as PI3K/mTOR dual inhibitors.
abstract: A novel series of 4-alkynyl-quinoline derivatives were designed, synthesized and biologically evaluated for their PI3Kα inhibitory activities and anti-proliferative effects against two cancer cell lines PC-3 and HCT-116. Most of them showed potent PI3Kα inhibitory activities with IC50 values at low nanomolar level and good to excellent anti-proliferative effects against both cell lines. Among them, compound 15d, the most potent one, was selected for further biological evaluation. As a result, 15d displayed strong inhibitory activity against other class I PI3K isoforms (PI3Kβ, PI3Kγ and PI3Kδ) and mTOR with an acceptable kinase selectivity profile. Moreover, the western blot assay indicated that the phosphorylation of Akt, another downstream effector of PI3K, can be remarkably suppressed by 15d at cellular level. All these experimental results suggested that 15d is a potent PI3K/mTOR dual inhibitor and could serve as a promising lead compound for the development of anticancer agents.
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: Huazhou
authors.initials: H
authors.lastname: Ying
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: 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: Peng
authors.initials: P
authors.lastname: Wu
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. Electronic address: huyz@zju.edu.cn.
authors.forename: Yongzhou
authors.initials: Y
authors.lastname: Hu
mesh_terms: D000480:Alkynes / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D062105:Molecular Docking Simulation; D019869:Phosphatidylinositol 3-Kinases / Q000737:chemistry / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011487:Protein Conformation; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D013379:Substrate Specificity; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
chemical_list: D000480:Alkynes; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011804:Quinolines; D058570:TOR Serine-Threonine Kinases
keywords: 4-Alkynyl-quinoline; Cancer; Inhibitor; PI3K; mTOR