Novel dissymmetric 3,5-bis(arylidene)-4-piperidones as potential antitumor agents with biological evaluation in vitro and in vivo

被引:53
作者
Li, Ning [1 ]
Xin, Wen-Yu [1 ]
Yao, Bin-Rong [1 ]
Wang, Chun-Hua [1 ]
Cong, Wei [1 ]
Zhao, Feng [1 ]
Li, Hong-Juan [1 ]
Hou, Yun [1 ]
Meng, Qing-Guo [2 ]
Hou, Gui-Ge [1 ]
机构
[1] Binzhou Med Univ, Sch Pharm, Key Lab Prescript Effect & Clin Evaluat, State Adm Tradit Chinese Med China, Yantai 264003, Peoples R China
[2] Yantai Univ, Sch Pharm, Key Lab Mol Pharmacol & Drug Evaluat, Minist Educ,Collaborat Innovat Ctr Adv Drug Deliv, Yantai 264005, Peoples R China
基金
中国国家自然科学基金;
关键词
3.5-bis(arylidene)-4-piperidone; Cytotoxicity; Cellular uptake; Molecular docking; Tumor xenograft; ANTICANCER ACTIVITY; CURCUMIN; DERIVATIVES; APOPTOSIS; EF24; KETONES; CYTOTOXICITY; INFLAMMATION; EXPRESSION; PATHWAYS;
D O I
10.1016/j.ejmech.2018.01.088
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Thirty-five novel dissymmetric 3,5-bis(arylidene)-4-piperidone derivatives (BAPS, 6a-h, 7a-h, 8a-g, 9a-g, 10a-e) were synthesized and evaluated the cytotoxicity. BAPS 6d, 7h, 8g, 9g demonstrated the most potentially inhibitory activities against HepG2 and THP-1 but lower cytotoxicity toward LO2. In vitro, 6d, 7h, 8g, 9g can effectively up-regulate BAX expression, down-regulate Bcl-2 expression in HepG2 cell. They could reasonably bind to the active site of Bcl-2 protein proved by molecular docking modes. The most active BAP 6d induced HepG2 cells apoptosis in a dose-dependent manner by flow cytometrey. The cellular uptake of HepG2 cells showed 6d mainly accumulated into the nuclei by confocal laser scanning microscopy (CLSM). In vivo, 6d suppressed the growth of HepG2 xenografts in nude mice and relatively nontoxic to mice. These results suggest that 6d could be therapeutically beneficial as potential therapeutic agent for the early clinical treatment of liver cancers. (C) 2018 Elsevier Masson SAS. All rights reserved.
引用
收藏
页码:21 / 33
页数:13
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