Synthesis and biological evaluation of novel bifendate derivatives bearing 6, 7-dihydro-dibenzo[c,e]azepine scaffold as potent P-glycoprotein inhibitors

被引：30

作者：

Gu, Xiaoke ^{[1
,2
]}

Ren, Zhiguang ^{[3
]}

Tang, Xiaobo ^{[1
,2
]}

Peng, Hui ^{[3
]}

Zhao, Qing ^{[3
]}

Lai, Yisheng ^{[1
,2
]}

Peng, Sixun ^{[1
,2
]}

Zhang, Yihua ^{[1
,2
]}

机构：

[1] China Pharmaceut Univ, State Key Lab Nat Med, Nanjing 210009, Peoples R China

[2] China Pharmaceut Univ, Ctr Drug Discovery, Nanjing 210009, Peoples R China

[3] Inst Basic Med Sci, Dept Mol Immunol, Beijing 100850, Peoples R China

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2012年 / 51卷

基金：

中国国家自然科学基金;

关键词：

Bifendate; dibenzo[c; e]azepine; P-gp inhibitor; Multidrug resistance; MULTIDRUG-RESISTANCE; CANCER-CELLS; EFFLUX PUMP; CHEMOTHERAPY; MODULATORS; LIGNANS; ANALOGS; DESIGN; DDB; GP;

D O I：

10.1016/j.ejmech.2012.02.034

中图分类号：

R914 [药物化学];

学科分类号：

100705 [微生物与生化药学];

摘要：

Overexpression of P-glycoprotein (P-gp) is one of the major problems in successful treatment of cancers. To find new P-gp inhibitors, a series of bifendate (DDB) derivatives bearing dibenzo[c,e]azepine scaffold were synthesized and evaluated. Compound 41 more potently reversed P-gp-mediated multidrug resistance (MDR) than DDB and verapamil (VRP) by blocking P-gp mediated drug efflux function and increasing drug accumulation in K562/A02 MDR cells, and persisted longer chemo-sensitizing effect (>24 h) than VRP (<6 h). Interestingly, unlike VRP, 41 showed no stimulation on the P-gp ATPase activity, suggesting it is not a substrate of P-gp. Given the low intrinsic cytotoxicity of 41 in vitro, it may represent a promising lead for developing therapeutics targeting P-gp-mediated MDR in combinational cancer chemotherapy. (C) 2012 Elsevier Masson SAS. All rights reserved.

引用

页码：137 / 144

页数：8

共 21 条

[1]

Recent Advances in the Development of P-gp Inhibitors [J].