Design, synthesis and evaluation of novel triazole core based P-glycoprotein-mediated multidrug resistance reversal agents

被引：22

作者：

Jiao, Lei ^{[1
]}

Qiu, Qianqian ^{[1
]}

Liu, Baomin ^{[1
,2
]}

Zhao, Tianxiao ^{[1
]}

Huang, Wenlong ^{[1
]}

Qian, Hai ^{[1
]}

机构：

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

[2] CTTQ Pharmaceut Res Inst, Nan Jing Res & Dev Ctr, Nanjing, Jiangsu, Peoples R China

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2014年 / 22卷 / 24期

基金：

中国国家自然科学基金;

关键词：

Click chemistry; Multidrug resistance; P-glycoprotein; Reversal activity; BIOLOGICAL EVALUATION; CLICK CHEMISTRY; INHIBITORS; DERIVATIVES; DISCOVERY; CELLS;

D O I：

10.1016/j.bmc.2014.10.032

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

A novel series of triazol-N-ethyl-tetrahydroisoquinoline based compounds were designed and synthesized via click chemistry. Most of the synthesized compounds showed P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) reversal activities. Among them, compound 7 with little cytotoxicity towards GES-1 cells (IC50 > 80 mu M) and K562/A02 cells (IC50 > 80 mu M) exhibited more potency than verapamil (VRP) on increasing anticancer drug accumulation in K562/A02 cells. Moreover, compound 7 could significantly reverse MDR in a dose-dependent manner and also persist longer chemo-sensitizing effect than VRP with reversibility. Further mechanism studies revealed that compound 7 in reversing MDR revealed that it could remarkably increase the intracellular accumulation of both rhodamine-123 (Rh123) and adriamycin (ADM) in K562/A02 cells as well as inhibit their efflux from the cells. These results suggested that compound 7 showed more potency than the classical P-gp inhibitor VRP under the same conditions, which may be a promising P-gp-mediated MDR modulator for further development. (C) 2014 Elsevier Ltd. All rights reserved.

引用

页码：6857 / 6866

页数：10

共 21 条

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New Insight into P-Glycoprotein as a Drug Target [J].