文献类型：期刊文献

英文题名：Design, synthesis and biological evaluation of chalcones as reversers of P-glycoprotein-mediated multidrug resistance

作者：Yin, Huanhuan[1];Dong, Jingjing[1];Cai, Yingchun[1];Shi, Ximeng[1];Wang, Hao[1];Liu, Guixia[1];Tang, Yun[1];Liu, Jianwen[1];Ma, Lei[1]

机构：[1]East China Univ Sci & Technol, Shanghai Key Lab New Drug Design, Sch Pharm, 130 Meilong Rd, Shanghai 200237, Peoples R China

年份：2019

卷号：180

起止页码：350

外文期刊名：EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000488307100028)】；

基金：This work was supported by the National Natural Science Foundation of China (Grants 81673318 and 81673356), and Shanghai Biomedical Technology Support Program (15401901100).

语种：英文

外文关键词：Chalcones; P-glycoprotein inhibitors; Structure-activity relationship; Multidrug resistance reversers; Inhibitors docking

摘要：Overexpression of P-glycoprotein (P-gp) is one of the major causes for multidrug resistance (MDR), which has become a major obstacle in cancer therapy. One hopeful approach to reverse the MDR is to develop inhibitors of P-gp in expression and/or function. Here, we designed and synthesized a series of chalcone derivatives as P-gp inhibitors and evaluated their potential reversal activities against MDR. Among them, the most active compound MY3 had little intrinsic cytotoxicity and showed the highest activity (RF = 50.19) in reversing DOX resistance in MCF-7/DOX cells. Further studies demonstrated that MY3 could increase intracellular accumulation of DOX and inhibit expression of P-gp at mRNA and protein levels. More importantly, MY3 significantly enhanced the efficacy of DOX against the tumor xenografts bearing MCF-7/DOX cells with the precondition of unchanged body weight. Therefore, MY3 might represent a promising lead to develop MDR reversal agents for cancer chemotherapy. (C) 2019 Elsevier Masson SAS. All rights reserved.