Investigation of chalcones and benzochalcones as inhibitors of breast cancer resistance protein
Investigation of chalcones and benzochalcones as inhibitors of breast cancer resistance protein
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DOI：
10.1016/j.bmc.2011.10.074
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发表时间：
2012-01-01
影响因子：
3.5
通讯作者：
Wiese, Michael
中科院分区：
文献类型：
--
作者：
Juvale, Kapil;Pape, Veronika F. S.;Wiese, Michael
乳腺癌耐药蛋白(BCRP/ABCG2)属于三磷酸腺苷结合盒转运蛋白家族。BCRP已被发现在癌细胞中具有多药耐药性。克服BCRP过度表达引起的耐药性的一个策略是研究有效和特异的BCRP抑制剂。本研究的目的是研究不同的多取代查尔酮对BCRP的抑制作用。合成了具有不同取代基的查尔酮和苯并查尔酮(即苯查尔酮)。O，OCH3，Cl)在查尔酮结构的环A和B上。用Hoechst 33342蓄积实验检测化合物对MCF7、MX和MDCK细胞表达BCRP的抑制活性。在钙黄素AM蓄积实验中还筛选了化合物的P-糖蛋白(P-gp)和多药耐药相关蛋白1(MRP1)抑制活性，并发现它们对BCRP的抑制具有选择性。查尔酮环A上20位和40位的取代基对活性有重要影响，B环上的3，4-二甲氧基取代效果最好，2-氯和4-氯取代对BCRP的抑制也有积极作用。(C)2011爱思唯尔有限公司。保留所有权利。
Breast cancer resistance protein (BCRP/ABCG2) belongs to the ATP binding cassette family of transport proteins. BCRP has been found to confer multidrug resistance in cancer cells. A strategy to overcome resistance due to BCRP overexpression is the investigation of potent and specific BCRP inhibitors. The aim of the current study was to investigate different multi-substituted chalcones for their BCRP inhibition. We synthesized chalcones and benzochalcones with different substituents (viz. OH, OCH3, Cl) on ring A and B of the chalcone structure. All synthesized compounds were tested by Hoechst 33342 accumulation assay to determine inhibitory activity in MCF-7 MX and MDCK cells expressing BCRP. The compounds were also screened for their P-glycoprotein (P-gp) and Multidrug resistance-associated protein 1 (MRP1) inhibitory activity in the calcein AM accumulation assay and were found to be selective towards inhibition of BCRP. Substituents at position 20 and 40 on chalcone ring A were found to be essential for activity; additionally there was a great influence of substituents on ring B. Presence of 3,4-dimethoxy substitution on ring B was found to be optimal, while presence of 2- and 4-chloro substitution also showed a positive effect on BCRP inhibition. (C) 2011 Elsevier Ltd. All rights reserved.