Investigation of chalcones and benzochalcones as inhibitors of breast cancer resistance protein

被引：113
作者：
Juvale, Kapil [1 ]
Pape, Veronika F. S. [1 ]
Wiese, Michael [1 ]
机构：
[1] Univ Bonn, Inst Pharmaceut, D-53121 Bonn, Germany
来源：
BIOORGANIC & MEDICINAL CHEMISTRY | 2012年 / 20卷 / 01期
关键词：
Chalcones; Multidrug resistance; Breast cancer resistance protein; Inhibitors; Hoechst; 33342; assay; MULTIDRUG-RESISTANCE; P-GLYCOPROTEIN; HALF-TRANSPORTER; FUMITREMORGIN C; ABCG2; CELLS; BCRP/ABCG2; BCRP; ATP; OVEREXPRESSION;
D O I：
10.1016/j.bmc.2011.10.074
中图分类号：
Q5 [生物化学]; Q7 [分子生物学];
学科分类号：
071010 ; 081704 ;
摘要：
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.
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页码：346 / 355
页数：10
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