Functionalized chalcones as selective inhibitors of P-glycoprotein and breast cancer resistance protein
Functionalized chalcones as selective inhibitors of P-glycoprotein and breast cancer resistance protein
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DOI：
10.1016/j.bmc.2007.10.006
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发表时间：
2008-01-01
影响因子：
3.5
通讯作者：
Go, Mei-Lin
中科院分区：
文献类型：
--
作者：
Liu, Xiao-Ling;Tee, Hui-Wearn;Go, Mei-Lin
通过钙调素-AM在MDCKII/MDR1细胞上的蓄积实验，筛选具有基本功能的查尔酮抑制P-糖蛋白(Pgp，ABCB1)文库。3个A环被5-(1-乙基哌啶-4-基)和2，4-二甲氧基取代的成员比PGP抑制剂维拉帕米更能增加钙黄素-AM的积累。这些化合物随后被证明能增强过表达Pgp的MCF-7细胞对阿霉素的摄取。然而，当通过米托蒽酮摄取试验测试对乳腺癌耐药蛋白(BCRP，ABCG2)的抑制时，同样的化合物表现不佳。相比之下，非碱性查尔酮(5-14，3-(4-chlorophenyl)-1-(2，4-dimethoxyphenyl)prop-2-en-1-one))使高表达BCRP5微米的MCF-7细胞(MCF-7/MX)摄取米托蒽醌的能力增加300%以上。因此，在查尔酮模板上引入碱性基团增强了对PgP的抑制，但以抑制BCRP为代价。碱性查尔酮也是比非碱性查尔酮更好的PGP抑制剂，而非碱性查尔酮可能是更好的BCRP抑制剂。结构活性分析表明，查尔酮的亲脂性不是影响Pgp抑制活性的主要因素。相反，良好的活性与适当放置的电子给体原子有关，其中A或B环上的间二取代二甲氧基基序特别相关。尽管对Pgp和Bcrp的抑制有不同的结构要求，查尔酮3-100[3-(2，4-dimethoxyphenyl)-1-(4-(piperazin-1-yl)phenyl)prop-2-en-1-one]对Pgp和Bcrp都有合理的抑制作用，可能是设计双重抑制剂的一个有用的起点。(C)2007爱思唯尔有限公司。保留所有权利。
A library of chalcones with basic functionalities were screened for inhibition of P-glycoprotein (Pgp, ABCB1) by the calcein-AM accumulation assay on MDCKII/MDR1 cells. Three members that had ring A substituted with 5-(1-ethylpiperidin-4-yl) and 2,4-dimethoxy groups were found to increase calcein-AM accumulation to a greater extent than verapamil, a Pgp inhibitor. These compounds were subsequently shown to enhance the uptake of doxorubicin by MCF-7 cells that over-expressed Pgp. However, when tested for inhibition of the breast cancer resistance protein (BCRP, ABCG2) by the mitoxantrone uptake assay, the same compounds fared poorly. In comparison, a non-basic chalcone (5-14, 3-(4-chlorophenyl)-1-(2,4-dimethoxyphenyl)prop-2-en-1-one) increased mitoxantrone uptake by BCRP over-expressing MCF-7 cells (MCF-7/MX) by more than 300% at 5 mu M. Thus, introducing a basic group on the chalcone template enhanced Pgp inhibition at the expense of BCRP inhibition. The basic chalcones were also better Pgp inhibitors than their non-basic counterparts which may in turn be better BCRP inhibitors. Structure activity analysis showed that lipophilicity of the chalcones was not the overriding factor for Pgp inhibitory activity. Rather, good activity was associated with appropriately placed electron donor atoms, of which the meta-disubstituted dimethoxy motif on either ring A or B was of particular relevance. In spite of differing structural requirements for inhibition of Pgp and BCRP, chalcone 3-100 [3-(2,4-dimethoxyphenyl)-1-(4-(piperazin-1-yl)phenyl)prop-2-en-1-one] inhibited both Pgp and BCRP to a reasonable extent and may be a useful starting point for the design of dual inhibitors. (C) 2007 Elsevier Ltd. All rights reserved.