Benzoyl indoles with metabolic stability as reversal agents for ABCG2-mediated multidrug resistance

被引：33

作者：

Cai, Chao-Yun ^{[1
,2
]}

Zhai, Hong ^{[1
]}

Lei, Zi-Ning ^{[2
]}

Tan, Cai-Ping ^{[1
]}

Chen, Bao-Li ^{[1
]}

Du, Zhao-Yi ^{[1
]}

Wang, Jing-Quan ^{[2
]}

Zhang, Yun-Kai ^{[2
]}

Wang, Yi-Jun ^{[2
]}

Gupta, Pranav ^{[2
]}

Wang, Bo ^{[1
]}

Chen, Zhe-Sheng ^{[2
]}

机构：

[1] Sun Yat Sen Univ, Sch Chem, MOE Key Lab Bioinorgan & Synthet Chem, 135 Xingang West Rd, Guangzhou 510275, Guangdong, Peoples R China

[2] St Johns Univ, Coll Pharm & Hlth Sci, Dept Pharmaceut Sci, 8000 Utopia Pkwy, Queens, NY 11439 USA

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2019年 / 179卷

基金：

美国国家卫生研究院; 中国国家自然科学基金;

关键词：

ABCG2; transporter; Multidrug resistance; Benzoyl indoles; Metabolic stability; Reversal agents; BREAST-CANCER RESISTANCE; IN-VITRO; DRUG-METABOLISM; PROTEIN; POTENT; EXPRESSION; INHIBITOR; ACYLATION; ABCG2; MUTATIONS;

D O I：

10.1016/j.ejmech.2019.06.066

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Ko143, a potent ABCG2 inhibitor that reverses multidrug resistance in cancer, cannot be used clinically due to its unsuitable metabolic stability. We identified benzoyl indoles as reversal agents that reversed ABCG2-mediated multidrug resistance (MDR), with synthetic tractability and enhanced metabolic stability compared to Ko143. Bisbenzoyl indole 2 and monobenzoyl indole 8 significantly increased the accumulation of mitoxantrone (MX) in ABCG2-overexpressing NCI-H460/MX20 cells, and sensitized NCI-H460/MX20 cells to mitoxantrone. Mechanistic studies were conducted by [H-3]-MX accumulation assay, Western blot analysis, immunofluorescence analysis and ABCG2 ATPase assay. The results revealed that the reversal efficacies of compounds 2 and 8 were not due to an alteration in the expression level or localization of ABCG2 in ABCG2-overexpressing cell lines. Instead, compounds 2 and 8 significantly stimulated the ATP hydrolysis of ABCG2 transporter, suggesting that these compounds could be competitive substrates of ABCG2 transporter. Overall, the results of our study indicated that compounds 2 and 8 significantly reversed ABCG2-mediated MDR by blocking the efflux of anticancer drugs. (C) 2019 Elsevier Masson SAS. All rights reserved.

引用

页码：849 / 862

页数：14

共 45 条

[1]

Allen JD, 2002, MOL CANCER THER, V1, P417

[2] NOVEL SYNTHESIS OF HETEROCYCLIC KETONES [J].