Publication in refereed journal
香港中文大学研究人员 ( 现职)
| 杜健华教授 (药剂学院) |
| 曹之宪教授 (生物医学学院) |
全文
| 数位物件识别号 (DOI) http://dx.doi.org/10.1016/j.ejmech.2015.06.049 |
引用次数
Web of Sciencehttp://aims.cuhk.edu.hk/converis/portal/Publication/6WOS source URL
其它资讯
摘要With an aim to generate non-toxic, specific and highly potent multidrug resistance (MDR) modulators, a novel series of anthranilic acid amide-substituted tariquidar derivatives were synthesized. The new compounds were evaluated for their cytotoxicity toward normal human colon fibroblasts (CCD18-Co), human gastric epithelial cell line (HFE) and primary rat liver cells, and for their ability to inhibit P-gp/BCRP-mediated drug efflux and reversal of P-gp and BCRP-mediated MDR in parental and drug-resistant cancer cell lines (LCChttp://aims.cuhk.edu.hk/converis/portal/Publication/6 MDR1, MCF-7 FLV1000, R-HepG2, SWhttp://aims.cuhk.edu.hk/converis/portal/Publication/620-Ad300). While tariquidar is highly toxic to normal cells, the new derivatives exhibited much lower or negligible cytotoxicity. Some of the new tariquidar derivatives inhibited both P-gp and BCRP-mediated drug efflux whereas a few of them bearing a sulfonamide functional group (1, 5, and 1http://aims.cuhk.edu.hk/converis/portal/Publication/6) are specific to P-gp. The new compounds were also found to potentiate the anticancer activity of the transporter substrate anticancer drugs in the corresponding transporter-overexpressing cell lines. The extent of resistance reversal was found to be consistent with the transporter inhibitory effect of the new derivatives. To further understand the mechanism of P-gp and BCRP inhibition, the tariquidar derivatives were found to interact with the transporters using an antibody-based UIC2 or 5D3 shift assay. Moreover, the transporters-inhibiting derivatives were found to modulate the ATPase activities of the two MDR transporters. Our data thus advocate further development of the new compounds for the circumvention of MDR. (C) 2015 Elsevier Masson SAS. All rights reserved.
着者Li XQ, Wang L, Lei Y, Hu T, Zhang FL, Cho CH, To KKW
期刊名称European Journal of Medicinal Chemistry
出版年份2015
月份8
日期28
卷号101
出版社ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
页次5http://aims.cuhk.edu.hk/converis/portal/Publication/60 - 572
国际标準期刊号0223-5234
电子国际标準期刊号17http://aims.cuhk.edu.hk/converis/portal/Publication/68-3254
语言英式英语
关键词Anthranilamide; Breast cancer resistance protein; Multidrug resistance; P-Glycoprotein; Sulfonamide
Web of Science 学科类别Chemistry, Medicinal; Pharmacology & Pharmacy
