Please use this identifier to cite or link to this item: http://hdl.handle.net/10397/12859
Title: Amine linked flavonoid dimers as modulators for P-glycoprotein-based multidrug resistance : structure-activity relationship and mechanism of modulation
Authors: Chan, KF
Wong, ILK
Kan, JWY
Yan, CSW
Chow, LMC 
Chan, TH
Issue Date: 2012
Publisher: Amer Chemical Soc
Source: Journal of medicinal chemistry, 2012, v. 55, no. 5, p. 1999-2014 How to cite?
Journal: Journal of Medicinal Chemistry 
Abstract: Here we report a great improvement in reversal potency of cancer drug resistance when flavonoid dimers possess a functionally substituted aminopolyethylene glycol linker. The most potent compound, 18, contains a N-benzyl group at the linker. It has many advantages including (1) high potencies in reversing P-glycoprotein (P-gp) mediated resistance in LCC6MDR cells to various anticancer drugs with EC 50 in the nanomolar range, (2) low toxicity and high therapeutic index, and (3) preferential inhibition of P-gp over multidrug resistance protein 1 and breast cancer resistance protein. Compound 18 stimulates P-gp-ATPase activity by 2.7-fold and mediates a dose-dependent inhibition of doxorubicin (DOX) transport activity. Lineweaver-Burk and Dixon plots suggest that 18 is a competitive inhibitor to DOX in binding to P-gp with a K i of 0.28-0.34 μM and a Hill coefficient of 1.17. Moreover, the LCC6MDR cell displays about 2.1-fold lower intracellular accumulation of 18 compared to the wild type, suggesting that 18 is a P-gp substrate as well.
URI: http://hdl.handle.net/10397/12859
ISSN: 0022-2623
DOI: 10.1021/jm201121b
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