期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 25, 期 3, 页码 1219-1226出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2016.12.034
关键词
Multidrug resistance (MDR); Cancer; Quercetin; Conjugate; Reversal activity
资金
- Basic Science Research Program through the National Research Foundation of Korea (NRF) - Ministry of Science, ICT and future Planning [NRF-2015R1A2A1A1 0053461]
- Priority Research Centers Program through the National Research Foundation of Korea (NRF) - Ministry of Education, Science and Technology [2009-0093824]
Previously, we have reported remarkable effect of a quercetin-glutamic acid conjugate to reverse multidrug resistance (MDR) of cancer cells to a broad spectrum of anticancer agents through inhibition of P-glycoprotein (Pgp)-mediated drug efflux. Due to the hydrolysable nature, MDR-reversal activity of the quercetin conjugate was attributed to its hydrolysis product, quercetin. However, several lines of evidence demonstrated that the intact quercetin-glutamic acid conjugate has stronger MDR-reversal activity than quercetin. In order to evaluate this hypothesis and to identify a novel scaffold for MDR-reversal agents, we prepared quercetin conjugates with a glutamic acid attached at the 7-0 position via a non-hydrolysable linker. Pgp inhibition assay, Pgp ATPase assay, and MDR-reversal activity assay were performed, and the non-hydrolysable quercetin conjugates showed significantly higher activities compared with those of quercetin. Unfortunately, the quercetin conjugates were not as effective as verapamil in Pgp-inhibition and thereby reversing MDR, but it is worth to note that the structurally modified quercetin conjugates with a non-cleavable linker showed significantly improved MDR-reversal activity compared with quercetin. Taken together, the quercetin conjugates with appropriate structural modifications were shown to have a potential to serve as a scaffold for the design of novel MDR-reversal agents. (C) 2016 Elsevier Ltd. All rights reserved.
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