Kim, Mi Kyoung Kim, Yunyoung Choo, Hyunah Chong, Youhoon 2024-01-20T02:04:07Z 2024-01-20T02:04:07Z 2021-09-01 2017-02-01 0968-0896 https://pubs.kist.re.kr/handle/201004/123090 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. English PERGAMON-ELSEVIER SCIENCE LTD FLAVONOID DIMERS BIVALENT MODULATORS HYDROXYL-GROUPS CYCLOSPORINE-A CANCER-CELLS IN-VITRO ACCUMULATION VERAPAMIL EFFLUX VX-710 Quercetin-glutamic acid conjugate with a non-hydrolysable linker; a novel scaffold for multidrug resistance reversal agents through inhibition of P-glycoprotein Article 10.1016/j.bmc.2016.12.034 1 BIOORGANIC & MEDICINAL CHEMISTRY, v.25, no.3, pp.1219 - 1226 BIOORGANIC & MEDICINAL CHEMISTRY 25 3 1219 1226 scie scopus 000394201900038 2-s2.0-85009495770 Biochemistry & Molecular Biology Chemistry, Medicinal Chemistry, Organic Biochemistry & Molecular Biology Pharmacology & Pharmacy Chemistry Article FLAVONOID DIMERS BIVALENT MODULATORS HYDROXYL-GROUPS CYCLOSPORINE-A CANCER-CELLS IN-VITRO ACCUMULATION VERAPAMIL EFFLUX VX-710 Multidrug resistance (MDR) Cancer Quercetin Conjugate Reversal activity