Water-Soluble and Cleavable Quercetin-Amino Acid Conjugates as Safe Modulators for P-Glycoprotein-Based Multidrug Resistance

Title
Water-Soluble and Cleavable Quercetin-Amino Acid Conjugates as Safe Modulators for P-Glycoprotein-Based Multidrug Resistance
Authors
김미경추현아정유훈
Keywords
Quercetin-amino acid conjugate; P-glycoprotein; multidrug resistance; water-soluble
Issue Date
2014-09
Publisher
Journal of medicinal chemistry
Citation
VOL 57, NO 17, 7216-7233
Abstract
Quercetin−amino acid conjugates with alanine or glutamic acid moiety attached at 7-O and/or 3-O position of quercetin were prepared, and their multidrug resistance (MDR)-modulatory effects were evaluated. A quercetin−glutamic acid conjugate, 7-O-Glu-Q (3a), was as potent as verapamil in reversing MDR and sensitized MDR MES-SA/Dx5 cells to various anticancer drugs with EC50 values of 0.8−0.9 μM. Analysis on Rh-123 accumulation confirmed that 3a inhibits drug efflux by Pgp, and Pgp ATPase assay showed that 3a interacts with the drug-binding site of Pgp to stimulate its ATPase activity. Physicochemical analysis of 3a revealed that solubility, stability, and cellular uptake of quercetin were significantly improved by the glutamic acid promoiety, which eventually dissociates from 3a to produce quercetin and quercetin metabolites in intracellular milieu. Taken together, potent MDRmodulating activity along with intracellular conversion into the natural flavonoid quercetin warrants development of the quercetin−amino acid conjugates as safe MDR modulators.
URI
http://pubs.kist.re.kr/handle/201004/48113
ISSN
00222623
Appears in Collections:
KIST Publication > Article
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