C-Isoprenylation of Flavonoids Enhances Binding Affinity toward P-Glycoprotein and Modulation of Cancer Cell Chemoresistance

Previous studies have shown that flavones bind to P-glycoprotein (Pgp) with higher affinity than isoflavones, flavanones, and glycosylated derivatives. In the present work, a series of C- or O-substituted hydrophobic derivatives of chrysin were synthesized to further investigate structural requireme...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2001-03, Vol.44 (5), p.763-768
Main Authors: Comte, Gilles, Daskiewicz, Jean-Baptiste, Bayet, Christine, Conseil, Gwenaëlle, Viornery-Vanier, Armelle, Dumontet, Charles, Di Pietro, Attilio, Barron, Denis
Format: Article
Language:English
Subjects:
Antineoplastic agents
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
ATP Binding Cassette Transporter, Subfamily B, Member 1 - metabolism
Biochemistry, Molecular Biology
Biological and medical sciences
Drug Resistance, Multiple
Drug Resistance, Neoplasm
Flavonoids - chemical synthesis
Flavonoids - chemistry
Flavonoids - metabolism
General aspects
Humans
Life Sciences
Medical sciences
Pharmacology. Drug treatments
Protein Binding
Spectrometry, Fluorescence
Structure-Activity Relationship
Tumor Cells, Cultured
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Summary:Previous studies have shown that flavones bind to P-glycoprotein (Pgp) with higher affinity than isoflavones, flavanones, and glycosylated derivatives. In the present work, a series of C- or O-substituted hydrophobic derivatives of chrysin were synthesized to further investigate structural requirements of the A ring toward Pgp modulation. Increasing hydrophobicity at either position 6, 8, or 7 increased the affinity of in vitro binding to a purified cytosolic domain of Pgp, but only benzyl and 3,3-dimethylallyl C-substitution produced a high maximal quenching of the protein intrinsic fluorescence. Inhibition of membrane Pgp within leukemic cells, characterized by intracellular drug accumulation, was specifically produced by isoprenylated derivatives, with 8-(3,3-dimethylallyl)chrysin being even more efficient than the commonly used cyclosporin A.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm991128y