Halogenated chalcones with high-affinity binding to P-glycoprotein: potential modulators of multidrug resistance.
Previous studies have shown that flavonoids are modulators of the transmembrane P-glycoprotein (P-gp) which mediates cell multidrug resistance. Some structural elements have been identified which seem to contribute to these compounds' activity. In the present study, a series of halogenated chalcones was prepared to further explore the structural requirements for the P-gp modulation. Four halogenated chalcones have been synthesized and evaluated as potential modulators of P-gp-mediated multidrug resistance of cancer cells by in vitro assays using a purified recombinant domain of the transporter containing the modulator binding site. Halogenated chalcones exhibited high-affinity binding, the 2',4', 6'-trihydroxy-4-iodochalcone behaving as the most potent compound with a KD value in the nanomolar range.
Laboratoire de Pharmacognosie, UFR de Pharmacie de Grenoble, Université Joseph Fourier, 38706 La Tronche, France.
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F
Bois
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Beney
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Boumendjel
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AM
Mariotte
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Conseil
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Di Pietro
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism*; D001665:Binding Sites; D002599:Chalcone / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism*; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D051379:Mice; D011994:Recombinant Proteins / Q000378:metabolism; D013329:Structure-Activity Relationship
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D011994:Recombinant Proteins; D002599:Chalcone