Synthesis and biological activity of 4-alkoxy chalcones: potential hydrophobic modulators of P-glycoprotein-mediated multidrug resistance.
A series of 4-alkoxy-2',4',6'-trihydroxychalcones have been synthesized and evaluated for their ability to inhibit P-glycoprotein-mediated multidrug resistance (MDR) by direct binding to a purified protein domain containing an ATP-binding site and a modulator-interacting region. The introduction of hydrophobic alkoxy groups at position 4 led to much more active compounds as compared to the parent chalcone. The binding affinity increased as a function of the chain length, up to the octyloxy derivative for which a K(D) of 20 nM was obtained.
Bois
F
F
Laboratoire de Pharmacognosie-UFR de Pharmacie de Grenoble, Université Joseph Fourier, La Tronche, France.
Boumendjel
A
A
Mariotte
A M
AM
Conseil
G
G
Di Petro
A
A
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D002599:Chalcone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D018432:Drug Resistance, Multiple / Q000502:physiology*; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011817:Rabbits; D013329:Structure-Activity Relationship
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002599:Chalcone; D000255:Adenosine Triphosphate