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. (C) 1999 Elsevier Science Ltd. All rights reserved.