RESUMEN

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.

Asunto(s)

Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/antagonistas & inhibidores , Chalcona/análogos & derivados , Resistencia a Múltiples Medicamentos/fisiología , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Adenosina Trifosfato/metabolismo , Animales , Sitios de Unión , Chalcona/síntesis química , Chalcona/farmacología , Evaluación Preclínica de Medicamentos , Técnicas In Vitro , Espectroscopía de Resonancia Magnética , Unión Proteica , Estructura Terciaria de Proteína , Conejos , Relación Estructura-Actividad