Aurones as Modulators of ABCG2 and ABCB1: Synthesis and Structure-Activity Relationships

Abstract

The ability of aurones to modulate the efflux activities of ABCG2 and ABCB1 was investigated by quantifying their effects on the accumulation of pheophorbideA (PhA) in ABCG2-overexpressing MDA-MB-231/R cells and calceinAM in ABCB1-overexpressing MDCKII/MDR1 cells. Key structural features for interactions at both ABCG2 and ABCB1 are a methoxylated ringA, an intact exocyclic double bond, and the location of the carbonyl bond on ringC. Modifications on ringsB and C were less critical and served primarily to moderate activity and selectivity for one or both transporters. These SAR trends were quantified by Free-Wilson analyses and are reflected in a pharmacophore model for PhA accumulation. Several compounds were found to be equipotent with fumitremorginC (FTC) in promoting PhA accumulation, and they also demonstrated strong affinities for ABCB1. These compounds were disubstituted on ringB with methoxy or a combination of methoxy and hydroxy groups. Taken together, our findings highlight the versatility of the aurone template as a lead scaffold for the design of dual-targeting ABCG2 and ABCB1 modulators. © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.