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

作者：Sim Hong May; Loh Ker Yun; Yeo Wee Kiang; Lee Chong Yew; Go Mei Lin^*

来源：ChemMedChem, 2011, 6(4): 713-724.

DOI：10.1002/cmdc.201000520

• ABCB1
• ABCG2
• aurones
• Free-Wilson analysis
• modulators
• structure-activity relationships

The ability of aurones to modulate the efflux activities of ABCG2 and ABCB1 was investigated by quantifying their effects on the accumulation of pheophorbide A (PhA) in ABCG2-overexpressing MDA-MB-231/R cells and calcein AM in ABCB1-overexpressing MDCKII/MDR1 cells. Key structural features for interactions at both ABCG2 and ABCB1 are a methoxylated ring A, an intact exocyclic double bond, and the location of the carbonyl bond on ring C. Modifications on rings B 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 fumitremorgin C (FTC) in promoting PhA accumulation, and they also demonstrated strong affinities for ABCB1. These compounds were disubstituted on ring B 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.

• 出版日期2011-4-4