Flavonoid derivatives as selective ABCC1 modulators: Synthesis and functional characterization

• A series of chromone-2-amines and -2-carboxamides was synthesized.
• Transporter modulation was investigated on cells expressing ABCC1, ABCB1 or ABCG2.
• Most potent ABCC1 modulators were comparable to reversan.
• In contrast to reversan, the most potent modulators were selective for ABCC1.
• The modulators reverted ABCC1-mediated chemoresistance in MDCKII-MRP1 cells.

A series of chromones, bearing substituted amino groups or N-substituted carboxamide moieties in position 2, was synthesized and characterized in cellular assays for modulation of the ABC transporters ABCC1 (MDCKII-MRP1 cells), ABCB1 (Kb-V1 cells) and ABCG2 (MCF-7/Topo cells). The most potent ABCC1 modulators identified among these flavonoid-type compounds were comparable to the reference compound reversan regarding potency, but superior in terms of selectivity concerning ABCB1 and ABCG2 (2-[4-(Benzo[c][1,2,5]oxadiazol-5-ylmethyl)piperazin-1-yl]-5,7-dimethoxy-4H-chromen-4-one (51): ABCC1, IC50 11.3 μM; inactive at ABCB1 and ABCG2). Compound 51 was as effective as reversan in reverting ABCC1-mediated resistance to cytostatics in MDCKII-MRP1 cells and proved to be stable in mouse plasma and cell culture medium. Modulators, such as compound 51, are of potential value as pharmacological tools for the investigation of the (patho)physiological role of ABCC1.

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