New, highly potent and non-toxic, chromone inhibitors of the human breast cancer resistance protein ABCG2

•Breast cancer resistance protein (BCRP/ABCG2) is one of the major transporters involved in multidrug resistance (MDR).•Inhibition of ABCG2-mediated transport is then considered a promising strategy for overcoming MDR in tumors.•The present work reports on the synthesis of a series of flavonoids.•The most potent analogue is derived from the selective chromone ABCG2 inhibitor MBL-II-141 previously reported.

Breast cancer resistance protein (BCRP/ABCG2) is one of the major transporters involved in the efflux of anticancer compounds, contributing to multidrug resistance (MDR). Inhibition of ABCG2-mediated transport is then considered a promising strategy for overcoming MDR in tumors. We recently identified a chromone derivative, namely MBL-II-141 as a selective ABCG2 inhibitor, with relevant in vivo activity. Here, we report the pharmacomodulation of MBL-II-141, with the aim of identifying key pharmacophoric elements to design more potent selective and non-toxic inhibitors. Through rational structural modifications of MBL-II-141, using simple and affordable chemistry, we obtained highly active and easily-made inhibitors of ABCG2. Among the investigated compounds, derivative 4a, was found to be 3-fold more potent than MBL-II-141. It was similarly efficient as the reference inhibitor Ko143 but with the advantage of a lower intrinsic cytotoxicity, and therefore constitutes the best ABCG2 inhibitor ever reported displaying a very high therapeutic ratio.

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