New structure-activity relationships of chalcone inhibitors of breast cancer resistance protein: polyspecificity toward inhibition and critical substitutions against cytotoxicity

作者：Rangel Luciana Pereira; Winter Evelyn; Gauthier Charlotte; Terreux Raphael; Chiaradia Delatorre Louise D; Mascarello Alessandra; Nunes Ricardo J; Yunes Rosendo A; Creczynski Pasa Tania B; Macalou Sira; Lorendeau Doriane; Baubichon Cortay Helene; Ferreira Pereira Antonio; Di Pietro Attilio^*

来源：Drug Design, Development and Therapy, 2013, 7: 1043-1052.

DOI：10.2147/DDDT.S46983

• ABC transporters
• BCRP/ABCG2
• cancer chemotherapy
• drug transport
• inhibitory chalcone derivatives
• multidrug resistance transporters

Adenosine triphosphate-binding cassette subfamily G member 2 (ABCG2) plays a major role in cancer cell multidrug resistance, which contributes to low efficacy of chemotherapy. Chalcones were recently found to be potent and specific inhibitors, but unfortunately display a significant cytotoxicity. A cellular screening against ABCG2-mediated mitoxantrone efflux was performed here by flow cytometry on 54 chalcone derivatives from three different series with a wide panel of substituents. The identified leads, with submicromolar IC50 (half maximal inhibitory concentration) values, showed that the previously identified 2%26apos;-OH-4%26apos;,6%26apos;-dimethoxyphenyl, as A-ring, could be efficiently replaced by a 2%26apos;-naphthyl group, or a 3%26apos;,4%26apos;-methylenedioxyphenyl with lower affinity. Such a structural variability indicates polyspecificity of the multidrug transporter for inhibitors. At least two methoxyl groups were necessary on B-ring for optimal inhibition, but substitution at positions 3, 4, and 5 induced cytotoxicity. The presence of a large O-benzyl substituent at position 4 and a 2%26apos;-naphthyl as A-ring markedly decreased the cytotoxicity, giving a high therapeutic ratio, which constitutes a critical requirement for future in-vivo assays in animal models.

• 出版日期2013