Luciana Pereira Rangel 1 , 2 , Evelyn Winter 1 , 3 , Charlotte Gauthier 1 , Raphaël Terreux 4 , Louise D Chiaradia-Delatorre 5 , Alessandra Mascarello 5 , Ricardo J Nunes 5 , Rosendo A Yunes 5 , Tania B Creczynski-Pasa 3 , Sira Macalou 1 , Doriane Lorendeau 1 , Hélène Baubichon-Cortay 1 , Antonio Ferreira-Pereira 2 , Attilio Di Pietro 1
30 September 2013
Adenosine triphosphate-binding cassette subfamily G member 2 (ABCG2) plays a major role in cancer cell multidrug resistance, which contributes to low eifficacy 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 IC 50 (half maximal inhibitory concentration) values, showed that the previously identified 2′-OH-4′,6′-dimethoxyphenyl, as A-ring, could be efficiently replaced by a 2′-naphthyl group, or a 3′,4′-methylenedioxyphenyl with lower affinity. Such a structural variability indicates 3polyspecificity 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′-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.