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Evelyn Winter,1,2,* Gustavo Jabor Gozzi,1,3,* Louise Domeneghini Chiaradia-Delatorre,4 Nathalia Daflon-Yunes,1 Raphael Terreux,5 Charlotte Gauthier,1 Alessandra Mascarello,4 Paulo César Leal,4 Silvia M Cadena,3 Rosendo Augusto Yunes,4 Ricardo José Nunes,4 Tania Beatriz Creczynski-Pasa,2 Attilio Di Pietro1 1Equipe Labellisée Ligue 2013, Université Lyon 1, Institut de Biologie et Chimie des Protéines, Lyon, France; 2Department of Pharmaceutical Sciences, Federal University of Santa Catarina, Florianopolis, Brazil; 3Department of Biochemistry and Molecular Biology, Federal University of Paraná, Curitiba, Brazil; 4Department of Chemistry, Federal University of Santa Catarina, Florianopolis, Brazil; 5Bioinformatique structures et interactions, Université Lyon 1, Institut de Biologie et Chimie des Protéines, Lyon, France *These authors contributed equally to this work Abstract: A series of chalcones substituted by a quinoxaline unit at the B-ring were synthesized and tested as inhibitors of breast cancer resistance protein-mediated mitoxantrone efflux. These compounds appeared more efficient than analogs containing other B-ring substituents such as 2-naphthyl or 3,4-methylenedioxyphenyl while an intermediate inhibitory activity was obtained with a 1-naphthyl group. In all cases, two or three methoxy groups had to be present on the phenyl A-ring to produce a maximal inhibition. Molecular modeling indicated both electrostatic and steric positive contributions. A higher potency was observed when the 2-naphthyl or 3,4-methylenedioxyphenyl group was shifted to the A-ring and methoxy substituents were shifted to the phenyl B-ring, indicating preferences among polyspecificity of inhibition. Keywords: ABC transporters, breast cancer resistance protein (BCRP)/ABCG2, quinoxaline derivatives, structure–activity relationships, drug efflux

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 Pietro11Equipe Labellisée Ligue 2013, BMSSI UMR 5086 CNRS/Université Lyon 1, Institut de Biologie et Chimie des Protéines, Lyon, France; 2Department of General Microbiology, Institute of Microbiology, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil; 3Department of Pharmaceutical Sciences, PPGFAR, Federal University of Santa Catarina, Florianopolis, Santa Catarina, Brazil; 4Equipe BISI, BMSSI UMR 5086 CNRS/Université Lyon 1, Institut de Biologie et Chimie des Protéines, Lyon, France; 5Department of Chemistry, Federal University of Santa Catarina, Florianopolis, Santa Catarina, Brazil*These authors contributed equally to this workAbstract: 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'-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 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'-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.Keywords: ABC transporters, BCRP/ABCG2, cancer chemotherapy, drug transport, inhibitory chalcone derivatives, multidrug resistance transporters.