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

• Published in: Drug design, development and therapy Vol. 7; no. default; pp. 1043 - 1052
• Main Authors: Rangel, Luciana Pereira, Winter, Evelyn, Gauthier, Charlotte, Terreux, Raphaël, Chiaradia-Delatorre, Louise D, Mascarello, Alessandra, Nunes, Ricardo J, Yunes, Rosendo A, Creczynski-Pasa, Tania B, Macalou, Sira, Lorendeau, Doriane, Baubichon-Cortay, Hélène, Ferreira-Pereira, Antonio, Di Pietro, Attilio
• Format: Journal Article
• Language: English
• Published: New Zealand Dove Medical Press Limited 01-01-2013; Taylor & Francis Ltd; Dove Press; Dove Medical Press
• Subjects: ABC transporters; Adenosine triphosphate; Analysis; Animal models; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; ATP; ATP Binding Cassette Transporter, Sub-Family G, Member 2; ATP-Binding Cassette Transporters - antagonists & inhibitors; BCRP/ABCG2; Biocompatibility; Biological Transport; Breast cancer; Cancer; cancer chemotherapy; Care and treatment; Chalcones - administration & dosage; Chalcones - chemistry; Chalcones - pharmacology; Chemotherapy; Cytotoxicity; Drug resistance; Drug Resistance, Multiple; Drug Resistance, Neoplasm; drug transport; Efflux; Flow Cytometry; Health aspects; HEK293 Cells; Humans; Inhibition; Inhibitors; inhibitory chalcone derivatives; Inhibitory Concentration 50; Mitoxantrone; Mitoxantrone - pharmacokinetics; Multidrug resistance; multidrug resistance transporters; Multidrug resistant organisms; Neoplasm Proteins - antagonists & inhibitors; Original Research; Rings (mathematics); Structure-Activity Relationship; Toxicity; France; drug transport; ABC transporters; multidrug resistance transporters; BCRP/ABCG2; inhibitory chalcone derivatives; cancer chemotherapy
• ISSN: 1177-8881; 1177-8881
• DOI: 10.2147/DDDT.S46983

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 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.