TY - JOUR
T1 - New structure-activity relationships of chalcone inhibitors of breast cancer resistance protein
T2 - Polyspecificity toward inhibition and critical substitutions against cytotoxicity
AU - Rangel, Luciana Pereira
AU - Winter, Evelyn
AU - Gauthier, Charlotte
AU - Terreux, Raphaël
AU - Chiaradia-Delatorre, Louise D.
AU - Mascarello, Alessandra
AU - Nunes, Ricardo J.
AU - Yunes, Rosendo A.
AU - Creczynski-Pasa, Tania B.
AU - Macalou, Sira
AU - Lorendeau, Doriane
AU - Baubichon-Cortay, Hélène
AU - Ferreira-Pereira, Antonio
AU - Di Pietro, Attilio
PY - 2013/9/27
Y1 - 2013/9/27
N2 - 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.
AB - 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.
KW - ABC transporters
KW - BCRP/ABCG2
KW - Cancer chemotherapy
KW - Drug transport
KW - Inhibitory chalcone derivatives
KW - Multidrug resistance transporters
UR - http://www.scopus.com/inward/record.url?scp=84884918573&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84884918573&partnerID=8YFLogxK
U2 - 10.2147/DDDT.S46983
DO - 10.2147/DDDT.S46983
M3 - Article
C2 - 24109177
AN - SCOPUS:84884918573
SN - 1177-8881
VL - 7
SP - 1043
EP - 1052
JO - Drug Design, Development and Therapy
JF - Drug Design, Development and Therapy
ER -