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

Content Provider	PubMed Central
Author	Rangel, Luciana Pereira Winter, Evelyn Gauthier, Charlotte Raphaël, Terreux Chiaradia-delatorre, Louise D. Mascarello, Alessandra Nunes, Ricardo J. Yunes, Rosendo A. Creczynski-pasa, Tania B. Sira, Macalou Lorendeau, Doriane Baubichon-cortay, Hélène Antonio, Ferreira-pereira Pietro, Attilio Di
Copyright Year	2013
Abstract	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 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.
Related Links	http://dx.doi.org/10.2147/dddt.s46983
Ending Page	1052
Page Count	10
Starting Page	1043
File Format	PDF
ISSN	11778881
e-ISSN	11778881
Journal	Drug Design, Development and Therapy
Volume Number	7
Language	English
Publisher	Dove Medical Press
Publisher Date	2013-09-01
Access Restriction	Open
Rights Holder	Dove Medical Press
Subject Keyword	Pharmacology Drug Discovery Pharmaceutical Science Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Drug Discovery Pharmacology Pharmaceutical Science

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