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Quinoxaline-substituted chalcones as new inhibitors of breast cancer resistance protein ABCG2: polyspecificity at B-ring position

Authors Winter E, Gozzi GJ, Chiaradia-Delatorre LD, Daflon-Yunes N, Terreux R, Gauthier C, Mascarello A, Leal PC, Cadena SM, Yunes RA, Nunes RJ, Creczynski-Pasa TB, Di Pietro A

Received 26 October 2013

Accepted for publication 28 February 2014

Published 27 May 2014 Volume 2014:8 Pages 609—619

DOI https://doi.org/10.2147/DDDT.S56625

Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 3

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


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