title: Quinoxaline-substituted chalcones as new inhibitors of breast cancer resistance protein ABCG2: polyspecificity at B-ring position.
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.
authors.affiliation: Equipe Labellisée Ligue 2013, Université Lyon 1, Institut de Biologie et Chimie des Protéines, Lyon, France ; Department of Pharmaceutical Sciences, Federal University of Santa Catarina, Florianopolis, Brazil.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Winter
authors.affiliation: Equipe Labellisée Ligue 2013, Université Lyon 1, Institut de Biologie et Chimie des Protéines, Lyon, France ; Department of Biochemistry and Molecular Biology, Federal University of Paraná, Curitiba, Brazil.
authors.forename: Gustavo Jabor
authors.initials: GJ
authors.lastname: Gozzi
authors.affiliation: Department of Chemistry, Federal University of Santa Catarina, Florianopolis, Brazil.
authors.forename: Louise Domeneghini
authors.initials: LD
authors.lastname: Chiaradia-Delatorre
authors.affiliation: Equipe Labellisée Ligue 2013, Université Lyon 1, Institut de Biologie et Chimie des Protéines, Lyon, France.
authors.forename: Nathalia
authors.initials: N
authors.lastname: Daflon-Yunes
authors.affiliation: Bioinformatique structures et interactions, Université Lyon 1, Institut de Biologie et Chimie des Protéines, Lyon, France.
authors.forename: Raphael
authors.initials: R
authors.lastname: Terreux
authors.affiliation: Equipe Labellisée Ligue 2013, Université Lyon 1, Institut de Biologie et Chimie des Protéines, Lyon, France.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Gauthier
authors.affiliation: Department of Chemistry, Federal University of Santa Catarina, Florianopolis, Brazil.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Mascarello
authors.affiliation: Department of Chemistry, Federal University of Santa Catarina, Florianopolis, Brazil.
authors.forename: Paulo César
authors.initials: PC
authors.lastname: Leal
authors.affiliation: Department of Biochemistry and Molecular Biology, Federal University of Paraná, Curitiba, Brazil.
authors.forename: Silvia M
authors.initials: SM
authors.lastname: Cadena
authors.affiliation: Department of Chemistry, Federal University of Santa Catarina, Florianopolis, Brazil.
authors.forename: Rosendo Augusto
authors.initials: RA
authors.lastname: Yunes
authors.affiliation: Department of Chemistry, Federal University of Santa Catarina, Florianopolis, Brazil.
authors.forename: Ricardo José
authors.initials: RJ
authors.lastname: Nunes
authors.affiliation: Department of Pharmaceutical Sciences, Federal University of Santa Catarina, Florianopolis, Brazil.
authors.forename: Tania Beatriz
authors.initials: TB
authors.lastname: Creczynski-Pasa
authors.affiliation: Equipe Labellisée Ligue 2013, Université Lyon 1, Institut de Biologie et Chimie des Protéines, Lyon, France.
authors.forename: Attilio
authors.initials: A
authors.lastname: Di Pietro
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D002478:Cells, Cultured; D047188:Chalcones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D011810:Quinoxalines / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D047188:Chalcones; D009363:Neoplasm Proteins; D011810:Quinoxalines
keywords: ABC transporters; breast cancer resistance protein (BCRP)/ABCG2; drug efflux; quinoxaline derivatives; structure–activity relationships