title: Substituted chromones as highly potent nontoxic inhibitors, specific for the breast cancer resistance protein.
abstract: A series of 13 disubstituted chromones was synthesized. Two types of substituents, on each side of the scaffold, contributed to both the potency of ABCG2 inhibition and the cytotoxicity. The best compound, 5-(4-bromobenzyloxy)-2-(2-(5-methoxyindolyl)ethyl-1-carbonyl)-4H-chromen-4-one (6g), displayed high-affinity inhibition and low cytotoxicity, giving a markedly high therapeutic index. The chromone derivative specifically inhibited ABCG2 versus other multidrug ABC transporters and was not transported. It constitutes a highly promising candidate for in vivo chemosensitization of ABCG2-expressing tumors.
authors.affiliation: Equipe Labellisée Ligue 2011, Institut de Biologie et Chimie des Protéines, BMSSI UMR 5086, CNRS/Université Lyon 1 , Lyon, France.
authors.forename: Glaucio
authors.initials: G
authors.lastname: Valdameri
authors.forename: Estelle
authors.initials: E
authors.lastname: Genoux-Bastide
authors.forename: Basile
authors.initials: B
authors.lastname: Peres
authors.forename: Charlotte
authors.initials: C
authors.lastname: Gauthier
authors.forename: Jérôme
authors.initials: J
authors.lastname: Guitton
authors.forename: Raphaël
authors.initials: R
authors.lastname: Terreux
authors.forename: Sheila M B
authors.initials: SM
authors.lastname: Winnischofer
authors.forename: Maria E M
authors.initials: ME
authors.lastname: Rocha
authors.forename: Ahcène
authors.initials: A
authors.lastname: Boumendjel
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* / Q000235:genetics / Q000378:metabolism; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002867:Chromones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D057809:HEK293 Cells; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008942:Mitoxantrone / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D014162:Transfection
chemical_list: C571193:5-(4-bromobenzyloxy)-2-(2-(5-methoxyindolyl)ethyl-1-carbonyl)-4H-chromen-4-one; C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D002867:Chromones; D007211:Indoles; D009363:Neoplasm Proteins; D008942:Mitoxantrone