title: Symmetric bis-chalcones as a new type of breast cancer resistance protein inhibitors with a mechanism different from that of chromones.
abstract: Potent ABCG2 inhibitors were recently identified as asymmetric chromones with different types of substituents. We here synthesized symmetric bis-chalcones that were differently substituted and screened for their ability to inhibit mitoxantrone efflux from ABCG2-transfected HEK293 cells. Potent bis-chalcone inhibitors were identified, the efficiency depending on both position of the central ketone groups and the number and positions of lateral methoxy substituents. The best derivative, namely, 1p, was selective for ABCG2 over P-glycoprotein and MRP1, appeared not to be transported by ABCG2, and was at least as active on various drug-selected cancer cells overexpressing ABCG2. Compound 1p stimulated the ABCG2 basal ATPase activity by contrast to a chromone lead that inhibited it, suggesting different mechanisms of interaction. Combination of both types of inhibitors produced synergistic effects, leading to complete inhibition at very low concentrations.
authors.affiliation: Equipe Labellisée Ligue 2014, BMSSI UMR5086 CNRS/Université Lyon 1, IBCP, 69367 Lyon, France.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Winter
authors.forename: Patrícia
authors.initials: P
authors.lastname: Devantier Neuenfeldt
authors.forename: Louise Domeneghini
authors.initials: LD
authors.lastname: Chiaradia-Delatorre
authors.forename: Charlotte
authors.initials: C
authors.lastname: Gauthier
authors.forename: Rosendo Augusto
authors.initials: RA
authors.lastname: Yunes
authors.forename: Ricardo José
authors.initials: RJ
authors.lastname: Nunes
authors.forename: Tânia Beatriz
authors.initials: TB
authors.lastname: Creczynski-Pasa
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* / Q000378:metabolism; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D047188:Chalcones / Q000737:chemistry / Q000494:pharmacology*; D002867:Chromones / Q000737:chemistry / Q000494:pharmacology*; D018432:Drug Resistance, Multiple / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D057809:HEK293 Cells; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology; D008942:Mitoxantrone / Q000494:pharmacology; D015394:Molecular Structure; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000473:pathology; 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; D002867:Chromones; D009363:Neoplasm Proteins; D008942:Mitoxantrone