title: Investigation of chalcones as selective inhibitors of the breast cancer resistance protein: critical role of methoxylation in both inhibition potency and cytotoxicity.
abstract: ABCG2 plays a major role in anticancer-drug efflux and related tumor multidrug resistance. Potent and selective ABCG2 inhibitors with low cytotoxicity were investigated among a series of 44 chalcones and analogues (1,3-diarylpropenones), by evaluating their inhibitory effect on the transport of mitoxantrone, a known ABCG2 substrate. Six compounds producing complete inhibition with IC(50) values below 0.5 μM and high selectivity for ABCG2 were identified. The number and position of methoxy substituents appeared to be critical for both inhibition and cytotoxicity. The best compounds, with potent inhibition and low toxicity, contained an N-methyl-1-indolyl (compound 38) or a 6'-hydroxyl-2',4'-dimethoxy-1-phenyl (compound 27) moiety (A-ring) and two methoxy groups at positions 2 and 6 of the 3-phenyl moiety (B-ring). Methoxy substitution contributed to inhibition at positions 3 and 5, but had a negative effect at position 4. Finally, methoxy groups at positions 3, 4, and 5 of the B-ring markedly increased cytotoxicity and, therefore, should be avoided.
authors.affiliation: Equipe Labellisée Ligue 2012, BMSSI UMR 5086 CNRS /Université Lyon 1, Institut de Biologie et Chimie des Protéines, Lyon, France.
authors.forename: Glaucio
authors.initials: G
authors.lastname: Valdameri
authors.forename: Charlotte
authors.initials: C
authors.lastname: Gauthier
authors.forename: Raphaël
authors.initials: R
authors.lastname: Terreux
authors.forename: Rémy
authors.initials: R
authors.lastname: Kachadourian
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Day
authors.forename: Sheila M B
authors.initials: SM
authors.lastname: Winnischofer
authors.forename: Maria E M
authors.initials: ME
authors.lastname: Rocha
authors.forename: Véronique
authors.initials: V
authors.lastname: Frachet
authors.forename: Xavier
authors.initials: X
authors.lastname: Ronot
authors.forename: Attilio
authors.initials: A
authors.lastname: Di Pietro
authors.forename: Ahcène
authors.initials: A
authors.lastname: Boumendjel
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000235:genetics; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D047188:Chalcones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D021281:Quantitative Structure-Activity Relationship; D014162:Transfection
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; D007211:Indoles; D009363:Neoplasm Proteins