title: Structure-activity relationships of chromone derivatives toward the mechanism of interaction with and inhibition of breast cancer resistance protein ABCG2.
abstract: We recently identified a chromone derivative, 5-(4-bromobenzyloxy)-2-(2-(5-methoxyindolyl)ethyl-1-carbonyl)-4H-chromen-4-one, named here as chromone 1, as a potent, selective, nontoxic, and nontransported inhibitor of ABCG2-mediated drug efflux (Valdameri et al. J. Med. Chem. 2012, 55, 966). We have now synthesized a series of 14 derivatives to study the structure-activity relationships controlling both drug efflux and ATPase activity of ABCG2 and to elucidate their molecular mechanism of interaction and inhibition. It was found that the 4-bromobenzyloxy substituent at position 5 and the methoxyindole are important for both inhibition of mitoxantrone efflux and inhibition of basal ATPase activity. Quite interestingly, methylation of the central amide nitrogen strongly altered the high affinity for ABCG2 and the complete inhibition of mitoxantrone efflux and coupled ATPase activity. These results allowed the identification of a critical central inhibitory moiety of chromones that has never been investigated previously in any series of inhibitors.
authors.affiliation: Equipe Labellisée Ligue 2013, BMSSI UMR 5086 CNRS/Université Lyon 1, IBCP , 69367 Lyon, France.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Winter
authors.forename: Florine
authors.initials: F
authors.lastname: Lecerf-Schmidt
authors.forename: Gustavo
authors.initials: G
authors.lastname: Gozzi
authors.forename: Basile
authors.initials: B
authors.lastname: Peres
authors.forename: Mark
authors.initials: M
authors.lastname: Lightbody
authors.forename: Charlotte
authors.initials: C
authors.lastname: Gauthier
authors.forename: Csilla
authors.initials: C
authors.lastname: Ozvegy-Laczka
authors.forename: Gergely
authors.initials: G
authors.lastname: Szakacs
authors.forename: Balazs
authors.initials: B
authors.lastname: Sarkadi
authors.forename: Tânia B
authors.initials: TB
authors.lastname: Creczynski-Pasa
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* / Q000737:chemistry; D002867:Chromones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015394:Molecular Structure; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / 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; D002867:Chromones; D009363:Neoplasm Proteins