title: Piperazinobenzopyranones and phenalkylaminobenzopyranones: potent inhibitors of breast cancer resistance protein (ABCG2).
abstract: In continuing research that led us to identify chromanone derivatives (J. Med. Chem. 2003, 46, 2125) as P-glycoprotein inhibitors, we obtained analogues able to modulate multidrug resistance (MDR) mediated by the breast cancer resistance protein (BCRP). The linkage of 5-hydroxybenzopyran-4-one to piperazines or phenalkylamines affords highly potent inhibitors of BCRP. By using sensitive (HCT116) and resistant colon cancer cells expressing BCRP, we evaluated the effect of 14 benzopyranone (chromone) derivatives on the accumulation and the cytotoxic effect of the anticancer drug, mitoxantrone. At 10 microM, three compounds increased both intracellular accumulation and cytotoxicity of mitoxantrone in HCT116/R cells with a comparable rate as fumitremorgin C and Gleevec used as reference inhibitors. The most potent molecules 5b and 5c are still active at 1 microM, whereas FTC shows weak inhibition. These molecules do not induce cell death as shown by the cell cycle distribution study, which makes them potential candidates for in vivo studies.
authors.affiliation: Département de Pharmacochimie Moléculaire, UMR-CNRS 5063, Faculté de Pharmacie de Grenoble, 5, Avenue de Verdun, BP 138, 38243 Meylan, France. Ahcene.Boumendjel@ujf-grenoble.fr
authors.forename: Ahcène
authors.initials: A
authors.lastname: Boumendjel
authors.forename: Edwige
authors.initials: E
authors.lastname: Nicolle
authors.forename: Thomas
authors.initials: T
authors.lastname: Moraux
authors.forename: Bastien
authors.initials: B
authors.lastname: Gerby
authors.forename: Madeleine
authors.initials: M
authors.lastname: Blanc
authors.forename: Xavier
authors.initials: X
authors.lastname: Ronot
authors.forename: Jean
authors.initials: J
authors.lastname: Boutonnat
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors*; D000970:Antineoplastic Agents / Q000494:pharmacology; D001549:Benzamides; D045744:Cell Line, Tumor; D002867:Chromones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D045325:HCT116 Cells; D006801:Humans; D000068877:Imatinib Mesylate; D007211:Indoles / Q000494:pharmacology; D008942:Mitoxantrone / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: C507027:2-(4-n-butylpiperazin-1-ylcarbonyl)-5-hydroxychromone; C507028:2-(N-(3,4-dimethoxyphenylethylaminocarbonyl))-5-hydroxychromone; C507029:2-(N-(4-methoxyphenylethylaminocarbonyl))-5-hydroxychromone; C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D001549:Benzamides; D002867:Chromones; D007211:Indoles; D009363:Neoplasm Proteins; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D008942:Mitoxantrone; C010522:tryptoquivaline