title: Multi-drug-resistance-reverting agents: 2-aryloxazole and 2-arylthiazole derivatives as potent BCRP or MRP1 inhibitors.
abstract: 2-Aryloxazole and 2-arylthiazole derivatives were evaluated for their inhibitory activity toward P-glycoprotein (P-gp) as well as their selectivity toward other ABC transporters involved in multi-drug resistance such as BCRP and MRP1. These derivatives have 6,7-dimethoxytetrahydroisoquinoline or cyclohexylpiperazine moieties, which are the same basic nuclei of the potent P-gp inhibitors MC70 (EC(50)=0.05 microM) and PB28 (EC(50)=0.55 microM), respectively. The results demonstrate that 2-aryloxazole and 2-arylthiazole derivatives, planned as cycloisosteres of MC70, were found to be less potent than the reference compound in inhibiting P-gp. These compounds were evaluated for their BCRP and MRP1 inhibitory activities. In particular, 6,7-dimethoxytetrahydroisoquinoline derivatives, unsubstituted, 3-Br, 3-Cl, and 3-OCH(3) 2-aryloxalzole derivatives showed the best BCRP inhibitory activity (EC(50) range: 0.24-0.46 microM). In contrast, all cyclohexylpiperazine derivatives except one (EC(50)=0.56 microM), showed decreased BCRP inhibitory activity. All compounds tested were unable to inhibit the MRP1 pump, with the exception of the 2-OCH(3) and 4-OCH(3) derivatives of the 6,7-dimethoxytetrahydroisoquinoline series, which displayed high MRP1 inhibitory activity (EC(50)=0.84 and 0.90 microM, respectively).
authors.affiliation: Dipartimento Farmacochimico, Università degli Studi di Bari, Italy. colabufo@farmchim.uniba.it
authors.forename: Nicola A
authors.initials: NA
authors.lastname: Colabufo
authors.forename: Francesco
authors.initials: F
authors.lastname: Berardi
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Perrone
authors.forename: Mariangela
authors.initials: M
authors.lastname: Cantore
authors.forename: Marialessandra
authors.initials: M
authors.lastname: Contino
authors.forename: Carmela
authors.initials: C
authors.lastname: Inglese
authors.forename: Mauro
authors.initials: M
authors.lastname: Niso
authors.forename: Roberto
authors.initials: R
authors.lastname: Perrone
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors*; D000818:Animals; D045744:Cell Line, Tumor; D004285:Dogs; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005452:Fluoresceins / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D010080:Oxazoles / Q000494:pharmacology*; D013056:Spectrophotometry, Ultraviolet; D013844:Thiazoles / Q000494:pharmacology*
chemical_list: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D005452:Fluoresceins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D010080:Oxazoles; D013844:Thiazoles; C116614:ABCG2 protein, human; C007740:fluorexon; C421109:multidrug resistance-associated protein 1