Multi-drug-resistance-reverting agents: 2-aryloxazole and 2-arylthiazole derivatives as potent BCRP or MRP1 inhibitors.
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).
Colabufo
Nicola A
NA
Dipartimento Farmacochimico, Università degli Studi di Bari, Italy. colabufo@farmchim.uniba.it
Berardi
Francesco
F
Perrone
Maria Grazia
MG
Cantore
Mariangela
M
Contino
Marialessandra
M
Inglese
Carmela
C
Niso
Mauro
M
Perrone
Roberto
R
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*
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