Naphthalenyl derivatives for hitting P-gp/MRP1/BCRP transporters.
Substituted naphthalenyl derivatives bearing oxazole, or thiazole or furyl heteronuclei have been carried out as bioisosters of aryl-oxazoles and -thiazoles derivatives previously reported in order to investigate the role of the hindrance on the activity towards P-gp/BCRP/and MRP1 transporters. In addition, the role of naphthalenyl group to modulate P-gp intrinsic activity of these compounds was ascertained. The results demonstrated that all naphthalenyl derivatives displayed comparable P-gp activity with respect to lead compounds previously characterized in our SAR studies but were less active towards BCRP and MRP1 pumps. In terms of intrinsic activity, the replacement of aryl with naphthalenyl moiety led to P-gp inhibitors, unambiguous or ambiguous substrates on the base of the heteronucleus and the substituent on the naphthalenyl fragment. Indeed, oxazole derivatives were: inhibitors (R=H, F, OH), unambiguous substrates (R=OCH(3)), or ambiguous substrate (R=Br); thiazole derivatives were: unambiguous substrates (R=OCH(3), Br), or ambiguous substrates (R=H, F). Finally furyl derivatives were ambiguous substrates.
Dipartimento Farmacia, Università degli Studi di Bari ALDO MORO, Via Orabona 4, 70125 Bari, Italy. nicolaantonio.colabufo@uniba.it
Nicola A
NA
Colabufo
Marialessandra
M
Contino
Mariangela
M
Cantore
Elena
E
Capparelli
Maria Grazia
MG
Perrone
Giuseppe
G
Cassano
Giuseppe
G
Gasparre
Marcello
M
Leopoldo
Francesco
F
Berardi
Roberto
R
Perrone
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D018938:Caco-2 Cells; D049109:Cell Proliferation / Q000187:drug effects; D004285:Dogs; D004337:Drug Carriers / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D061985:Madin Darby Canine Kidney Cells; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009281:Naphthalenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D010080:Oxazoles / Q000737:chemistry; D020112:Rhodamine 123 / Q000737:chemistry; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013844:Thiazoles / Q000737:chemistry
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D004337:Drug Carriers; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009281:Naphthalenes; D010080:Oxazoles; D020112:Rhodamine 123; D013844:Thiazoles; C031721:naphthalene