title: Functionalized Coumarine Fragment to Obtain Fluorescent and Selective P-Glycoprotein Ligands.
abstract: Starting from our lead compound MC70 displaying high P-glycoprotein (P-gp) inhibition activity but low selectivity, a new class of coumarine derivatives was studied to develop selective and fluorescent P-gp ligands. In this series, the biphenyl moiety of MC70 was replaced with the coumarine fluorophore as a bioisostere of the biphenyl nucleus in order to improve the selectivity toward P-gp and the fluorescent properties for in vitro studies. Moreover, the presence and position of substituents on the coumarine nucleus were probed to develop suitable fluorescent probes to study the expression and activity of P-gp in living cells. The best result was found for compound 4c, which exerts a good P-gp activity profile (EC50  = 13 μM) as substrate and a high selectivity toward the pump since it is inactive toward MRP1.
authors.affiliation: Department of Pharmacy, University of Bari "Aldo Moro", Bari, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Capparelli
authors.affiliation: Department of Pharmacy, University of Bari "Aldo Moro", Bari, Italy.
authors.forename: Marialessandra
authors.initials: M
authors.lastname: Contino
authors.affiliation: Department of Pharmacy, University of Bari "Aldo Moro", Bari, Italy.
authors.forename: Maria G
authors.initials: MG
authors.lastname: Perrone
authors.affiliation: Department of Pharmacy, University of Bari "Aldo Moro", Bari, Italy.|Biofordrug srl, Department of Pharmacy, University of Bari "Aldo Moro", Bari, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Berardi
authors.affiliation: Department of Pharmacy, University of Bari "Aldo Moro", Bari, Italy.|Biofordrug srl, Department of Pharmacy, University of Bari "Aldo Moro", Bari, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Perrone
authors.affiliation: Department of Pharmacy, University of Bari "Aldo Moro", Bari, Italy.|Biofordrug srl, Department of Pharmacy, University of Bari "Aldo Moro", Bari, Italy.
authors.forename: Marcello
authors.initials: M
authors.lastname: Leopoldo
authors.affiliation: Department of Pharmacy, University of Bari "Aldo Moro", Bari, Italy.|Biofordrug srl, Department of Pharmacy, University of Bari "Aldo Moro", Bari, Italy.
authors.forename: Nicola A
authors.initials: NA
authors.lastname: Colabufo
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism*; D000818:Animals; D001713:Biphenyl Compounds / Q000737:chemistry*; D002867:Chromones / Q000138:chemical synthesis / Q000737:chemistry*; D003374:Coumarins / Q000138:chemical synthesis / Q000737:chemistry*; D004285:Dogs; D005456:Fluorescent Dyes / Q000138:chemical synthesis / Q000737:chemistry*; D007546:Isoquinolines / Q000138:chemical synthesis / Q000737:chemistry*; D008024:Ligands; D061985:Madin Darby Canine Kidney Cells; D044005:Tetrahydroisoquinolines / Q000737:chemistry*
chemical_list: C569748:4'-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-ylmethyl)biphenyl-4-ol; C000613686:7-(diethylamino)-3-((6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)methyl)-2H-chromen-2-one; D018435:ATP Binding Cassette Transporter, Subfamily B; D001713:Biphenyl Compounds; D002867:Chromones; D003374:Coumarins; D005456:Fluorescent Dyes; D007546:Isoquinolines; D008024:Ligands; D044005:Tetrahydroisoquinolines
keywords: Coumarine derivatives; Fluorescent probes; MRP1; P-gp; P-gp ligands