title: Structure-Activity Relationship Studies on Tetrahydroisoquinoline Derivatives: [4'-(6,7-Dimethoxy-3,4-dihydro-1H-isoquinolin-2-ylmethyl)biphenyl-4-ol] (MC70) Conjugated through Flexible Alkyl Chains with Furazan Moieties Gives Rise to Potent and Selective Ligands of P-glycoprotein.
abstract: P-glycoprotein (P-gp) is a well-known membrane transporter expressed in a number of strategic biological barriers, where it exerts a protective effect of paramount importance. Conversely it is one of the main causes of multidrug resistance (MDR), being capable of effluxing many chemotherapeutics. In a development of previous research, a small library of compounds was created conjugating diversely substituted furazan rings with MC70, a well-known P-gp inhibitor. These compounds were assessed for their potency against P-gp and another transporter (MRP1), for their apparent permeability (Papp) and for their ability to induce ATPase activity, thus delineating a complete functional profile. They displayed a substrate mechanism of action and high selectivity toward P-gp, unlike the lead compound. Data relating to their activity range from low micromolar to sub-nanomolar EC50, the most interesting compounds being 15 (0.97 nM), 19 (1.3 nM), 25 (0.60 nM), and 27 (0.90 nM).
authors.affiliation: Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino Via P. Giuria 9, 10125 Torino, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Guglielmo
authors.affiliation: Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino Via P. Giuria 9, 10125 Torino, Italy.
authors.forename: Loretta
authors.initials: L
authors.lastname: Lazzarato
authors.affiliation: Dipartimento di Farmacia-Scienze del Farmaco Università degli Studi di Bari "A. Moro" , Via Orabona 4, 70125 Bari, Italy.
authors.forename: Marialessandra
authors.initials: M
authors.lastname: Contino
authors.affiliation: Dipartimento di Farmacia-Scienze del Farmaco Università degli Studi di Bari "A. Moro" , Via Orabona 4, 70125 Bari, Italy.
authors.forename: Maria G
authors.initials: MG
authors.lastname: Perrone
authors.affiliation: Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino Via P. Giuria 9, 10125 Torino, Italy.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Chegaev
authors.affiliation: Dipartimento di Farmacia-Scienze del Farmaco Università degli Studi di Bari "A. Moro" , Via Orabona 4, 70125 Bari, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Carrieri
authors.affiliation: Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino Via P. Giuria 9, 10125 Torino, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Fruttero
authors.affiliation: Dipartimento di Farmacia-Scienze del Farmaco Università degli Studi di Bari "A. Moro" , Via Orabona 4, 70125 Bari, Italy.|Biofordrug s.r.l., Spin-off dell'Università degli Studi di Bari "A. Moro" Via Orabona 4, 70125 Bari, Italy.
authors.forename: Nicola A
authors.initials: NA
authors.lastname: Colabufo
authors.affiliation: Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino Via P. Giuria 9, 10125 Torino, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Gasco
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D001713:Biphenyl Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D044005:Tetrahydroisoquinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C569748:4'-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-ylmethyl)biphenyl-4-ol; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001713:Biphenyl Compounds; D008024:Ligands; D044005:Tetrahydroisoquinolines