title: A Potent and Selective P-gp Modulator for Altering Multidrug Resistance Due to Pump Overexpression.
abstract: P-glycoprotein (P-gp) is a membrane protein responsible for the active transport of several endogenous and exogenous substances. It constitutes a defense mechanism and, at the same time, it severely compromises the success rate of antitumor chemotherapy. In this study a small library of alkyl/oxyalkyl derivatives of MC70 [4'-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-ylmethyl)biphenyl-4-ol], a well-known P-gp inhibitor, was synthesized through straightforward functionalization of the phenolic group present in the structure of MC70. All compounds were characterized for their effect on P-gp, proving capable of blocking P-gp-mediated calcein-AM efflux with micromolar potency, following their ability to act as high-affinity substrates of this transporter. Excitingly, compound 4 [6,7-dimethoxy-2-((4'-butoxybiphen-4-yl)methyl)-1,2,3,4-tetrahydroisoquinoline] exhibited low nanomolar potency (5.2 nm) and had a peculiar activity profile, acting both as a positive allosteric modulator and as a substrate of the transporter. A new and more efficient synthesis of MC70 is also described.
authors.affiliation: Department of Drug Science and Technology, Università degli Studi di Torino, Via P. Giuria 9, 10125, Turin, Italy. stefano.guglielmo@unito.it.
authors.forename: Stefano
authors.identifier: http://orcid.org/0000-0002-3313-4369
authors.initials: S
authors.lastname: Guglielmo
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: Department of Drug Science and Technology, Università degli Studi di Torino, Via P. Giuria 9, 10125, Turin, 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: Maria Grazia
authors.initials: MG
authors.lastname: Perrone
authors.affiliation: Department of Drug Science and Technology, Università degli Studi di Torino, Via P. Giuria 9, 10125, Turin, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Blangetti
authors.affiliation: Department of Drug Science and Technology, Università degli Studi di Torino, Via P. Giuria 9, 10125, Turin, 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. nicolaantonio.colabufo@uniba.it.|Biofordrug s.r.l., Spin-off dell'Università degli Studi di Bari "A. Moro", via Orabona 4, 70125, Bari, Italy. nicolaantonio.colabufo@uniba.it.
authors.forename: Nicola Antonio
authors.initials: NA
authors.lastname: Colabufo
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000494:Allosteric Regulation / Q000187:drug effects; D001713:Biphenyl Compounds / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D018432:Drug Resistance, Multiple / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D010539:Permeability; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D044005:Tetrahydroisoquinolines / Q000737:chemistry* / Q000493:pharmacokinetics / 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; D054852:Small Molecule Libraries; D044005:Tetrahydroisoquinolines
keywords: C−C coupling; P-glycoprotein; antitumor agents; multidrug resistance; proteins