title: Small P-gp modulating molecules: SAR studies on tetrahydroisoquinoline derivatives.
abstract: The development of small molecules as P-gp modulating agents and SAR studies on these ligands represented the aim of the present work. A series of 6,7-dimethoxytetrahydroisoquinoline derivatives was prepared and their ability to inhibit P-gp activity has been evaluated. The basic nucleus of these compounds, common to the best P-gp inhibitors such as Tariquidar and Elacridar, has been functionalized with no-basic moiety from our studied sigma receptor ligands displaying potent P-gp inhibition. The best results were obtained for compounds 3c and 3a (EC(50)=1.64 and 4.86 microM, respectively) and these results were remarkable because Elacridar showed in the same biological evaluation similar inhibitory activity (EC(50)=2 microM). SAR studies displayed that the removal of double bond on the spacer or its shifting into tetraline ring decreased the P-gp inhibiting activity. Moreover, the P-gp inhibition mechanism of tested compounds was investigated by three selected biological experiments. The results displayed that only compound 3c was P-gp inhibitor as Elacridar, while compound 3a and reference compounds Cyclosporin A and Verapamil modulated P-gp activity saturating the efflux pump as substrates. Flow cytometry studies carried out in Doxorubicin resistant breast cancer cell line (MCF7/Adr) confirmed that compound 3c increased Doxorubicin cell accumulation 5.7-fold. In addition, in MCF7/Adr, antiproliferative effect of 5 microM Doxorubicin shifted from 5% to 95% when co-administered with compound 3c (20 microM). The present study suggested a new class of small molecules displaying P-gp inhibitor activity differing from reference compounds Elacridar and Tariquidar for a simplified, and in the meantime, efficacious no-basic moiety.
authors.affiliation: Dipartimento Farmacochimico, Università degli Studi di Bari, via Orabona, 4, 70125 Bari, Italy. colabufo@farmchim.uniba.it
authors.forename: Nicola Antonio
authors.initials: NA
authors.lastname: Colabufo
authors.forename: Francesco
authors.initials: F
authors.lastname: Berardi
authors.forename: Mariangela
authors.initials: M
authors.lastname: Cantore
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Perrone
authors.forename: Marialessandra
authors.initials: M
authors.lastname: Contino
authors.forename: Carmela
authors.initials: C
authors.lastname: Inglese
authors.forename: Mauro
authors.initials: M
authors.lastname: Niso
authors.forename: Roberto
authors.initials: R
authors.lastname: Perrone
authors.forename: Amalia
authors.initials: A
authors.lastname: Azzariti
authors.forename: Grazia Maria
authors.initials: GM
authors.lastname: Simone
authors.forename: Letizia
authors.initials: L
authors.lastname: Porcelli
authors.forename: Angelo
authors.initials: A
authors.lastname: Paradiso
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000166:Acridines; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology; D004347:Drug Interactions; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D005260:Female; D006801:Humans; D007546:Isoquinolines / Q000737:chemistry* / Q000494:pharmacology*; D008024:Ligands; D011804:Quinolines; D013329:Structure-Activity Relationship; D044005:Tetrahydroisoquinolines
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000166:Acridines; D000970:Antineoplastic Agents; D007546:Isoquinolines; D008024:Ligands; D011804:Quinolines; D044005:Tetrahydroisoquinolines; D004317:Doxorubicin; C402343:tariquidar; C083501:Elacridar