Small P-gp modulating molecules: SAR studies on tetrahydroisoquinoline derivatives

Nicola Antonio Colabufo, Francesco Berardi, Mariangela Cantore, Maria Grazia Perrone, Marialessandra Contino, Carmela Inglese, Mauro Niso, Roberto Perrone, Amalia Azzariti, Grazia Maria Simone, Letizia Porcelli, Angelo Paradiso

Research output: Contribution to journalArticlepeer-review


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 (EC50 = 1.64 and 4.86 μM, respectively) and these results were remarkable because Elacridar showed in the same biological evaluation similar inhibitory activity (EC50 = 2 μM). 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 μM Doxorubicin shifted from 5% to 95% when co-administered with compound 3c (20 μM). 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.

Original languageEnglish
Pages (from-to)362-373
Number of pages12
JournalBioorganic and Medicinal Chemistry
Issue number1
Publication statusPublished - Jan 1 2008


  • Caco-2 cells
  • MCF-7/Adr cells
  • P-Glycoprotein
  • P-gp inhibitors
  • Tetrahydroisoquinoline derivatives
  • Vinblastine transport

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Organic Chemistry
  • Drug Discovery
  • Pharmaceutical Science


Dive into the research topics of 'Small P-gp modulating molecules: SAR studies on tetrahydroisoquinoline derivatives'. Together they form a unique fingerprint.

Cite this