New Tetrahydroisoquinoline-based P-glycoprotein Modulators: Decoration of the Biphenyl Core Gives Selective Ligands

Overview

Journal Medchemcomm

Publisher Royal Society of Chemistry

Specialty Chemistry

Date 2018 Aug 16

PMID 30108975

Citations 5

Authors

Marialessandra Contino

Stefano Guglielmo

Maria Grazia Perrone

Roberta Giampietro

Barbara Rolando

Antonio Carrieri

Daniele Zaccaria

Konstantin Chegaev

Vanessa Borio

Chiara Riganti

Katarzyna Zabielska-Koczywas

Nicola A Colabufo

Roberta Fruttero

Affiliations

Soon will be listed here.

Abstract

P-glycoprotein (P-gp, MDR1) is a membrane transporter expressed in several regions of our body. It plays a crucial defense role as it mediates the efflux of hundreds of potentially toxic substances. However, P-gp is one of the main causes of failure in cancer chemotherapy, as a number of chemotherapeutic agents are P-gp substrates. Another interesting implication concerns the correlation between P-gp expression impairment and the onset of several central nervous system pathologies such as Alzheimer's and Parkinson's diseases. In view of these considerations, in the present study, a new series of P-gp modulators have been designed, synthesized and evaluated for their activity towards P-gp and two other sister proteins (BCRP and MRP1). The compounds, structurally correlated to the potent but non-selective P-gp inhibitor [4'-(6,7-dimethoxy-3,4-dihydro-1-isoquinolin-2-ylmethyl)biphenyl-4-ol], proved fairly selective towards P-gp, with a potency in the micromolar range. Compounds , and proved capable of restoring doxorubicin toxicity in resistant cancer cells.

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