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New tetrahydroisoquinoline based P-glycoprotein modulators: decoration of the biphenyl core gives selective ligands.

Abstract

P-glycoprotein (P-gp, MDR1) is a membrane transporter expressed in several districts of our body. It exerts a crucial defense role as it effluxes hundreds of potentially toxic substances. Hovewer, P-gp is one of the main causes of the failure in cancer chemotherapy, as a number of chemotherapeutic agents are P-gp substrates. Another interesting implication regards 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 has been designed, synthesized and evaluated for their activity towards P-gp and other two sister proteins (BCRP and MRP1). The compounds, structurally correlated to the potent but non-selective P-gp inhibitor MC70 [4’-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-ylmethyl)biphenyl-4-ol], proved fairly selective towards P-gp, with a potency in the micromolar range. Compounds 5a, 5d and 12d proved capable to restore doxorubicin toxicity in resistant cancer cells.

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Supplementary files

Publication details

The article was received on 08 Feb 2018, accepted on 30 Mar 2018 and first published on 03 Apr 2018


Article type: Research Article
DOI: 10.1039/C8MD00075A
Citation: Med. Chem. Commun., 2018, Accepted Manuscript
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    New tetrahydroisoquinoline based P-glycoprotein modulators: decoration of the biphenyl core gives selective ligands.

    M. Contino, S. guglielmo, M. G. Perrone, R. Giampietro , B. Rolando, A. Carrieri, D. zaccaria, K. Chegaev, V. Borio, C. Riganti, K. A. Zabielska-Koczywąs, A. N. Colabufo and R. Fruttero, Med. Chem. Commun., 2018, Accepted Manuscript , DOI: 10.1039/C8MD00075A

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