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

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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 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 of restoring doxorubicin toxicity in resistant cancer cells.

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

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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, Advance Article
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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. Zabielska-Koczywąs, N. A. Colabufo and R. Fruttero, Med. Chem. Commun., 2018, Advance Article , DOI: 10.1039/C8MD00075A

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