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Issue 5, 2015
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Novel non-substrate modulators of the transmembrane efflux pump P-glycoprotein (ABCB1)

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Abstract

Novel N- and 4-substituted 1,4-dihydropyridines with a C2-symmetric molecular scaffold have been profiled as highly active modulators of the transmembrane efflux pump P-glycoprotein (P-gp, ABCB1) in an exclusively P-gp overexpressing cell line model. Structure–activity relationships have been discussed for varied substituents of both the N- and the 4-residue. The influence of potential hydrogen bond acceptor functions has been characterized in relation to the number and position of the substituents. Cellular toxicity has been closely considered and the P-gp substrate properties are suggested as the limiting molecular properties of known P-gp modulators. The non-toxicity and non-substrate properties of our novel inhibitors qualify this novel compound class as a prospective tool to effectively combat the efflux pump-mediated cellular resistance of anticancer drug substrates, as could be demonstrated in the first in vitro studies.

Graphical abstract: Novel non-substrate modulators of the transmembrane efflux pump P-glycoprotein (ABCB1)

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Publication details

The article was received on 07 Nov 2014, accepted on 14 Jan 2015 and first published on 27 Feb 2015


Article type: Concise Article
DOI: 10.1039/C4MD00506F
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Citation: Med. Chem. Commun., 2015,6, 860-866
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    Novel non-substrate modulators of the transmembrane efflux pump P-glycoprotein (ABCB1)

    S. Krawczyk, C. Baumert, J. Molnár, C. Ritter, J. Höpner, C. Kloft and A. Hilgeroth, Med. Chem. Commun., 2015, 6, 860
    DOI: 10.1039/C4MD00506F

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