Issue 5, 2015

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

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)

Supplementary files

Article information

Article type
Concise Article
Submitted
07 Nov 2014
Accepted
14 Jan 2015
First published
27 Feb 2015

Med. Chem. Commun., 2015,6, 860-866

Author version available

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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