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

Sören Krawczyk, Christiane Baumert, J. Molnár, Christoph Ritter, Jens Höpner, Charlotte Kloft, Andreas Hilgeroth

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)860-866
Number of pages7
JournalMedChemComm
Volume6
Issue number5
DOIs
Publication statusPublished - May 1 2015

Fingerprint

P-Glycoprotein
Structure-Activity Relationship
Drug Resistance
Modulators
Hydrogen
Pumps
Cell Line
Substrates
Scaffolds
Toxicity
Hydrogen bonds
Cells
Pharmaceutical Preparations
1,4-dihydropyridine
In Vitro Techniques

ASJC Scopus subject areas

  • Biochemistry
  • Pharmaceutical Science

Cite this

Krawczyk, S., Baumert, C., Molnár, J., Ritter, C., Höpner, J., Kloft, C., & Hilgeroth, A. (2015). Novel non-substrate modulators of the transmembrane efflux pump P-glycoprotein (ABCB1). MedChemComm, 6(5), 860-866. https://doi.org/10.1039/c4md00506f

Novel non-substrate modulators of the transmembrane efflux pump P-glycoprotein (ABCB1). / Krawczyk, Sören; Baumert, Christiane; Molnár, J.; Ritter, Christoph; Höpner, Jens; Kloft, Charlotte; Hilgeroth, Andreas.

In: MedChemComm, Vol. 6, No. 5, 01.05.2015, p. 860-866.

Research output: Contribution to journalArticle

Krawczyk, S, Baumert, C, Molnár, J, Ritter, C, Höpner, J, Kloft, C & Hilgeroth, A 2015, 'Novel non-substrate modulators of the transmembrane efflux pump P-glycoprotein (ABCB1)', MedChemComm, vol. 6, no. 5, pp. 860-866. https://doi.org/10.1039/c4md00506f
Krawczyk, Sören ; Baumert, Christiane ; Molnár, J. ; Ritter, Christoph ; Höpner, Jens ; Kloft, Charlotte ; Hilgeroth, Andreas. / Novel non-substrate modulators of the transmembrane efflux pump P-glycoprotein (ABCB1). In: MedChemComm. 2015 ; Vol. 6, No. 5. pp. 860-866.
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