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Communication

Discovery of Novel Symmetrical 1,4-Dihydropyridines as Inhibitors of Multidrug-Resistant Protein (MRP4) Efflux Pump for Anticancer Therapy

1
Research Group of Drug Development, Institute of Pharmacy, Martin Luther University Halle-Wittenberg, 06120 Halle, Germany
2
Department of Clinical Pharmacy, Institute of Pharmacy, Ernst Moritz Arndt University Greifswald, 17489 Greifswald, Germany
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Academic Editor: Qiao-Hong Chen
Molecules 2021, 26(1), 18; https://doi.org/10.3390/molecules26010018
Received: 8 October 2020 / Revised: 11 December 2020 / Accepted: 17 December 2020 / Published: 22 December 2020
(This article belongs to the Special Issue Anticancer Agents: Design, Synthesis and Evaluation II)
Despite the development of targeted therapies in cancer, the problem of multidrug resistance (MDR) is still unsolved. Most patients with metastatic cancer die from MDR. Transmembrane efflux pumps as the main cause of MDR have been addressed by developed inhibitors, but early inhibitors of the most prominent and longest known efflux pump P-glycoprotein (P-gp) were disappointing. Those inhibitors have been used without knowledge about the expression of P-gp by the treated tumor. Therefore the use of inhibitors of transmembrane efflux pumps in clinical settings is reconsidered as a promising strategy in the case of the respective efflux pump expression. We discovered novel symmetric inhibitors of the symmetric efflux pump MRP4 encoded by the ABCC4 gene. MRP4 is involved in many kinds of cancer with resistance to anticancer drugs. All compounds showed better activities than the best known MRP4 inhibitor MK571 in an MRP4-overexpressing cell line assay, and the activities could be related to the various substitution patterns of aromatic residues within the symmetric molecular framework. One of the best compounds was demonstrated to overcome the MRP4-mediated resistance in the cell line model to restore the anticancer drug sensitivity as a proof of concept. View Full-Text
Keywords: anticancer drug; drug resistance; structure activity; inhibition; substituent anticancer drug; drug resistance; structure activity; inhibition; substituent
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MDPI and ACS Style

Döring, H.; Kreutzer, D.; Ritter, C.; Hilgeroth, A. Discovery of Novel Symmetrical 1,4-Dihydropyridines as Inhibitors of Multidrug-Resistant Protein (MRP4) Efflux Pump for Anticancer Therapy. Molecules 2021, 26, 18. https://doi.org/10.3390/molecules26010018

AMA Style

Döring H, Kreutzer D, Ritter C, Hilgeroth A. Discovery of Novel Symmetrical 1,4-Dihydropyridines as Inhibitors of Multidrug-Resistant Protein (MRP4) Efflux Pump for Anticancer Therapy. Molecules. 2021; 26(1):18. https://doi.org/10.3390/molecules26010018

Chicago/Turabian Style

Döring, Henry, David Kreutzer, Christoph Ritter, and Andreas Hilgeroth. 2021. "Discovery of Novel Symmetrical 1,4-Dihydropyridines as Inhibitors of Multidrug-Resistant Protein (MRP4) Efflux Pump for Anticancer Therapy" Molecules 26, no. 1: 18. https://doi.org/10.3390/molecules26010018

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