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Open AccessArticle

Synthesis and Anticancer Cytotoxicity of Azaaurones Overcoming Multidrug Resistance

1
Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, 1117 Budapest, Hungary
2
Département de Pharmacochimie Moléculaire (DPM), UMR 5063, Univ. Grenoble Alpes, 38041 Grenoble, France
3
Creative Cell Ltd., 1119 Budapest, Hungary
4
Drug Resistance & Membrane Proteins group, Molecular Microbiology and Structural Biochemistry Laboratory (CNRS UMR 5086), University of Lyon, IBCP, 7 Passage du Vercors, 69367 Lyon, France
5
Institute of Cancer Research, Medical University of Vienna, Borschkegasse 8A, A-1090 Vienna, Austria
*
Author to whom correspondence should be addressed.
These senior investigators contributed equally.
Molecules 2020, 25(3), 764; https://doi.org/10.3390/molecules25030764 (registering DOI)
Received: 16 December 2019 / Revised: 6 February 2020 / Accepted: 8 February 2020 / Published: 10 February 2020
The resistance of tumors against anticancer drugs is a major impediment for chemotherapy. Tumors often develop multidrug resistance as a result of the cellular efflux of chemotherapeutic agents by ABC transporters such as P-glycoprotein (ABCB1/P-gp), Multidrug Resistance Protein 1 (ABCC1/MRP1), or Breast Cancer Resistance Protein (ABCG2/BCRP). By screening a chemolibrary comprising 140 compounds, we identified a set of naturally occurring aurones inducing higher cytotoxicity against P-gp-overexpressing multidrug-resistant (MDR) cells versus sensitive (parental, non-P-gp-overexpressing) cells. Follow-up studies conducted with the P-gp inhibitor tariquidar indicated that the MDR-selective toxicity of azaaurones is not mediated by P-gp. Azaaurone analogs possessing pronounced effects were then designed and synthesized. The knowledge gained from structure–activity relationships will pave the way for the design of a new class of anticancer drugs selectively targeting multidrug-resistant cancer cells. View Full-Text
Keywords: aurone; azaaurone; multidrug resistance; P-gp; overexpression; anticancer; cytotoxicity aurone; azaaurone; multidrug resistance; P-gp; overexpression; anticancer; cytotoxicity
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MDPI and ACS Style

Tóth, S.; Szepesi, Á.; Tran-Nguyen, V.-K.; Sarkadi, B.; Német, K.; Falson, P.; Di Pietro, A.; Szakács, G.; Boumendjel, A. Synthesis and Anticancer Cytotoxicity of Azaaurones Overcoming Multidrug Resistance. Molecules 2020, 25, 764.

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