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Open AccessArticle

Synthesis and Anticancer Cytotoxicity of Azaaurones Overcoming Multidrug Resistance

Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, 1117 Budapest, Hungary
Département de Pharmacochimie Moléculaire (DPM), UMR 5063, Univ. Grenoble Alpes, 38041 Grenoble, France
Creative Cell Ltd., 1119 Budapest, Hungary
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
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; (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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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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