2. Academic Validation
  3. A novel class of ethacrynic acid derivatives as promising drug-like potent generation of anticancer agents with established mechanism of action

A novel class of ethacrynic acid derivatives as promising drug-like potent generation of anticancer agents with established mechanism of action

  • Eur J Med Chem. 2016 Oct 21:122:656-673. doi: 10.1016/j.ejmech.2016.05.063.
Serge Mignani 1,  Nabil El Brahmi 2,  Saïd El Kazzouli 3,  Laure Eloy 4,  Delphine Courilleau 5,  Joachim Caron 2,  Mosto M Bousmina 6,  Anne-Marie Caminade 7,  Thierry Cresteil 8,  Jean-Pierre Majoral 9
Affiliations

Affiliations

  • 1 Laboratoire de Chimie et de Biochimie pharmacologiques et toxicologique, CNRS UMR 860, Université Paris Descartes, PRES Sorbonne Paris Cité, 45, rue des Saints Pères, 75006, Paris, France. Electronic address: serge.mignani@parisdescartes.fr.
  • 2 Euromed Research Institute, Engineering Division, Euro-Mediterranean University of Fes, Fès-Shore, Route de Sidi Hrazem, 30070, Fès, Morocco; Laboratoire de Chimie de Coordination CNRS, 205 route de Narbonne, BP 44099, 31077, Toulouse Cedex 4, France; Université de Toulouse, UPS, INPT, F-31077, Toulouse Cedex4, France.
  • 3 Euromed Research Institute, Engineering Division, Euro-Mediterranean University of Fes, Fès-Shore, Route de Sidi Hrazem, 30070, Fès, Morocco. Electronic address: s.elkazzouli@ueuromed.org.
  • 4 Institut de Chimie des Substances Naturelles, CNRS UPR2301, Avenue de la terrasse, 91190, Gif sur Yvette, France.
  • 5 IPSIT Faculté de Pharmacie, Université Paris Sud, 92290, Chatenay-Malabry, France.
  • 6 Euromed Research Institute, Engineering Division, Euro-Mediterranean University of Fes, Fès-Shore, Route de Sidi Hrazem, 30070, Fès, Morocco.
  • 7 Laboratoire de Chimie de Coordination CNRS, 205 route de Narbonne, BP 44099, 31077, Toulouse Cedex 4, France; Université de Toulouse, UPS, INPT, F-31077, Toulouse Cedex4, France.
  • 8 Institut de Chimie des Substances Naturelles, CNRS UPR2301, Avenue de la terrasse, 91190, Gif sur Yvette, France; IPSIT Faculté de Pharmacie, Université Paris Sud, 92290, Chatenay-Malabry, France. Electronic address: thierry.cresteil@u-psud.fr.
  • 9 Laboratoire de Chimie de Coordination CNRS, 205 route de Narbonne, BP 44099, 31077, Toulouse Cedex 4, France; Université de Toulouse, UPS, INPT, F-31077, Toulouse Cedex4, France. Electronic address: jean-pierre.majoral@lcc-toulouse.fr.
PMID: 27448922 DOI: 10.1016/j.ejmech.2016.05.063
Abstract

The well-known diuretic Ethacrynic acid (EA, Edecrin), showing low anti-proliferative activities, was chemically modified at different positions. The new EA derivatives have been tested in vitro in anti-proliferative assays on both tumor KB (epidermal carcinoma) and leukemia HL60 (promyelocytic) cells suitable targets for Anticancer activity. Reduction of the α-β double bond of EA completely abolished anti-cancer activities, whereas introduction of either 2-(4-substituted phenyl)ethanamine (series A) or 4-(4-substituted phenyl)piperazine (series B) moieties generated compounds showing moderate to strong anti-proliferative activities against human Cancer cell lines. Several substitutions on the phenyl of these two moieties are tolerated. The mechanism of action of the EA derivatives prepared in this study is more complex than the inhibition of Glutathione S-transferase π ascribed as unique effect to EA and might help to overcome tumor resistances.

Keywords

Anticancer agents; Ethacrynic acid; Ethacrynic acid derivatives; Glutathione S-Transferase π.

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