title: A novel class of ethacrynic acid derivatives as promising drug-like potent generation of anticancer agents with established mechanism of action.
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.
authors.affiliation: 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.
authors.forename: Serge
authors.initials: S
authors.lastname: Mignani
authors.affiliation: 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.
authors.forename: Nabil
authors.initials: N
authors.lastname: El Brahmi
authors.affiliation: 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.
authors.forename: Saïd
authors.initials: S
authors.lastname: El Kazzouli
authors.affiliation: Institut de Chimie des Substances Naturelles, CNRS UPR2301, Avenue de la terrasse, 91190, Gif sur Yvette, France.
authors.forename: Laure
authors.initials: L
authors.lastname: Eloy
authors.affiliation: IPSIT Faculté de Pharmacie, Université Paris Sud, 92290, Chatenay-Malabry, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Courilleau
authors.affiliation: 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.
authors.forename: Joachim
authors.initials: J
authors.lastname: Caron
authors.affiliation: Euromed Research Institute, Engineering Division, Euro-Mediterranean University of Fes, Fès-Shore, Route de Sidi Hrazem, 30070, Fès, Morocco.
authors.forename: Mosto M
authors.initials: MM
authors.lastname: Bousmina
authors.affiliation: 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.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Caminade
authors.affiliation: 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.
authors.forename: Thierry
authors.initials: T
authors.lastname: Cresteil
authors.affiliation: 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.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Majoral
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D004789:Enzyme Activation / Q000187:drug effects; D004976:Ethacrynic Acid / Q000737:chemistry* / Q000494:pharmacology*; D051549:Glutathione S-Transferase pi / Q000037:antagonists & inhibitors; D018922:HL-60 Cells; D006801:Humans; D007624:KB Cells
chemical_list: D000970:Antineoplastic Agents; D051549:Glutathione S-Transferase pi; D053148:Caspase 3; D053179:Caspase 7; D004976:Ethacrynic Acid
keywords: Anticancer agents; Ethacrynic acid; Ethacrynic acid derivatives; Glutathione S-Transferase π