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

作者：Mignani Serge^*; El Brahmi Nabil; El Kazzouli Said^*; Eloy Laure; Courilleau Delphine; Caron Joachim; Bousmina Mosto M; Caminade Anne Marie; Cresteil Thierry^*; Majoral Jean Pierre^*

来源：European Journal of Medicinal Chemistry, 2016, 122: 656-673.

DOI：10.1016/j.ejmech.2016.05.063

• Anticancer agents
• Ethacrynic acid
• Ethacrynic acid derivatives
• Glutathione S-Transferase pi

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 alpha-beta double bond of EA completely abolished anticancer 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 pi ascribed as unique effect to EA and might help to overcome tumor resistances.

• 出版日期2016-10-21