Mignani Serge, El Brahmi Nabil, El Kazzouli Saïd, Eloy Laure, Courilleau Delphine, Caron Joachim, Bousmina Mosto M, Caminade Anne-Marie, Cresteil Thierry, Majoral Jean-Pierre
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.
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.
Eur J Med Chem. 2016 Oct 21;122:656-673. doi: 10.1016/j.ejmech.2016.05.063. Epub 2016 Jun 11.
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.
著名的利尿剂依他尼酸（EA，利尿酸）显示出较低的抗增殖活性，已在不同位置进行了化学修饰。新的EA衍生物已在体外针对肿瘤KB（表皮癌）和白血病HL60（早幼粒细胞）细胞进行了抗增殖试验，这两种细胞是抗癌活性的合适靶点。EA的α-β双键还原完全消除了抗癌活性，而引入2-（4-取代苯基）乙胺（A系列）或4-（4-取代苯基）哌嗪（B系列）部分则产生了对人癌细胞系显示出中度至强抗增殖活性的化合物。这两个部分的苯基上的几种取代是可以接受的。本研究中制备的EA衍生物的作用机制比将谷胱甘肽S-转移酶π的抑制归因于EA的独特作用更为复杂，可能有助于克服肿瘤耐药性。
