A series of ethacrynic acid (2-[2,3-dichloro-4-(2-methylidenebutanoyl)phenoxy]acetic acid) (EA, Edecrin) containing sulfonamides linked via three types of linkers namely 1,2-ethylenediamine, piperazine and 4-aminopiperidine was synthesized and subsequently evaluated in vitro against HL60 and HCT116 cancer cell lines. All the EA analogs, excluding 6a and 6c, showed anti-proliferative activity with IC_50s in the micromolar range (less than 4 uM). Three derivatives 6b, 7b and 7e were selected for their interesting dual activity on HL60 cell line in order to be further evaluated against a panel of cancer cell lines (HCT116, A549, MCF7, PC3, U87-MG and SKOV3) as well as on MRC5 as a normal cell line. These compounds displayed IC₅₀ values in nanomolar range against A549, MCF7, PC3 and HCT116 cell lines, deducing the discovery that piperazine or 4-aminopiperidine is the linker's best choice to develop EA analogs with highly potent anti-proliferative activities own up to 24 nM. Besides, in terms of selectivity, those linkers are more suitable offering safety ratios of up to 63.8.

2016-10-01·European journal of medicinal chemistry1区 · 医学

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

1区 · 医学

Article

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

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.

2016-06-01·Bioorganic & medicinal chemistry letters4区 · 医学

Potent anti-proliferative actions of a non-diuretic glucosamine derivative of ethacrynic acid

4区 · 医学

Article

作者: Mostofa, A G M ; Madala, Hanumantha Rao ; Basak, Debasish ; Punganuru, Surendra R ; Srivenugopal, Kalkunte S

Ethacrynic acid (EA), a known inhibitor of the neoplastic marker glutathione S-transferase P1 and other GSTs, exerts a weak antiproliferative activity against human cancer cells. The clinical use of EA (Edecrin) as an anticancer drug is limited by its potent loop diuretic activity. In this study, we developed a non-diuretic 2-amino-2-deoxy-d-glucose conjugated EA (EAG) to target tumors cells via the highly expressed glucose transporter 1 (GLUT1). Cell survival assays revealed that EAG had little effect on normal cells, but was cytotoxic 3 to 4.5-fold greater than EA. Mechanistically, the EAG induced selective cell death in cancer cells by inhibiting GSTP1 and generating abundant reactive oxygen species. Furthermore, EAG induced p21(cip1) expression and a G2/M cell cycle block irrespective of the p53 gene status in tumor cells. These data encourage the development of new EA analogs.

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KEGG	Wiki	ATC	Drug Bank
D04079	利尿酸钠	C03CC01	DBSALT001225

研发状态

10 条最早获批的记录,

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适应症	国家/地区	公司	日期
腹水	美国	Bausch Health Americas, Inc.	1967-01-10
水肿	美国	Bausch Health Americas, Inc.	1967-01-10
先天性心脏缺损	美国	Bausch Health Americas, Inc.	1967-01-10
肾病综合征	美国	Bausch Health Americas, Inc.	1967-01-10