Novel oxadiazole analogues derived from ethacrynic acid: design, synthesis, and structure-activity relationships in inhibiting the activity of glutathione S-transferase P1-1 and cancer cell proliferation.

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Yang X, Liu G, Li H, Zhang Y, Song D, Li C, Wang R, Liu B, Liang W, Jing Y, Zhao G

J Med Chem. 2010 Feb 11;53(3):1015-22. doi: 10.1021/jm9011565.

PubMed ID

20055416 [ View in PubMed

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Abstract

Ethacrynic acid (EA) is a glutathione S-transferase P1-1 (GST P1-1) inhibitor with weak antiproliferative ability in tumor cells. By use of the principle of bioisosterism, a series of novel EA oxadiazole analogues were designed and synthesized. The structure-activity relationships of inhibiting GST P1-1 activity and cell proliferation of those EA analogues were investigated in human leukemia HL-60 cells. Our data revealed that those EA oxadiazole analogues had improved antiproliferative activity and most of them had similar or better inhibitory effects on GST P1-1 activity than EA. Compound 6u was one of the potent antiproliferative agents without inhibition of GST P1-1 activity. Compounds 6r and 6s were two potent cell growth inhibitors in several solid tumor cell lines with the concentrations inhibiting half of cell growth of less than 5 microM. Our data suggest that these EA oxadiazole analogues are promising antitumor agents that may act through GST P1-1 inhibition-dependent and/or -independent pathways.

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Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Etacrynic acid	Glutathione S-transferase P	IC 50 (nM)	3400	N/A	N/A	Details