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.
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.
Yang
Xinmei
X
School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong 250012, PR China.
Liu
Guyue
G
Li
Hongcai
H
Zhang
Yun
Y
Song
Dandan
D
Li
Chunmin
C
Wang
Rui
R
Liu
Bo
B
Liang
Wen
W
Jing
Yongkui
Y
Zhao
Guisen
G
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects*; D004976:Ethacrynic Acid / Q000737:chemistry*; D051549:Glutathione S-Transferase pi / Q000037:antagonists & inhibitors*; D006801:Humans; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D010069:Oxadiazoles / Q000737:chemistry*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D010069:Oxadiazoles; D051549:Glutathione S-Transferase pi; D004976:Ethacrynic Acid