title: 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.
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.
authors.affiliation: School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong 250012, PR China.
authors.forename: Xinmei
authors.initials: X
authors.lastname: Yang
authors.forename: Guyue
authors.initials: G
authors.lastname: Liu
authors.forename: Hongcai
authors.initials: H
authors.lastname: Li
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhang
authors.forename: Dandan
authors.initials: D
authors.lastname: Song
authors.forename: Chunmin
authors.initials: C
authors.lastname: Li
authors.forename: Rui
authors.initials: R
authors.lastname: Wang
authors.forename: Bo
authors.initials: B
authors.lastname: Liu
authors.forename: Wen
authors.initials: W
authors.lastname: Liang
authors.forename: Yongkui
authors.initials: Y
authors.lastname: Jing
authors.forename: Guisen
authors.initials: G
authors.lastname: Zhao
mesh_terms: 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
chemical_list: D000970:Antineoplastic Agents; D010069:Oxadiazoles; D051549:Glutathione S-Transferase pi; D004976:Ethacrynic Acid