title: In Vitro Inhibition of Human Placental Glutathione S-Transferase by 3-Arylcoumarin Derivatives.
abstract: Glutathione S-transferases (EC: 2.5.1.18, GSTs) are phase II detoxification enzymes that catalyze the conjugation of various electrophilic compounds to glutathione (GSH), thus usually producing less reactive and more water soluble compounds. However, there is evidence that elevated expression of GSTs, especially GSTP1, is involved in the resistance of tumor cells against chemotherapeutic agents. In this study, we synthesized and investigated the inhibitory effects of differently substituted 3-arylcoumarin derivatives on human placental GST, identified as GSTP1-1, using 1-chloro-2,4-dinitrobenzene as a substrate. A known potent inhibitor of GST, ethacrynic acid was used as a positive control. Among the tested compounds, 6,7-dihydroxy substituted coumarin derivatives exhibited the highest inhibitory activity (IC50 = 13.50-20.83 μM). These results suggest that 6,7-dihydroxy-3-arylcoumarins may represent a new promising scaffold to discover potent GST inhibitors.
authors.affiliation: Department of Medicinal Biochemistry, Faculty of Medicine, Çukurova University, Adana, Turkey.
authors.forename: Mustafa Muhlis
authors.initials: MM
authors.lastname: Alparslan
authors.affiliation: Department of Chemistry, Faculty of Arts and Sciences, Marmara University, Istanbul, Turkey.
authors.forename: Özkan
authors.initials: Ö
authors.lastname: Danış
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D003374:Coumarins / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D004137:Dinitrochlorobenzene / Q000378:metabolism; D015195:Drug Design; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D004976:Ethacrynic Acid / Q000494:pharmacology; D005260:Female; D051549:Glutathione S-Transferase pi / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D015394:Molecular Structure; D010920:Placenta / Q000187:drug effects* / Q000201:enzymology; D011247:Pregnancy; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D003374:Coumarins; D004137:Dinitrochlorobenzene; D004791:Enzyme Inhibitors; C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi; D004976:Ethacrynic Acid
keywords: Arylcoumarin; GSTP1-1; Glutathione S-transferase; Multidrug resistance