title: Designer xanthone: an inhibitor scaffold for MDR-involved human glutathione transferase isoenzyme A1-1.
abstract: Glutathione transferases (GSTs) are cell detoxifiers involved in multiple drug resistance (MDR), hampering the effectiveness of certain anticancer drugs. To our knowledge, this is the first report on well-defined synthetic xanthones as GST inhibitors. Screening 18 xanthones revealed three derivatives bearing a bromomethyl and a methyl group (7) or two bromomethyl groups (8) or an aldehyde group (17), with high inhibition potency (>85%), manifested by low IC(50) values (7: 1.59 ± 0.25 µM, 8: 5.30 ± 0.30 µM, and 17: 8.56 ± 0.14 µM) and a competitive modality of inhibition versus CDNB (Ki(7) = 0.76 ± 0.18 and Ki(17) = 1.69 ± 0.08 µM). Of them, derivative 17 readily inhibited hGSTA1-1 in colon cancer cell lysate (IC(50) = 10.54 ± 2.41 µM). Furthermore, all three derivatives were cytotoxic to Caco-2 intact cells, with 17 being the least cytotoxic (LC(50) = 151.3 ± 16.3 µM). The xanthone scaffold may be regarded as a pharmacophore for hGSTA1-1 and the three derivatives, especially 17, as potent precursors for the synthesis of new inhibitors and conjugate prodrugs for human GSTs.
authors.affiliation: 1Laboratory of Enzyme Technology, Department of Biotechnology, Agricultural University of Athens, Athens, Greece.
authors.forename: Ourania G
authors.initials: OG
authors.lastname: Zoi
authors.forename: Trias N
authors.initials: TN
authors.lastname: Thireou
authors.forename: Vagelis E
authors.initials: VE
authors.lastname: Rinotas
authors.forename: Petros G
authors.initials: PG
authors.lastname: Tsoungas
authors.forename: Elias E
authors.initials: EE
authors.lastname: Eliopoulos
authors.forename: Eleni K
authors.initials: EK
authors.lastname: Douni
authors.forename: Nikolaos E
authors.initials: NE
authors.lastname: Labrou
authors.forename: Yannis D
authors.initials: YD
authors.lastname: Clonis
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001667:Binding, Competitive; D018938:Caco-2 Cells; D002470:Cell Survival / Q000187:drug effects; D003979:Diazonium Compounds / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D057075:Enzyme Assays; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D062105:Molecular Docking Simulation; D011994:Recombinant Proteins / Q000378:metabolism; D013329:Structure-Activity Relationship; D044004:Xanthones / Q000138:chemical synthesis / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D003979:Diazonium Compounds; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D011994:Recombinant Proteins; D044004:Xanthones; C484555:GSTA1 protein, human; D005982:Glutathione Transferase
keywords: enzyme inhibition; glutathione transferase; multiple drug resistance; xanthone analogue