Designer xanthone: an inhibitor scaffold for MDR-involved human glutathione transferase isoenzyme A1-1

• Published in: Journal of biomolecular screening Vol. 18; no. 9; p. 1092
• Main Authors: Zoi, Ourania G, Thireou, Trias N, Rinotas, Vagelis E, Tsoungas, Petros G, Eliopoulos, Elias E, Douni, Eleni K, Labrou, Nikolaos E, Clonis, Yannis D
• Format: Journal Article
• Language: English
• Published: United States 01-10-2013
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacology; Binding, Competitive; Caco-2 Cells; Cell Survival - drug effects; Diazonium Compounds - pharmacology; Dose-Response Relationship, Drug; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Enzyme Assays; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - pharmacology; Glutathione Transferase - antagonists & inhibitors; Glutathione Transferase - metabolism; Humans; Isoenzymes - antagonists & inhibitors; Isoenzymes - metabolism; Molecular Docking Simulation; Recombinant Proteins - metabolism; Structure-Activity Relationship; Xanthones - chemical synthesis; Xanthones - pharmacology; glutathione transferase; multiple drug resistance; enzyme inhibition; xanthone analogue
• ISSN: 1552-454X
• DOI: 10.1177/1087057113492335

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.