title: Organometallic ruthenium inhibitors of glutathione-S-transferase P1-1 as anticancer drugs.
abstract: Ruthenium-arene complexes conjugated to ethacrynic acid were prepared as part of a strategy to develop novel glutathione-S-transferase (GST) inhibitors with alternate modes of activity through the organometallic fragment, ultimately to provide targeted ruthenium-based anticancer drugs. Enzyme kinetics and electrospray mass spectrometry experiments using GST P1-1 and its cysteine-modified mutant forms revealed that the complexes are effective enzyme inhibitors, but they also rapidly inactivate the enzyme by covalent binding at Cys 47 and, to a lesser extent, Cys 101. They are highly effective against the GST Pi-positive A2780 and A2780cisR ovarian carcinoma cell lines, are among the most effective ruthenium complexes reported so far, and target ubiquitous GST Pi overexpressed in many cancers.
authors.affiliation: Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland. weehan.ang@epfl.ch
authors.forename: Wee Han
authors.initials: WH
authors.lastname: Ang
authors.forename: Anastasia
authors.initials: A
authors.lastname: De Luca
authors.forename: Catherine
authors.initials: C
authors.lastname: Chapuis-Bernasconi
authors.forename: Lucienne
authors.initials: L
authors.lastname: Juillerat-Jeanneret
authors.forename: Mario
authors.initials: M
authors.lastname: Lo Bello
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Dyson
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors*; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D009942:Organometallic Compounds / Q000737:chemistry / Q000494:pharmacology*; D017975:Ruthenium Compounds / Q000737:chemistry / Q000494:pharmacology*; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D009942:Organometallic Compounds; D017975:Ruthenium Compounds; D005982:Glutathione Transferase