Arene Osmium Complexes with Ethacrynic Acid-Modified Ligands: Synthesis, Characterization, and Evaluation of Intracellular Glutathione S-Transferase Inhibition and Antiproliferative Activity

Abstract

Four arene osmium complexes were prepared containing derivatives of ethacrynic acid, a potent inhibitor of glutathione S-transferases, either by direct coordination or via N- or P-donor ligands. The complexes were characterized by spectroscopic and analytical methods and, for Os(η6-p-cymene)(acetylacetonato)(2-(2,3-dichloro-4-(2-ethylenebutanoyl)phenoxy)acetato) and Os(η6-p-cymene)Cl2(2-(2-(2,3-dichloro-4-(2-methylenebutanoyl)phenoxy)acetoxy)ethyl nicotinato), by single-crystal X-ray diffraction. The cytotoxicity of the complexes toward human ovarian cancer cells and nontumorous human embryonic kidney cells was investigated, and two of the complexes, for which ruthenium analogues are known, helped to delineate the influence of the metal ion. Inhibition studies of intracellular glutathione S-transferases (GSTs, detoxification enzymes implicated in drug resistance) indicate that the observed cytotoxicity of the complexes involves GST inhibition, as well as other targets following dissociation of the ethacry...