Organometallic Glutathione S-Transferase Inhibitors

Abstract

A new family of organometallic p-cymene ruthenium(II) and osmium(II) complexes conjugated to ethacrynic acid, a glutathione transferase (GST) inhibitor, is reported. The ethacrynic acid moiety (either one or two) is tethered to the arene ruthenium(II) and osmium(II) fragments via strongly coordinating modified bipyridine ligands. The solid-state structure of one of the complexes, i.e. [Os(η 6 -p-cymene)Cl][(4′-methyl-[2,2′-bipyridin]-4-yl)methyl-2-(2,3-dichloro-4-(2-methylenebutanoyl)phenoxy)acetate]Cl, was established by single-crystal X-ray diffraction, corroborating the expected structure. The complexes are efficient inhibitors of GST P1-1, an enzyme expressed in cancer cells and implicated in drug resistance, and are cytotoxic to the GST-overexpressing chemoresistant A2780cisR ovarian cancer cell line.

Organoruthenium Prodrugs as a New Class of Cholinesterase and Glutathione‐S‐Transferase Inhibitors

“…RAPTAs have been evaluated against many peptide and protein targets, which have included glutathione, lysozyme, ubiquitin, cytochrome c, superoxide dismutase, the human serum proteins albumin and transferrin, poly(adenosine diphosphate‐ribose)polymerases, and metallothioneins . Very recently, a series of RAPTA derivatives and osmium RAPTA analogues were designed as inhibitors of human GST . These had the structural fragment of ethacrynic acid, a known potent GST inhibitor conjugated to the metal species either covalently through the arene ring, or by coordination through imidazole, triphenylphosphine or bipyridine linkers.…”

“…[36] Very recently, a series of RAPTA derivatives and osmium RAPTA analogues were designed as inhibitors of human GST. [37] These had the structural fragment of ethacrynic acid, a known potent GST inhibitor conjugated to the metal species either covalently through the arene ring, or by coordination through imidazole, triphenylphosphine or bipyridine linkers.…”

Bis‐conjugation of Bioactive Molecules to Cisplatin‐like Complexes through (2,2′‐Bipyridine)‐4,4′‐Dicarboxylic Acid with Optimal Cytotoxicity Profile Provided by the Combination Ethacrynic Acid/Flurbiprofen

“…The enzymatic activity of GST P1 (20 n m ) was spectrophotometrically assayed at 340 nm at 37 °C by measuring the CDNB–GSH (1‐chloro‐2,4‐dinitrobenzene‐glutathione) conjugation rate as a function of time, by using a protocol reported earlier [14a] . The assay mixture contained 1 m m CDNB (1‐chloro‐2,4‐dinitrobenzene) and 2 m m GSH (glutathione) of 0.1 m of potassium phosphate buffer (pH 6.5).…”

“…[13] In an umber of cases, the conjugationo ft hese organic compounds to varioust ransition metal speciesh as been shown to enhancet he anticancer behavior of the resulting complexes. [14][15][16] Results and Discussion…”

“…Herein, we describe the straightforward synthesis of new Pt II compounds containing a series of bipyridine ligands doubly modified with bioactive species, including unusual examples of heterofunctionalization (triple‐action compounds). Various substituted bipyridine ligands have been employed as robust scaffolds for the conjugation of bioactive molecules to other metal complexes [14a, 10] . In our case, we selected the commercially available 2,2′‐bipyridine‐4,4′‐dicarboxylic acid as a suitable platform for functionalization through sequential Steglich esterification reactions.…”