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.

A Ruthenium-Containing Organometallic Compound Reduces Tumor Growth through Induction of the Endoplasmic Reticulum Stress GeneCHOP

“…Activation of p53 or p73 by some of these drugs partly corroborated this hypothesis (23)(24)(25). Alternative modes of action have also been described, including production of reactive oxygen species (26), inhibition of kinases (27), modification of enzymatic activities (28), or redox reactions (29). Obviously, the variety of these effects might be linked to the structural diversity of the ruthenium complexes.…”

Diuretic drug binding to human glutathione transferase P1‐1: potential role of Cys‐101 revealed in the double mutant C47S/Y108V

“…Among the four cysteine residues per subunit of GST P1-1, the Cys-47 and Cys-101 have shown to be the most reactive toward electrophilic compounds (Ricci et al, 1991;Lo Bello et al, 1995, 2001Ang et al, 2007) whereas the remaining two cysteine residues are buried in the core of the molecule (Reinemer et al, 1992). Modification of the two most reactive cysteine residues interferes with the catalytic activity of GST P1-1 (Lo Bello et al, 1990;Tamai et al, 1990Tamai et al, , 1991Nishihira et al, 1992;Caccuri et al, 1992;Van Iersel et al, 1997;Hegazy et al, 2008).…”

New Dinuclear Ru2(CO)4 Sawhorse‐Type Complexes Containing Bridging Carboxylato Ligands

“…Ethacrynic acid and chlorambucil are two biologi- cally active acids, ethacrynic acid is a Glutathione S-Transferase inhibitor (an enzyme involved in the process of detoxification of the cell) [14], while chlorambucil is an alkylating agent inducing death cell by apoptosis [15]. According to the X-ray analysis structures of complexes 2 and 3, the coordination of ethacrynic acid and chlorambucil do not induce any changes in their structure.…”