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

Abstract

A small library of 17 organoruthenium compounds with the general formula [Ru^II (fcl)(chel)(L)]ⁿ⁺ (in which fcl=face capping ligand, chel=chelating bidentate ligand, and L=monodentate ligand) were screened for inhibitory activity against cholinesterases and glutathione-S-transferases of human and animal origins. Compounds were selected to include different chelating ligands (i.e., N,N-, N,O-, O,O-, S,O-) and monodentate ligands that can modulate the aquation rate of the metal species. Compounds with a labile ruthenium chloride bond that provided rapid aquation were found to inhibit both sets of enzymes in reversible competitive modes and at pharmaceutically relevant concentrations. When applied at concentrations that completely abolish the activity of human acetylcholinesterase, the lead compound [(η⁶ -p-cymene)Ru(pyrithionato)Cl] (C1 a) showed no undesirable physiological responses on the neuromuscular system. Finally, C1 a was not cytotoxic against non-transformed cells at pharmaceutically relevant concentrations.

Keywords: cholinesterase; electrophysiology; glutathione-S-transferase; neuromuscular system; organoruthenium complexes.