ABSTRACT
In this study, we present the synthesis, kinetic studies of inhibitory activity toward aldo-keto reductase 1C (AKR1C) enzymes, and anticancer potential toward chemoresistant ovarian cancer of 10 organoruthenium compounds bearing diketonate (1-6) and hydroxyquinolinate (7-10) chelating ligands with the general formula [(η6-p-cymene)Ru(chel)(X)]n+ where chel represents the chelating ligand and X the chlorido or pta ligand. Our studies show that these compounds are potent inhibitors of the AKR enzymes with an uncommon inhibitory mechanism, where two inhibitor molecules bind to the enzyme in a first fast and reversible step and a second slower and irreversible step. The binding potency of each step is dependent on the chemical structure of the monodentate ligands in the metalloinhibitors with the chlorido complexes generally acting as reversible inhibitors and pta complexes as irreversible inhibitors. Our study also shows that compounds 1-9 have a moderate yet better anti-proliferative and anti-migration action on the chemoresistant ovarian cancer cell line COV362 compared to carboplatin and similar effects to cisplatin.
ABSTRACT
A small library of 17 organoruthenium compounds with the general formula [RuII (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.
Subject(s)
Cholinesterase Inhibitors/pharmacology , Coordination Complexes/pharmacology , Glutathione Transferase/antagonists & inhibitors , Prodrugs/pharmacology , Ruthenium/chemistry , Acetylcholinesterase/metabolism , Animals , Butyrylcholinesterase/metabolism , Cell Line , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/chemistry , Cholinesterase Inhibitors/toxicity , Coordination Complexes/chemical synthesis , Coordination Complexes/chemistry , Coordination Complexes/toxicity , Diaphragm/drug effects , Electrophorus , Horses , Humans , Membrane Potentials/drug effects , Mice , Muscle Contraction/drug effects , Muscle, Skeletal/drug effects , Prodrugs/chemical synthesis , Prodrugs/chemistry , Prodrugs/toxicity , Small Molecule LibrariesABSTRACT
Four novel ruthenium organometallic complexes: [(η6-p-cymene)Ru(4,4,4-trifluoro-1-(4-bromophenyl)-1,3-butanedione)Cl] (1), [(η6-p-cymene)Ru(4,4,4-trifluoro-1-(4-bromophenyl)-1,3-butanedione)pta]PF6 (2), [(η6-p-cymene)Ru(4,4,4-trifluoro-1-(4-iodophenyl)-1,3-butanedione)Cl] (3) and [(η6-p-cymene)Ru(4,4,4-trifluoro-1-(4-iodophenyl)-1,3-butanedione)pta]PF6 (4) were synthesized and characterized by elemental analysis, infrared (IR), UV-Vis, NMR and mass spectroscopy and single-crystal X-ray diffraction. The crystal structures and spectroscopic data were compared to the previously published complexes [(η6-p-cymene)Ru(4,4,4-trifluoro-1-(4-chloro-phenyl)-1,3-butanedione)Cl] (5) and [(η6-p-cymene)Ru(4,4,4-trifluoro-1-(4-chlorophenyl)-1,3-butanedione)pta]PF6 (6). The pairs of complexes 1 and 3 as well as 2 and 4 are isostructural, with the former crystallizing in triclinic P-1 and the latter in monoclinic P21/c. The ruthenium(II) ion is found in a pseudo-octahedral "piano-stool" geometry in all compounds. Bond lengths and angles are consistent with other complexes of this type. Complexes 2 and 4 exhibit some moderate dynamic disorder. The lack of hydrogen bonding and major π-π interactions means that most of intramolecular interactions are fairly weak and involve halogen atoms present. This was further confirmed by ¹H-NMR spectra, where a significant difference is observed only on the ligand near the halogen atom, following an expected trend. The combined data show that the difference in any activity depends substantially on the type of the ligand's substituted halogen atom.
