Ruthenium Half-Sandwich Type Complexes with Bidentate Monosaccharide Ligands Show Antineoplastic Activity in Ovarian Cancer Cell Models through Reactive Oxygen Species Production

Abstract

Ruthenium complexes are developed as substitutes for platinum complexes to be used in the chemotherapy of hematological and gynecological malignancies, such as ovarian cancer. We synthesized and screened 14 ruthenium half-sandwich complexes with bidentate monosaccharide ligands in ovarian cancer cell models. Four complexes were cytostatic, but not cytotoxic on A2780 and ID8 cells. The IC50 values were in the low micromolar range (the best being 0.87 µM) and were similar to or lower than those of the clinically available platinum complexes. The active complexes were cytostatic in cell models of glioblastoma, breast cancer, and pancreatic adenocarcinoma, while they were not cytostatic on non-transformed human skin fibroblasts. The bioactive ruthenium complexes showed cooperative binding to yet unidentified cellular target(s), and their activity was dependent on reactive oxygen species production. Large hydrophobic protective groups on the hydroxyl groups of the sugar moiety were needed for biological activity. The cytostatic activity of the ruthenium complexes was dependent on reactive species production. Rucaparib, a PARP inhibitor, potentiated the effects of ruthenium complexes.

Reactive Oxygen Species Production Is Responsible for Antineoplastic Activity of Osmium, Ruthenium, Iridium and Rhodium Half-Sandwich Type Complexes with Bidentate Glycosyl Heterocyclic Ligands in Various Cancer Cell Models

“…In our previous study [ 30 ], the central heterocyclic ring of the carbohydrate ligand appeared most important ( c.f. oxadiazole II = Ru-3 and V = Ru-6 in Figure 1 ), therefore, to further investigate the effect of the five-membered heterocycle to the biological activity of such types of complexes, the replacement of the 1,3,4-oxadiazole ring with an isomeric 1,2,4-oxadiazole was envisaged.…”

“…Since the most effective [(η 6 - p -cym)Ru II (N-N)Cl]PF 6 complexes have 2-pyridyl-substituted glycosyl azole ligands ( Figure 1 , II = Ru-3 , III = Ru-4 , IV = Ru-5 , V = Ru-6 ), as published earlier [ 30 ], replacement of the Ru(II) to Os(II) ion was also carried out. The previously prepared O -perbenzoylated 2-(β-D-glycopyranosyl)-5-(2-pyridyl)-1,3,4-oxadiazoles [ 30 ] ( L-3‒L5 ) and 1-(β-D-glucopyranosyl)-4-(2-pyridyl)-1,2,3-triazole [ 30 ] ( L-6 ) were treated with dichloro(η 6 - p -cymene)osmium(II) dimer [ 37 ] ([(η 6 - p -cym)OsCl 2 ] 2 , Os-dimer ) and TlPF 6 was used for chloride abstraction. The target complexes, Os-3‒Os-6 , were obtained as mixtures of diastereoisomers in good yields ( Table 1 ).…”

“…It was also evidenced that these ruthenium complexes exerted biological activity through reactive species production [ 30 ], which is similar to other ruthenium complexes [ 23 , 27 , 31 , 32 ]. To a lesser extent, PARP activation may also contribute to cytostasis [ 30 ], a feature that was observed for a subset of ruthenium complexes [ 31 , 32 , 33 , 34 ].…”

“…In our previous study [ 30 ], a series of half-sandwich-type Ru(II) complexes ( Figure 1 , I ) were shown to be cytostatic and non-toxic, be able to generate free radicals, and to display cooperative binding in (sub)micromolar concentrations against different cancer cell lines (ovarian and breast cancer, pancreatic adenocarcinoma and glioblastoma). More specifically, O -perbenzoylated (as opposed to its O -peracetylated and O -unprotected counterparts) C -glycosyl 1,3,4-oxadiazole ligands II–IV exhibited low micromolar efficiency against, e.g., the A2780 ovarian cancer cell line.…”

“…In this study, we assessed a novel set of molecules that have a similar gross buildup to those in our previous report ( Figure 1 , I–V ) [ 30 ]; however, the compounds have been changed in crucial structural elements: complexes of additional platinum-group metals with different coordinating hexahapto arene and pentahapto arenyl groups, and modified C -glycosyl heterocyclic chelators were prepared and studied as to their effects on the biological activity of these molecules. These particular modifications are summarized in target compounds VI–VIII in Figure 1 .…”