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

Abstract

Platinum complexes are used in chemotherapy, primarily as antineoplastic agents. In this study, we assessed the cytotoxic and cytostatic properties of a set of osmium(II), ruthenium(II), iridium(III) and rhodium(III) half-sandwich-type complexes with bidentate monosaccharide ligands. We identified 5 compounds with moderate to negligible acute cytotoxicity but with potent long-term cytostatic activity. These structure-activity relationship studies revealed that: 1) osmium(II) p-cymene complexes were active in all models, while rhodium(III) and iridium(III) Cp* complexes proved largely inactive; 2) the biological effect was influenced by the nature of the central azole ring of the ligands—1,2,3-triazole was the most effective, followed by 1,3,4-oxadiazole, while the isomeric 1,2,4-oxadiazole abolished the cytostatic activity; 3) we found a correlation between the hydrophobic character of the complexes and their cytostatic activity: compounds with O-benzoyl protective groups on the carbohydrate moiety were active, compared to O-deprotected ones. The best compound, an osmium(II) complex, had an IC50 value of 0.70 µM. Furthermore, the steepness of the inhibitory curve of the active complexes suggested cooperative binding; cooperative molecules were better inhibitors than non-cooperative ones. The cytostatic activity of the active complexes was abolished by a lipid-soluble antioxidant, vitamin E, suggesting that oxidative stress plays a major role in the biological activity of the complexes. The complexes were active on ovarian cancer, pancreatic adenocarcinoma, osteosarcoma and Hodgkin’s lymphoma cells, but were inactive on primary, non-transformed human fibroblasts, indicating their applicability as potential anticancer agents.

Targeting Multiresistant Gram-Positive Bacteria by Ruthenium, Osmium, Iridium and Rhodium Half-Sandwich Type Complexes With Bidentate Monosaccharide Ligands

“…We synthesized a set of half-sandwich complexes of ruthenium(II), osmium(II), iridium(III) and rhodium(III) incorporating real C - and N -glycopyranosyl azole type N,N-bidentate ligands ( Figure 1 ) ( Kacsir et al, 2021 ; Kacsir et al, 2022 ). To get the 1,3,4-oxadiazole type L - 1 – L - 3 ring-transformation of C -glycosyl tetrazoles I with picolinic acid was performed ( Bokor et al, 2017 ), while for 1,2,3-triazole-based chelator L - 4 copper(I) catalyzed azide alkyne cycloadditon (CuAAc) ( Agrahari et al, 2021 ) of glucosyl azide II was used.…”

“…The ligands were reacted with dimeric chloro-bridged platinum-group metal complexes in the presence of TlPF 6 to result in complexes Ru-1‒Ru-4 , Os-1‒Os-4 , Ir-1‒Ir-4 and Rh-1‒Rh-4 ( Figures 1 , 2 ). These complexes were identified to show cytostatic properties on carcinomas (representative data listed in Table 1 ), sarcomas and lymphomas in the low micromolar or submicromolar range, but have no bioactivity on primary, non-transformed fibroblasts ( Kacsir et al, 2021 ; Kacsir et al, 2022 ). The compounds exert their cytostatic activity through inducing oxidative stress ( Kacsir et al, 2021 ; Kacsir et al, 2022 ).…”

“…These complexes were identified to show cytostatic properties on carcinomas (representative data listed in Table 1 ), sarcomas and lymphomas in the low micromolar or submicromolar range, but have no bioactivity on primary, non-transformed fibroblasts ( Kacsir et al, 2021 ; Kacsir et al, 2022 ). The compounds exert their cytostatic activity through inducing oxidative stress ( Kacsir et al, 2021 ; Kacsir et al, 2022 ). The cytostatic activity of the compounds can be alleviated by vitamin E, an apolar, membrane antioxidant ( Kacsir et al, 2021 ; Kacsir et al, 2022 ) suggesting that the compounds likely target the cell membrane or other apolar compartments in the cells.…”

“…The compounds exert their cytostatic activity through inducing oxidative stress ( Kacsir et al, 2021 ; Kacsir et al, 2022 ). The cytostatic activity of the compounds can be alleviated by vitamin E, an apolar, membrane antioxidant ( Kacsir et al, 2021 ; Kacsir et al, 2022 ) suggesting that the compounds likely target the cell membrane or other apolar compartments in the cells. On the analogy of the bacteriotoxic activity of platinum or palladium compounds ( Quirante et al, 2011 ; Vieites et al, 2011 ; Zhang et al, 2011 ; McCarron et al, 2012 ; Yuan et al, 2018 ; Hummell and Kirienko, 2020 ; Yufanyi et al, 2020 ; Frei et al, 2021 ; Mansour, 2021 ) we set out to assess whether the above cytostatic complexes Ru-1‒Ru-4 , Os-1‒Os-4 , Ir-1‒Ir-4 and Rh-1‒Rh-4 in Figure 2 ( Kacsir et al, 2021 ; Kacsir et al, 2022 ), might have bacteriostatic properties.…”

“…The cytostatic activity of the compounds can be alleviated by vitamin E, an apolar, membrane antioxidant ( Kacsir et al, 2021 ; Kacsir et al, 2022 ) suggesting that the compounds likely target the cell membrane or other apolar compartments in the cells. On the analogy of the bacteriotoxic activity of platinum or palladium compounds ( Quirante et al, 2011 ; Vieites et al, 2011 ; Zhang et al, 2011 ; McCarron et al, 2012 ; Yuan et al, 2018 ; Hummell and Kirienko, 2020 ; Yufanyi et al, 2020 ; Frei et al, 2021 ; Mansour, 2021 ) we set out to assess whether the above cytostatic complexes Ru-1‒Ru-4 , Os-1‒Os-4 , Ir-1‒Ir-4 and Rh-1‒Rh-4 in Figure 2 ( Kacsir et al, 2021 ; Kacsir et al, 2022 ), might have bacteriostatic properties. For comparative studies, the precursors of these complexes ( Kacsir et al, 2021 ; Kacsir et al, 2022 ), such as the chloro-bridged platinum-metal dimeric complexes ( Ru-dimer , Os-dimer , Ir-dimer and Rh-dimer ) and the glycosyl heterocyclic N,N-bidentate ligands ( L-1‒L-4 ), as well as, the reference platinum-based anticancer drugs (cisplatin, carboplatin, oxaliplatin) were also planned to be tested ( Figure 2 ).…”