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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
| Content Provider | MDPI |
|---|---|
| Author | Attila, Bényei Buglyó, Péter Somsák, László Kacsir, István Sipos, Adrienn Janka, Eszter Bai, Péter Bokor, Éva |
| Copyright Year | 2022 |
| Description | 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 $IC_{50}$ 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. |
| Starting Page | 813 |
| e-ISSN | 14220067 |
| DOI | 10.3390/ijms23020813 |
| Journal | International Journal of Molecular Sciences |
| Issue Number | 2 |
| Volume Number | 23 |
| Language | English |
| Publisher | MDPI |
| Publisher Date | 2022-01-12 |
| Access Restriction | Open |
| Subject Keyword | International Journal of Molecular Sciences Medicinal Chemistry Osmium Complex Iridium Complex Ruthenium Complex Rhodium Complex Half-sandwich Cooperative Binding Reactive Oxygen Species Production Glycosyl Heterocycle Oxadiazole Triazole Ovarian Cancer Hodgkin's Lymphoma Osteosarcoma |
| Content Type | Text |
| Resource Type | Article |
