4.7 Article

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

Journal

Publisher

MDPI
DOI: 10.3390/ijms221910454

Keywords

ovarian cancer; ruthenium complex; half-sandwich; cooperative binding; reactive oxygen species production; glycosyl heterocycle; oxadiazole; triazole; rucaparib

Funding

  1. National Research, Development, and Innovation Office of Hungary [K123975, FK125067]
  2. EU - European Regional Development Fund [GINOP-2.3.2-15-2016-00006, GINOP-2.3.2-15-2016-00008, GINOP-2.3.3-15-2016-00004]
  3. Momentum fellowship of the Hungarian Academy of Sciences
  4. University of Debrecen
  5. Thematic Excellence Program of the Ministry for Innovation and Technology in Hungary [TKP2020-IKA-04]

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Ruthenium complexes have been developed as alternatives to platinum complexes for the treatment of hematological and gynecological malignancies, showing cytostatic effects on various cancer cell models. These active complexes demonstrated cooperative binding to cellular targets, dependent on reactive oxygen species production. The cytostatic activity of ruthenium complexes was enhanced by the PARP inhibitor Rucaparib.
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 mu M) 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.

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