Dinuclear RuII(bipy)2 Derivatives: Structural, Biological, and in Vivo Zebrafish Toxicity Evaluation
| Autor: | Alexandra R. Fernandes, Fernanda Marques, Laura Sánchez, Jorge Guerra-Varela, David Pérez-Fernández, Digna Vázquez-García, Margarita López-Torres, Alberto Fernández, Catarina Roma-Rodrigues, Jesús J. Fernández, Oscar A Lenis-Rojas |
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| Rok vydání: | 2017 |
| Předmět: |
Cisplatin
chemistry.chemical_classification Programmed cell death Reactive oxygen species 010405 organic chemistry Stereochemistry Intercalation (chemistry) chemistry.chemical_element 010402 general chemistry 01 natural sciences 0104 chemical sciences Ruthenium Inorganic Chemistry chemistry In vivo Cancer cell medicine Structure–activity relationship Physical and Theoretical Chemistry medicine.drug |
| Zdroj: | Inorganic Chemistry. 56:7127-7144 |
| ISSN: | 1520-510X 0020-1669 |
| DOI: | 10.1021/acs.inorgchem.7b00790 |
| Popis: | Ruthenium-based drugs exhibit interesting properties as potential anticancer pharmaceuticals. We herein present the synthesis and characterization of a new family of ruthenium complexes with formulas [{Ru(bipy)2}2(μ-L)][CF3SO3]4 (L = bptz, 1a) and [{Ru(bipy)2}2(μ-L)][CF3SO3]2 (L = arphos, 2a; dppb, 3a; dppf, 4a), which were synthesized from the Ru(II) precursor compound cis-Ru(bipy)2Cl2. The complexes were characterized by elemental analysis, mass spectrometry, 1H and 31P{1H} NMR, IR spectroscopy, and conductivity measurements. The molecular structures for three Ru(II) compounds were determined by single-crystal X-ray diffraction. The newly developed compounds interact with CT-DNA by intercalation, in particular, 2a, 3a, and 4a, which also seemed to induce some extent of DNA degradation. This effect seemed to be related with the formation of reactive oxygen species. The cytotoxic activity was evaluated against A2780, MCF7, and MDAMB231 human tumor cells. Compounds 2a and 4a were the most cytotoxic with activity compared to cisplatin (∼2 μM, 72 h) in the A2780 cisplatin sensitive cells. All the compounds induced A2780 cell death by apoptosis, however, to a lesser extent for compounds 4a and 2a. For these compounds, the mechanism of cell death in addition to apoptosis seemed to involve autophagy. In vivo toxicity was evaluated using the zebrafish embryo model. LC50 estimates varied from 5.397 (3a) to 39.404 (1a) mg/L. Considering the in vivo toxicity in zebrafish embryos and the in vitro cytotoxicity in cancer cells, compound 1a seems to be the safest having no effect on dechirionation and presenting a good antiproliferative activity against ovarian carcinoma cells. |
| Databáze: | OpenAIRE |
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