PUBLICATION
Half-Sandwich Ru(p-cymene) Compounds with Diphosphanes: In Vitro and In Vivo Evaluation As Potential Anticancer Metallodrugs
- Authors
- Lenis-Rojas, O.A., Robalo, M.P., Tomaz, A.I., Fernandes, A.R., Roma-Rodrigues, C., Teixeira, R.G., Marques, F., Folgueira, M., Yáñez, J., Gonzalez, A.A., Salamini-Montemurri, M., Pech-Puch, D., Vázquez-García, D., Torres, M.L., Fernández, A., Fernández, J.J.
- ID
- ZDB-PUB-210212-9
- Date
- 2021
- Source
- Inorganic chemistry 60(5): 2914-2930 (Journal)
- Registered Authors
- Folgueira Otero, Monica
- Keywords
- none
- MeSH Terms
-
- Animals
- Antineoplastic Agents/chemical synthesis
- Antineoplastic Agents/metabolism
- Antineoplastic Agents/pharmacology*
- Antineoplastic Agents/toxicity
- Apoptosis/drug effects
- Autophagy/drug effects
- Cell Line, Tumor
- Cell Proliferation/drug effects
- Coordination Complexes/chemical synthesis
- Coordination Complexes/metabolism
- Coordination Complexes/pharmacology*
- Coordination Complexes/toxicity
- DNA/metabolism
- Drug Screening Assays, Antitumor
- Fibroblasts/drug effects
- Humans
- Phosphines/chemical synthesis
- Phosphines/metabolism
- Phosphines/pharmacology*
- Phosphines/toxicity
- Protein Binding
- Reactive Oxygen Species/metabolism
- Ruthenium/chemistry
- Serum Albumin, Human/metabolism
- Zebrafish
- PubMed
- 33570919 Full text @ Inorg. Chem.
Citation
Lenis-Rojas, O.A., Robalo, M.P., Tomaz, A.I., Fernandes, A.R., Roma-Rodrigues, C., Teixeira, R.G., Marques, F., Folgueira, M., Yáñez, J., Gonzalez, A.A., Salamini-Montemurri, M., Pech-Puch, D., Vázquez-García, D., Torres, M.L., Fernández, A., Fernández, J.J. (2021) Half-Sandwich Ru(p-cymene) Compounds with Diphosphanes: In Vitro and In Vivo Evaluation As Potential Anticancer Metallodrugs. Inorganic chemistry. 60(5):2914-2930.
Abstract
Ruthenium(II) complexes are currently considered attractive alternatives to the widely used platinum-based drugs. We present herein the synthesis and characterization of half-sandwich ruthenium compounds formulated as [Ru(p-cymene)(L)Cl][CF3SO3] (L = 1,1-bis(methylenediphenylphosphano)ethylene, 1; L = 1,1-bis(diphenylphosphano)ethylene, 2), which were characterized by elemental analysis, mass spectrometry, 1H and 31P{1H} NMR, UV-vis and IR spectroscopy, conductivity measurements and cyclic voltammetry. The molecular structures for both complexes were determined by single-crystal X-ray diffraction. Their cytotoxic activity was evaluated using the MTT assay against human tumor cells, namely ovarian (A2780) and breast (MCF7 and MDA-MB-231). Both complexes were active against breast adenocarcinoma cells, with complex 1 exhibiting a quite remarkable cytotoxicity in the submicromolar range. Interestingly, at concentrations equivalent to the IC50 values in the MCF7 cancer cells, complexes 1 and 2 presented lower cytotoxicity in normal human primary fibroblasts. The antiproliferative effects of 1 and 2 in MCF7 cells might be associated with the induction of reactive oxygen species (ROS), leading to a combined cell death mechanism via apoptosis and autophagy. Despite the fact that in vitro a partial intercalation between complexes and DNA was observed, no MCF7 cell cycle delay or arrest was observed, indicating that DNA might not be a direct target. Complexes 1 and 2 both exhibited a moderate to strong interaction with human serum albumin, suggesting that protein targets may be involved in their mode of action. Their acute toxicity was evaluated in the zebrafish model. Complex 1 (the most toxic of the two) exhibited a lethal toxicity LC50 value about 1 order of magnitude higher than any IC50 concentrations found for the cancer cell models used, highlighting its therapeutic relevance as a drug candidate in cancer chemotherapy.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping