Half-Sandwich Ru(p-cymene) Compounds with Diphosphanes: In Vitro and In Vivo Evaluation As Potential Anticancer Metallodrugs.
Oscar A Lenis-RojasM Paula RobaloAna Isabel TomazAlexandra Ramos FernandesCatarina Roma-RodriguesRicardo G TeixeiraFernanda MarquesMónica FolgueiraJulián YáñezAnabel Alba GonzalezMartín Salamini-MontemurriDawrin Pech-PuchDigna Vázquez-GarcíaMargarita López TorresAlberto FernándezJesús J FernándezPublished in: Inorganic chemistry (2021)
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.
Keyphrases
- cell cycle arrest
- cell death
- cell cycle
- breast cancer cells
- high resolution
- reactive oxygen species
- induced apoptosis
- mass spectrometry
- oxidative stress
- endothelial cells
- single molecule
- endoplasmic reticulum stress
- squamous cell carcinoma
- cell proliferation
- magnetic resonance
- pi k akt
- drug induced
- cystic fibrosis
- ionic liquid
- dna damage
- circulating tumor
- high intensity
- papillary thyroid
- emergency department
- risk assessment
- climate change
- cell free
- solid state
- small molecule
- locally advanced
- lymph node metastasis
- protein protein
- single cell
- contrast enhanced
- electron microscopy
- anti inflammatory