Half-sandwich Ru(p-cymene) compounds with diphosphanes: In Vitro and In Vivo evaluation as potential anticancer metallodrugs

• Autor(a) principal: Lenis Rojas, Oscar
• Data de Publicação: 2021
• Outros Autores: Robalo, M. Paula, Tomaz, Ana Isabel, Fernandes, Alexandra, Roma-Rodrigues, Catarina, Gonçalves Teixeira, Ricardo, Marques, Fernanda, FOLGUEIRA, MONICA, Yáñez, Julián, Alba-González, Anabel, Salamini-Montemurri, Martin, Pech-Puch, Dawrin, Vázquez-García, Digna, López-Torres, Margarita, Fernandez, Alberto, Fernandez, Jesus J.
• Tipo de documento: Artigo
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10400.21/13233
• topic: Half-sandwich ruthenium; Human tumor cells; Ovarian (A2780); Breast (MCF7 and MDA-MB-231); Reactive oxygen species (ROS); Apoptosis and autophagy

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, H-1 and P-31{H-1} 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.