Half-Sandwich Ru(-cymene) Compounds with Diphosphanes: and Evaluation As Potential Anticancer Metallodrugs.

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(-cymene)(L)Cl][CFSO] (L = 1,1-bis(methylenediphenylphosphano)ethylene, ; L = 1,1-bis(diphenylphosphano)ethylene, ), which were characterized by elemental analysis, mass spectrometry, H and P{H} 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 exhibiting a quite remarkable cytotoxicity in the submicromolar range. Interestingly, at concentrations equivalent to the IC values in the MCF7 cancer cells, complexes and presented lower cytotoxicity in normal human primary fibroblasts. The antiproliferative effects of and 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 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 and 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 (the most toxic of the two) exhibited a lethal toxicity LC value about 1 order of magnitude higher than any IC concentrations found for the cancer cell models used, highlighting its therapeutic relevance as a drug candidate in cancer chemotherapy.