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Study in vitro and in vivo of Ru(II) phosphine complexes with anticancer activities

Abstract

In the search for new coordination compounds with antitumor, and without toxicity, or with less toxicity than the platinum based-compounds, ruthenium compounds are very promising. Thus, it is necessary to evaluate the antitumor potentiality of these new compounds and try to understand the possible relationship between the intracelular localization of the compounds and their mechanism of action. The objective of this project is based on the synthesis and characterization of new ruthenium/phosphine complexes, containing mercapto derivatives, naphtoquinones and acylthioureas as ligands, as recent study developed in our laboratory showed that these classes of complexes, are very active and selective. Thus, new ruthenium/phosphine complexes will be synthesized, characterized and their cytotoxicity against tumor cells will be evaluated. The localization of the complexes in the cells, characterizing the target associated with the compounds in human tumor cells such as triple-negative breast (MDA-MB-231) and double positive breast (MCF-7), also in non-tumorigenic breast cell (MCF-10A) will be evaluated. The mechanism of action related to the cytotoxicity of the compounds will be evaluated as well, by interaction studies with DNA and HSA, determination of the levels of reactive oxygen species (ROS) intracellular. In addition, the pattern of cell death by flow cytometry and fluorescence microscopy. Western blotting analyzes will improve the understanding the major expressed proteins and their metabolic pathways involved in cytotoxicity and through confocal microscopy it will be possible to relate them to sub-cellular locatization. In addition, in vivo experiment will be performed in this work with mice. All these results together will provide us subsidies to elucidate the possible mechanisms of action for these complexes, contributing to the rational drug design and development of novel and even more effective anti-cancer agents. (AU)

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