"Half-Sandwich" Ruthenium Complexes with Alizarin as Anticancer Agents: In Vitro and In Vivo Studies.

Upon exploration of the chemistry of the combination of ruthenium/arene with anthraquinone alizarin (L), three new complexes with the general formulas [Ru(L)Cl(η--cymene)] (), [Ru(L)(η--cymene)(PPh)]PF (), and [Ru(L)(η--cymene)(PEt)]PF () were synthesized and characterized using spectroscopic techniques (mass, IR, and 1D and 2D NMR), molar conductivity, elemental analysis, and X-ray diffraction. Complex exhibited fluorescence, such as free alizarin, while in and , the emission was probably quenched by monophosphines and the crystallographic data showed that hydrophobic interactions are predominant in intermolecular contacts. The cytotoxicity of the complexes was evaluated in the MDA-MB-231 (triple-negative breast cancer), MCF-7 (breast cancer), and A549 (lung) tumor cell lines and MCF-10A (breast) and MRC-5 (lung) nontumor cell lines. Complexes and were more selective to the breast tumor cell lines, and was the most cytotoxic (IC = 6.5 μM for MDA-MB-231). In addition, compound performs a covalent interaction with DNA, while and present only weak interactions; however, internalization studies by flow cytometry and confocal microscopy showed that complex does not accumulate in viable MDA-MB-231 cells and is detected in the cytoplasm only after cell permeabilization. Investigations of the mechanism of action of the complexes indicate that promotes cell cycle arrest in the Sub-G phase in MDA-MB-231, inhibits its colony formation, and has a possible antimetastatic action, impeding cell migration in the wound-healing experiment (13% of wound healing in 24 h). The toxicological experiments with zebrafish indicate that and exhibit the most zebrafish embryo developmental toxicity (inhibition of spontaneous movements and heartbeats), while , the most promising anticancer drug in the preclinical tests, revealed the lowest toxicity in preclinical screening.