Organoruthenium(II) Complexes Bearing an Aromatase Inhibitor: Synthesis, Characterization, in Vitro Biological Activity and in Vivo Toxicity in Zebrafish Embryos

Third-generation aromatase inhibitors such as anastrozole (ATZ) and letrozole (LTZ) are widely used to treat estrogen receptor-positive (ER+) breast cancers in postmenopausal women. Investigating their ability to coordinate metals could lead to the emergence of a new category of anticancer drug candidates with a broader spectrum of pharmacological activities. In this study, a series of ruthenium(II) arene complexes bearing the aromatase inhibitor anastrozole was synthesized and characterized. Among these complexes, [Ru(eta(6)-C6H6)(PPh3)(eta(1)-ATZ)Cl]-BPh4 (3) was found to be the most stable in cell culture media, to lead to the highest cellular uptake and in vitro cytotoxicity in two ER+ human breast cancer cell lines (MCF7 and T47D), and to induce a decrease in aromatase activity in H295R cells. Exposure of zebrafish embryos to complex 3 (12.5 mu M) did not lead to noticeable signs of toxicity over 96 h, making it a suitable candidate for further in vivo investigations.