Rare-Earth Salicylate Phenanthroline Complexes Cause Cell Death in Human Tumor Cells

Rare-earth (RE) salicylate phenanthroline complexes [RE(sal)₃(phen)] (RE = Y, Eu, Dy, Yb; sal = salicylate; Phen = 1,10-phenanthroline) are conveniently prepared starting from RE homoleptic carbamate precursors and salicylic aldehyde in the presence of phenanthroline. The yttrium derivative is structurally characterized by single-crystal X-ray diffraction, IR, and NMR spectroscopy, showing the mononuclear nature of the complex, while the structure of the other paramagnetic complexes are assigned on comparative IR spectra bases and elemental analyses. The antiproliferative effect of the complexes are studied in vitro on a panel of human tumor cell lines (A2780, ovarian carcinoma sensitive to cisplatin; A2780cis, ovarian carcinoma resistant to cisplatin and LN229, glioblastoma), and on nontumorigenic mesothelial cells (MeT-5A). The reactive oxygen species production is determined to investigate the intracellular mechanism of action. For the most interesting complex [Dy(sal)₃(phen)] (3), the effects on mitochondrial transmembrane potential and on cell cycle are also analyzed. Finally, epifluorescence images allow to demonstrate the uptake of the complex and to observe relevant morphological changes in cells, suggesting the occurrence of mitotic catastrophe.