Synthesis, Characterization, Cytotoxic Activity, and Metabolic Studies of Ruthenium(II) Polypyridyl Complexes Containing Flavonoid Ligands

Four novel monocationic Ru­(II) polypyridyl complexes were synthesized with the general formula [Ru­(DIP)₂flv]­X, where DIP is 4,7-diphenyl-1,10-phenanthroline, flv stands for the flavonoid ligand (5-hydroxyflavone in [Ru­(DIP)₂(5-OHF)]­(PF₆), genistein in [Ru­(DIP)₂(gen)]­(PF₆), chrysin in [Ru­(DIP)₂(chr)]­(OTf), and morin in [Ru­(DIP)₂(mor)]­(OTf)), and X is the counterion, PF₆⁻, and OTf ̅ (triflate, CF₃SO₃̅), respectively. Following the chemical characterization of the complexes by ¹H and ¹³C NMR, mass spectrometry, and elemental analysis, their cytotoxicity was tested against several cancer cell lines. The most promising complex, [Ru­(DIP)₂(gen)]­(PF₆), was further investigated for its biological activity. Metabolic studies revealed that this complex severely impaired mitochondrial respiration and glycolysis processes, contrary to its precursor, Ru­(DIP)₂Cl₂, which showed a prominent effect only on the mitochondrial respiration. In addition, its preferential accumulation in MDA-MB-435S cells (a human melanoma cell line previously described as mammary gland/breast; derived from metastatic site: pleural effusion), which are used for the study of metastasis, explained the better activity in this cell line compared to MCF-7 (human, ductal carcinoma).