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).