Cytotoxic Ruthenium(II)‐Diphosphine Complexes Affect the Mitochondrial Respiration of Lung Cancer Cells

In this work, we studied six Ruthenium(II)‐diphosphine compounds containing different mercapto ligands (N−S), with general formula [Ru(N−S)(dppm)₂]Cl (dppm=1,1‐bis(diphenylphosphino)methane). These compounds were characterized by several techniques (NMR [¹H, ³¹P(¹H), and ¹³C], HRMS, IR, UV‐Vis and XRD) and their purity confirmed by elemental analysis. DLS experiments revealed low diameters and polydispersity indexes, and positive log P values in n‐octanol/PBS indicated their preference for the organic phase. In general, these compounds are stable in different media over 48 h. Cytotoxicity experiments revealed promising IC₅₀ values on A549 breast cancer cells, 0.48 μM and 0.80 μM for [Ru(mtz)(dppm)₂]Cl (1) and [Ru(mmi)(dppm)₂]Cl (2), respectively (mtz and mmi are 2‐mercapto‐2‐thiazoline and mercapto‐1‐methylimidazole in their deprotonated form, respectively). Clonogenic and migration experiments indicated their antiproliferative and anti‐migratory capacity. ICP‐MS results indicated their cellular accumulation in the nucleus, with little amounts in mitochondria. No covalent DNA binding was observed by ICP‐MS. JC‐1 and cell Mito Stress test confirmed mitochondrial dysfunction, which was verified by mitochondrial membrane potential uncoupling and drastic alterations in the oxygen consumption rate. Taken together, our results provide crucial insights regarding the anticancer potential of ruthenium(II)‐phosphine compounds.