A Ru(II)-p-cymene compound bearing naproxen-pyridineamide. Synthesis, spectroscopic studies, computational analysis and in vitro anticancer activity against lung cells compared to Ru(II)-p-cymene-naproxen and the corresponding drug ligands

A new Ru(η6-p-cymene) bearing the naproxen-pyridineamide (Npxpya) is synthesized and characterized by ESI-MS, NMR, ATR/FT-IR, UV/VIS and DFT computational calculations. Photophysical properties, antiproliferative activity, effects on mitochondrial membrane potential and cell cycle arrest in lung cancer cells are reported. All data are compared with those of Ru(II)-p-cymene-naproxenate, and the Npxpya and naproxen drugs. [Display omitted] •The new Ru(II)-p-cymene bearing naproxen-pyridineamide (Npxpya) is synthesized.•Characterization is performed by ESI-MS, NMR, ATR/FT-IR, UV/VIS, DFT calculations.•Photophysical properties are described.•Biological properties in lung cancer cells are reported.•Comparative data for Ru(II)-p-cymene-naproxenate, Npxpya and naproxen are provided. The design of new Ru(II) organometallics is a subject of interest to the field of anticancer metallodrugs. This work reports the interaction of the Ru(II)-η6-p-cymene framework with naproxen-pyridineamide (Npxpya, L1), a structurally modified form of the naproxen (HNpx, HL2) drug, to give the new organometallic [Ru(η6-p-cymene)(L1)Cl2] (1) bearing the Npxpya ligand. The reported naproxenate-derived, [Ru(η6-p-cymene)(L2)Cl] (2), is re-prepared, also from the precursor [Ru(η6-p-cymene)Cl2]2(3), and additional investigation is performed. The two Ru(II)-arenes and the L1 ligand are fully characterized by ESI-MS, NMR, ATR/FT-IR and UV/VIS, and their structures corroborated by DFT computational calculations. Time-dependent 1H MNR studies show that both Ru(II)-arenes, despite being stable in non-coordinating solvents, undergo distinct step dissociation in dimethylsulfoxide solvent to give the corresponding drug ligands and [Ru(η6-p-cymene)(dmso)Cl2] (4) species. Electronic absorption spectroscopy experimental data show good correlation with DFT calculations. Organometallics 1 and 2, as well as their corresponding parent drug ligands, exhibit luminescence properties mainly associated to the naproxen moiety. Screening in NCI-H460 and A549 lung cancer cells reveals lack of activity for 2 and L2, while the new organometallic 1 is found to inhibit cell proliferation of both types of cell lines in similar way to the L1 drug. The structural modification, by inserting the pyridineamide moiety into the original structure of naproxen to form the Npxpya conjugated drug, is shown to be crucial for the anticancer activity. Compound 1, despite having IC50 close to the IC50 of L1, does not show significant