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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.

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Title: 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.
Authors: Tabares, Julie Pauline Gaitan1 (AUTHOR), Santos, Rodrigo Luis S.R.1 (AUTHOR), Cassiano, Jefferson Luiz1 (AUTHOR), Zaim, Marcio H.1 (AUTHOR), Honorato, João1 (AUTHOR), Batista, Alzir A.1 (AUTHOR), Teixeira, Sarah F.1 (AUTHOR), Ferreira, Adilson Kleber1 (AUTHOR), Viana, Rommel B.1 (AUTHOR), Martínez, Sandra Quispe1 (AUTHOR), Stábile, Antonio Carlos1 (AUTHOR), de Oliveira Silva, Denise1 (AUTHOR) deosilva@iq.usp.br
Source: Inorganica Chimica Acta. Apr2019, Vol. 489, p27-38. 12p.
Subjects: Ligands (Chemistry), Ruthenium compounds, Cells
Abstract: Graphical abstract 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. Highlights • 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. Abstract 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)Cl 2 ] (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)Cl 2 ] 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)Cl 2 ] (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 IC 50 close to the IC 50 of L1 , does not show significant effect on the mitochondrial membrane potential (MMP), in contrast to the behavior of the free L1 parent drug which significantly decreases the MMP in NCI-H460 cells. Interestingly, since 1H MNR studies indicate that organometallic 1 is completely dissociated in dmso (the solvent used to prepare the drug solutions for cell treatment in the biological assays) to give the L1 free drug and species 4 , it is plausible to infer that the presence of Npxpya-free Ru species, probably in the form of species 4 , might play a role in inhibiting the mechanism related to the mitochondrial function when the cells are treated with 1 , in comparison with the cell treatment with the L1 free drug. [ABSTRACT FROM AUTHOR]
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Database: Engineering Source
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Abstract:Graphical abstract 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. Highlights • 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. Abstract 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)Cl 2 ] (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)Cl 2 ] 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)Cl 2 ] (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 IC 50 close to the IC 50 of L1 , does not show significant effect on the mitochondrial membrane potential (MMP), in contrast to the behavior of the free L1 parent drug which significantly decreases the MMP in NCI-H460 cells. Interestingly, since 1H MNR studies indicate that organometallic 1 is completely dissociated in dmso (the solvent used to prepare the drug solutions for cell treatment in the biological assays) to give the L1 free drug and species 4 , it is plausible to infer that the presence of Npxpya-free Ru species, probably in the form of species 4 , might play a role in inhibiting the mechanism related to the mitochondrial function when the cells are treated with 1 , in comparison with the cell treatment with the L1 free drug. [ABSTRACT FROM AUTHOR]
ISSN:00201693
DOI:10.1016/j.ica.2019.01.030