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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

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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Author(s):
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Gaitan Tabares, Julie Pauline [1] ; Santos, Rodrigo Luis S. R. [1, 2] ; Cassiano, Jefferson Luiz [1] ; Zaim, Marcio H. [3] ; Honorato, Joao [4] ; Batista, Alzir A. [4] ; Teixeira, Sarah F. [3] ; Ferreira, Adilson Kleber [5] ; Viana, Rommel B. [6, 7] ; Martinez, Sandra Quispe [1] ; Stabile, Antonio Carlos [1] ; Silva, Denise de Oliveira [1]
Total Authors: 12
Affiliation:
[1] Univ Sao Paulo, Inst Chem, Lab Synthet & Struct Inorgan Chem Bioinorgan & Me, Dept Fundamental Chem, Av Prof Lineu Prestes 748, BR-05508000 Sao Paulo, SP - Brazil
[2] Univ Estadual Santa Cruz, Dept Exact & Technol Sci, Rod Jorge Amado, Km 16, BR-45662900 Ilheus, BA - Brazil
[3] Univ Sao Paulo, Inst Chem, Dept Fundamental Chem, Catalysis & Transfer Phase Lab, Av Prof Lineu Prestes 748, BR-05508000 Sao Paulo, SP - Brazil
[4] Univ Fed Sao Carlos, Dept Chem, CP 676, BR-13565905 Sao Carlos, SP - Brazil
[5] Univ Sao Paulo, Dept Immunol, Lab Tumor Immunol, Inst Biomed Sci, Av Prof Lineu Prestes 1730, BR-05508000 Sao Paulo, SP - Brazil
[6] Univ Sao Paulo, Sao Carlos Chem Inst, Dept Chem & Mol Phys, Av Trabalhador Sao Carlene 400, BR-13566590 Sao Carlos, SP - Brazil
[7] Univ Fed Alfenas, Chem Inst, Alfenas, MG - Brazil
Total Affiliations: 7
Document type: Journal article
Source: Inorganica Chimica Acta; v. 489, p. 27-38, APR 1 2019.
Web of Science Citations: 2
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)eta(6)-p-cymene framework with naproxen-pyridineamide (Npxpya, L1), a structurally modified form of the naproxen (HNpx, HL2) drug, to give the new organometallic {[}Ru(eta(6)-p-cymene)(L1)Cl-2] (1) bearing the Npxpya ligand. The reported naproxenate-derived, {[}Ru(eta(6)-p-cymene)(L2)Cl] (2), is re-prepared, also from the precursor {[}Ru(eta-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 H-1 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(eta(6)-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 Ll 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 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 H-1 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. (AU)

FAPESP's process: 15/18528-7 - Development of new drug candidate for the treatment of non-small cell lung cancer: CHY-1 as a novel inhibitor of autophagy and prototype of a novel class of inhibitors of the enzyme CTP: phosphoethanolamine citidililtransferase
Grantee:Adilson Kleber Ferreira
Support type: Research Grants - Young Investigators Grants
FAPESP's process: 14/23047-5 - Anticancer metallodrugs of ruthenium containing bioactive ligands: synthesis, interaction with biomolecules and preparation of biocompatible nanoparticle drug delivery systems
Grantee:Denise de Oliveira Silva
Support type: Regular Research Grants