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Ruthenium(II) Phosphine/Mercapto Complexes: Their in Vitro Cytotoxicity Evaluation and Actions as Inhibitors of Topoisomerase and Proteasome Acting as Possible Triggers of Cell Death Induction

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Autor(es):
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Ribeiro, Gabriel H. [1] ; Guedes, Adriana P. M. [1] ; de Oliveira, Tamires D. [1] ; de Correia, Camila R. S. T. B. [2] ; Colina-Vegas, Legna [1, 3] ; Lima, Mauro A. [1] ; Nobrega, Joaquim A. [1] ; Cominetti, Marcia R. [4] ; Rocha, V, Fillipe ; Ferreira, Antonio G. [5] ; Castellano, Eduardo E. [6] ; Teixeira, Felipe R. [2] ; Batista, Alzir A. [5]
Número total de Autores: 13
Afiliação do(s) autor(es):
[1] Univ Fed Sao Carlos, Dept Quim, BR-13565905 Sao Carlos, SP - Brazil
[2] Univ Fed Sao Carlos, Dept Genet & Evolucao, BR-13565905 Sao Carlos, SP - Brazil
[3] Univ Fed Rio Grande do Sul, Inst Quim, BR-91501970 Porto Alegre, RS - Brazil
[4] Univ Fed Sao Carlos, Dept Gerontol, BR-13565905 Sao Carlos, SP - Brazil
[5] Rocha, Fillipe, V, Univ Fed Sao Carlos, Dept Quim, BR-13565905 Sao Carlos, SP - Brazil
[6] Univ Sao Paulo, Inst Fis Sao Carlos, BR-13560970 Sao Carlos, SP - Brazil
Número total de Afiliações: 6
Tipo de documento: Artigo Científico
Fonte: Inorganic Chemistry; v. 59, n. 20, p. 15004-15018, OCT 19 2020.
Citações Web of Science: 0
Resumo

In this paper, a series of new ruthenium complexes of the general formula {[}Ru(NS)(dpphpy)(dppb)]PF6 (Ru1-Ru3), where dpphpy = diphenyl-2-pyridylphosphine, NS ligands = 2-thiazoline-2-thiol (tzdt, Ru1), 2-mercaptopyrimidine (pySm, Ru2), and 4,6-diamino-2-mercaptopyrimidine (damp, Ru3), and dppb = 1,4-bis(diphenylphosphino)butane, were synthesized and characterized by elemental analysis, spectroscopic techniques (IR, UV/ visible, and 1D and 2D NMR), and X-ray diffraction. In the characterization, the correlation between the phosphorus atoms and their respective aromatic hydrogen atoms of the compounds in the assignment stands outs, by H-1-P-31 HMBC experiments. The compounds show anticancer activities against A549 (lung) and MDA-MB-231 (breast) cancer cell lines, higher than the clinical drug cisplatin. All of the complexes are more cytotoxic against the cancer cell lines than against the MRC-5 (lung) and MCF-10A (breast) nontumorigenic human cell lines. For A549 tumor cells, cell cycle analysis upon treatment with Ru2 showed that it inhibits the mitotic phase because arrest was observed in the Sub-G1 phase. Additionally, the compound induces cell death by an apoptotic pathway in a dose-dependent manner, according to annexin V-PE assay. The multitargeted character of the compounds was investigated, and the biomolecules were DNA, topoisomerase IB, and proteasome, as well as the fundamental biomolecule in the pharmacokinetics of drugs, human serum albumin. The experimental results indicate that the complexes do not target DNA in the cells. At low concentrations, the compounds showed the ability to partially inhibit the catalytic activity of topoisomerase IB in the process of relaxation of the DNA plasmid. Among the complexes assayed in cultured cells, complex Ru3 was able to diminish the proteasomal chymotrypsin-like activity to a greater extent. (AU)

Processo FAPESP: 16/16312-0 - Citotoxidade e mecanismo de ação de complexos de rutênio contendo produtos naturais ou derivados
Beneficiário:Alzir Azevedo Batista
Linha de fomento: Auxílio à Pesquisa - Regular
Processo FAPESP: 16/23130-5 - Determinação da biodistribuição celular de Cu, Ru e Pt em células humanas tumorais e não tumorais de mama mediante a técnica de espectrometria de massas com plasma acoplado indutivamente
Beneficiário:Legna Andreina Colina Vegas
Linha de fomento: Bolsas no Brasil - Pós-Doutorado