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

Author(s):Show less -

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]

Affiliation

^[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

• Document type: Journal article
• Source: Inorganic Chemistry; v. 59, n. 20, p. 15004-15018, OCT 19 2020.
• Web of Science Citations: 0

Abstract

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)

• FAPESP's process: 16/16312-0 - CYTOTOXICITY AND MECHANISM OF ACTION OF RUTHENIUM COMPLEXES CONTAINING NATURAL PRODUCTS OR DERIVATIVES
• Grantee: Alzir Azevedo Batista
• Support type: Regular Research Grants
• FAPESP's process: 16/23130-5 - Determination of cellular biodistribution of Cu, Ru and Pt in human tumor and non tumor breast cells by Inductively Coupled Plasma Mass Spectrometry
• Grantee: Legna Andreina Colina Vegas
• Support type: Scholarships in Brazil - Post-Doctorate