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

Abstract

In this paper, a series of new ruthenium complexes of the general formula [Ru(NS)(dpphpy)(dppb)]PF 6 (Ru1−Ru3), where dpphpy = diphenyl-2-pyridylphosphine, NS ligands = 2-thiazoline-2-thiol (tzdt, Ru1), 2-mercaptopyrimidine (pySm, Ru2), and 4,6diamino-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 1 H− 31 P 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.

Ru(II)-Based Acetylacetonate Complexes Induce Apoptosis Selectively in Cancer Cells

“…Previous data on Ru naphthoquinone complexes incorporated with phosphorous-based ligands have shown excellent selectivity toward MDA-MB-231 cells as compared to MCF-10A cells . Selectivity toward MDA-MB-231 over MCF-10A cells was also seen by several reported Ru phosphine/mercapto complexes, though to a much lesser extent . However, studies on other Ru polypyridyl complexes with acac-based ferrocenyl β-diketonate ligands showed no selectivity toward cancerous HCT116 p53 +/+ cells over noncancerous ARPE-19 cells .…”

“…81 Selectivity toward MDA-MB-231 over MCF-10A cells was also seen by several reported Ru phosphine/mercapto complexes, though to a much lesser extent. 82 However, studies on other Ru polypyridyl complexes with acac-based ferrocenyl β-diketonate ligands showed no selectivity toward cancerous HCT116 p53 +/+ cells over noncancerous ARPE-19 cells. 36 Similarly, other studies on bpy-based Ru complexes with similar acacbased ligands showed higher toxicity compared to our complexes when tested against cancerous cell lines like HL60, MIA PaCa-2, and DU-145 cells, but no studies regarding selectivity of these complexes toward cancerous vs non-cancerous cell lines have been mentioned by the authors.…”

A Novel Ruthenium(II) Complex With Lapachol Induces G2/M Phase Arrest Through Aurora-B Kinase Down-Regulation and ROS-Mediated Apoptosis in Human Prostate Adenocarcinoma Cells

“…Ruthenium(II) complexes designed in the present study were tested against several cancer cells, presenting important cytotoxic activity. Other recent studies have shown that complexes of ruthenium with different phosphine ligands can induce cytotoxic activity against cancer cell lines ( 54 – 56 ). Lapachol and its derivatives showed antiproliferative effects in different histological types of cells, including ovary, colon, lung, breast, leukemia, esophageal, cervical, melanoma, and prostate ( 7 , 57 – 63 ).…”

Antitumor Effect of Organometallic Half-Sandwich Ru(II)–Arene Complexes Bearing a Glutathione S-Transferase Inhibitor

“…In addition, the inevitable drug resistance is another limitation of the platinum drugs . Considering the disadvantages of platinum drugs, other metal-based anticancer compounds have been designed as alternatives to platinum drugs, especially ruthenium-based anticancer agents, which has shown great promising in cancer therapy due to their unique biological properties and low toxicity. − …”