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Upon exploration of the chemistry of the combination of ruthenium/arene with anthraquinone alizarin (L), three new complexes with the general formulas [Ru(L)Cl(η 6 - p -cymene)] ( C1 ), [Ru(L)(η 6 - p -cymene)(PPh 3 )]PF 6 ( C2 ), and [Ru(L)(η 6 - p -cymene)(PEt 3 )]PF 6 ( C3 ) were synthesized and characterized using spectroscopic techniques (mass, IR, and 1D and 2D NMR), molar conductivity, elemental analysis, and X-ray diffraction. Complex C1 exhibited fluorescence, such as free alizarin, while in C2 and C3 , the emission was probably quenched by monophosphines and the crystallographic data showed that hydrophobic interactions are predominant in intermolecular contacts. The cytotoxicity of the complexes was evaluated in the MDA-MB-231 (triple-negative breast cancer), MCF-7 (breast cancer), and A549 (lung) tumor cell lines and MCF-10A (breast) and MRC-5 (lung) nontumor cell lines. Complexes C1 and C2 were more selective to the breast tumor cell lines, and C2 was the most cytotoxic (IC 50 = 6.5 μM for MDA-MB-231). In addition, compound C1 performs a covalent interaction with DNA, while C2 and C3 present only weak interactions; however, internalization studies by flow cytometry and confocal microscopy showed that complex C1 does not accumulate in viable MDA-MB-231 cells and is detected in the cytoplasm only after cell permeabilization. Investigations of the mechanism of action of the complexes indicate that C2 promotes cell cycle arrest in the Sub-G 1 phase in MDA-MB-231, inhibits its colony formation, and has a possible antimetastatic action, impeding cell migration in the wound-healing experiment (13% of wound healing in 24 h). The in vivo toxicological experiments with zebrafish indicate that C1 and C3 exhibit the most zebrafish embryo developmental toxicity (inhibition of spontaneous movements and heartbeats), while C2 , the most promising anticancer drug in the in vitro preclinical tests, revealed the lowest toxicity in in vivo preclinical screening.

For the first time, we herein report on the syntheses of two new Ru(II)/bipyridine/phenanthroline complexes containing lapachol as ligand: complex (1), [Ru (bipy) 2 (Lap)]PF 6 and complex (2), [Ru(Lap)(phen) 2 ]PF 6 , where bipy = 2,2'-bipyridine and ph en = 1,10-phenanthroline; Lap = lapachol (2-hydroxy-3-(3-methylbut-2-en-1- yl)naphthalene-1,4-dione). The complexes were synthesized and characterized by elemental analyses, molar conductivity, mass spectrometry, ultraviolet-visible and infrared spectroscopies, nuclear magnetic resonance ( 1 H, 13 C), and single crystal X-ray diffraction, for complex (2). In addition, in vitro cytotoxicity was tested against six cancer cells: A549 (lung carcinoma); DU-145 (human prostate carcinoma); HepG2 (human hepatocellular carcinoma), PC-3 (human prostate adenocarcinoma); MDA-MB-231 (human breast adenocarcinoma); Caco-2 (human colorectal adenocarcinoma), and against two non-cancer cells, FGH (human gingival normal fibroblasts) and PNT-2 (prostate epithelial cells). Complex (1) was slightly more toxic and selective than complex (2) for all cell lines, except against the A549 cells, where (2) was more potent than complex (1). The complexes induced an increase in the reactive oxygen species, and the co-treatment with N-acetyl-L-cysteine remarkably suppressed the ROS generation and prevented the reduction of cell viability, suggesting that the cytotoxicity of the complexes is related to the ROS-mediated pathway. Further studies indicated that the complexes may bind to DNA via minor groove interaction. Our studies also revealed that free Lap induces gene mutations in Salmonella Typhimurium, nevertheless, the complexes demonstrated the absence of genotoxicity by the Ames test. The present study provides a relevant contribution to understanding the anti-cancer potential and genetic toxicological events of new ruthenium complexes containing the lapachol molecule as a ligand., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Published by Elsevier Inc.)

For some cancer subtypes, such as triple-negative breast cancer, there are no specific therapies, which leads to a poor prognosis associated with invasion and metastases. Ruthenium complexes have been developed to act in all steps of tumor growth and its progression. In this study, we investigated the effects of Ruthenium (II) complexes coupled to the amino acids methionine (RuMet) and tryptophan (RuTrp) on the induction of cell death, clonogenic survival ability, inhibition of angiogenesis, and migration of MDA-MB-231 cells (human triple-negative breast cancer). The study also demonstrated that the RuMet and RuTrp complexes induce cell cycle blockage and apoptosis of MDA-MB-231 cells, as evidenced by an increase in the number of Annexin V-positive cells, p53 phosphorylation, caspase 3 activation, and poly(ADP-ribose) polymerase cleavage. Moreover, morphological changes and loss of mitochondrial membrane potential were detected. The RuMet and RuTrp complexes induced DNA damage probably due to reactive oxygen species production related to mitochondrial membrane depolarization. Therefore, the RuMet and RuTrp complexes acted directly on breast tumor cells, leading to cell death and inhibiting their metastatic potential; this reveals the potential therapeutic action of these drugs., (Published by Elsevier Inc.)

This study reports the synthesis, structural characterization and cytotoxic activity of four new palladium/pyridylporphyrin complexes, with the general formula {TPyP[PdCl(P-P)] 4 }(PF 6 ) 4 , where P-P is 1,2-bis(diphenylphosphino)ethane (dppe), 1,3-bis(diphenylphosphino)propane (dppp), 1,2-bis(diphenylphosphino)butane (dppb) or 1,1'-bis(diphenylphosphino)ferrocene (dppf). The complexes were characterized by elemental analysis, and by FT-IR, UV/Vis, 1 H and 31 P{ 1 H} NMR (1D/2D) spectroscopy. The slow evaporation of a methanolic solution of {TPyP[PdCl(dppb)] 4 }(PF 6 ) 4 (in an excess of NaBF 4 salt) resulted in single crystals suitable for X ray diffraction, allowing the determination of the tridimensional structure of this complex, which crystallized in the P 2 1 / a space group. The cytotoxicity of the complexes against MDA-MB-231 (breast cancer cells) and MCF-10A (non-tumor breast cancer cells), was determined by the colorimetric MTT method, which revealed that all four complexes show selective indexes close to 1.2, lower than that of cisplatin for the same cells (12.12). The interaction of the complexes with CT-DNA was evaluated by UV-visible and viscosity measurements and it was determined that the complexes interact moderately with CT-DNA, probably by H-bonding/π-π stacking and electrostatic interactions.

Lapachol is a well-studied natural product that has been receiving great interest due to its anticancer properties that target oxidative stress. In the present work, two novel lapachol-containing ruthenium(II) complexes [Ru(Lap)(dppm)(bipy)]PF 6 ( 1 ) and [Ru(Lap)(dppm)(phen)]PF 6 ( 2 ) [Lap = lapachol, dppm = 1,1'-bis(diphosphino)methane, bipy = 2,2'-bipyridine, phen = 1,10-phenantroline] were synthesized, fully characterized, and investigated for their cellular and molecular responses on cancer cell lines. We found that both complexes exhibited a potent cytotoxic effect in a panel of cancer cell lines in monolayer cultures, as well as in a 3D model of multicellular spheroids formed from DU-145 human prostate adenocarcinoma cells. Furthermore, the complex ( 2 ) suppressed the colony formation, induced G2/M-phase arrest, and downregulated Aurora-B. The mechanism studies suggest that complex ( 2 ) stimulate the overproduction of reactive oxygen species (ROS) and triggers caspase-dependent apoptosis as a result of changes in expression of several genes related to cell proliferation and caspase-3 and -9 activation. Interestingly, we found that N-acetyl-L-cysteine, a ROS scavenger, suppressed the generation of intracellular ROS induced by complex ( 2 ), and decreased its cytotoxicity, indicating that ROS-mediated DNA damage leads the DU-145 cells into apoptosis. Overall, we highlighted that coordination of lapachol to phosphinic ruthenium(II) compounds considerably improves the antiproliferative activities of resulting complexes granting attractive selectivity to human prostate adenocarcinoma cells. The DNA damage response to ROS seems to be involved in the induction of caspase-mediated cell death that plays an important role in the complexes' cytotoxicity. Upon further investigations, this novel class of lapachol-containing ruthenium(II) complexes might indicate promising chemotherapeutic agents for prostate cancer therapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 De Grandis, Oliveira, Guedes, dos Santos, Aissa, Batista and Pavan.)

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 4,6-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 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.

Antimetastatic activity, high selectivity and cytotoxicity for human tumor cell lines make ruthenium(ii) complexes attractive for the development of new chemotherapeutic agents for cancer treatment. In this study, cytotoxic activities and the possible mechanism of cell death induced by three ruthenium complexes were evaluated, [Ru(MIm)(bipy)(dppf)]PF 6 (1), [RuCl(Im)(bipy)(dppf)]PF 6 (2) and [Ru(tzdt)(bipy)(dppf)]PF 6 (3). The results showed high cytotoxicity and selectivity indexes for the human triple-negative breast tumor cell line (MDA-MB-231) with IC 50 value and selectivity index for complex 1 (IC 50 = 0.33 ± 0.03 μM, SI = 4.48), complex 2 (IC 50 = 0.80 ± 0.06 μM, SI = 2.31) and complex 3 (IC 50 = 0.48 ± 0.02 μM, SI = 3.87). The mechanism of cell death induced in MDA-MB-231 cells, after treatment with complexes 1-3, indicated apoptosis of the cells as a consequence of the increase in the percentage of cells in the Sub-G1 phase in the cell cycle analysis, characteristic morphological changes and the presence of apoptotic cells labeled with Annexin-V. Multiple targets of action were identified for complexes 1 and 3 with an induction of DNA damage in cells treated with complexes 1 and 3, mitochondrial depolarization with a reduction in mitochondrial membrane potential, an increase in reactive oxygen species levels and increased expression levels of caspase 3 and p53. In addition, antimetastatic activities for complexes 1 and 3 were observed by inhibition of cell migration by the wound healing assay and Boyden chamber assay, as well as inhibition of angiogenesis caused by MDA-MB-231 tumor cells in the CAM model.

Three ruthenium/iron-based compounds, 1: [Ru(MIm)(bipy)(dppf)]PF 6 (MIm = 2-mercapto-1-methylimidazole anion), 2: [RuCl(Im)(bipy)(dppf)]PF 6 (Im = imidazole), and 3: [Ru(tzdt)(bipy)(dppf)]PF 6 (tzdt = 1,3-thiazolidine-2-thione anion) (dppf = 1,1'-bis(diphenylphosphine)ferrocene and bipy = 2,2'-bipyridine), were synthesized, and characterized by elemental analyses, conductivity, UV/Vis, IR, 1 H, 13 C and 31 P{1H} NMR spectroscopies, and by electrochemical technique. The complex 3 was also characterized by single-crystal X-ray. The three ruthenium(II) complexes show cytotoxicity against DU-145 (prostate carcinoma cells) and A549 (lung carcinoma cells) tumor cells. The free ligands do not exhibit any cytotoxic activity, such as evident by the IC 50 values higher than 200 μM. UV/Vis and viscosity experiments showed that the complexes interact weakly with the DNA molecule, via electrostatic forces. The interaction of the complexes 1-3 with the HSA is moderate, with K b values in range of 10 5 -10 7  M -1 , presenting a static mechanism of interaction stabilized by hydrophobic. Complexes 2 and 3 showed high affinity for the FA7 HSA site as evidenced by fluorescence spectroscopy and molecular docking. Complexes 1-3 were tested as potential human Topoisomerase IB inhibitors by analysing the different steps of the enzyme catalytic cycle. The results indicate that all compounds efficiently inhibit the DNA relaxation and the cleavage reaction, in which the effect increases upon pre-incubation. Complexes 1 and 2 are also able to slow down the religation reaction., (Copyright © 2017 Elsevier Inc. All rights reserved.)