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We have synthesized and characterized three new ruthenium(II) diphosphine complexes containing an acylthiourea ligand, with the general formula [Ru(DPEPhos)(O,S)(bipy)]PF 6 , where DPEPhos = bis(2-(diphenylphosphino)phenyl)ether, bipy = 2,2'-bipyridine, and O,S = N , N -dimethyl- N '-(benzoyl)thiourea (1), N , N -dimethyl- N '-(furoyl)thiourea (2), and N , N -dimethyl- N '-(thiophenyl)thiourea (3), by several physicochemical techniques. We evaluated the ruthenium complexes for their cytotoxicity against two human cancer cell lines, A549 (lung) and MDA-MB-231 (breast), and two corresponding lines of non-cancer cells, MRC-5 (lung) and MCF-10A (breast). All the complexes are cytotoxic against the cancer cell lines; the IC 50 values lie in the micromolar range (0.07-0.70 μM). Ruthenium complex 1 is more selective (7 times more active) toward lung cancer cells (A549) than toward non-cancer cells (MRC-5) and is 160 times more cytotoxic than cisplatin against A549 cells. Investigations of the mechanism of action of complex 1 in A549 cells demonstrated that it inhibits colony formation and promotes cell cycle arrest in the G1 phase and apoptotic cell death. DNA binding studies revealed that complexes 1-3 interact with the biomolecule via minor grooves. These complexes also interact with human serum albumin (HSA) and have affinity for site I by hydrophobic forces. Therefore, this new class of ruthenium complexes can act as cytotoxic agents, mainly for lung cancer treatment.

Metal complexes based on ruthenium have established excellent activity with less toxicity and great selectivity for tumor cells. This study aims to assess the anticancer potential of ruthenium(II)/allopurinol complexes called [RuCl 2 (allo) 2 (PPh 3 ) 2 ] (1) and [RuCl 2 (allo) 2 (dppb)] (2), where allo means allopurinol, PPh 3 is triphenylphosphine and dppb, 1,4-bis(diphenylphosphino)butane. The complexes were synthesized and characterized by elemental analysis, IR, UV-Vis and NMR spectroscopies, cyclic voltammetry, molar conductance measurements, as well as the X-ray crystallographic analysis of complex 2. The antitumor effects of compounds were determined by cytotoxic activity and cellular and molecular responses to cell death mechanisms. Complex 2 showed good antitumor profile prospects because in addition to its cytotoxicity, it causes cell cycle arrest, induction of DNA damage, morphological and biochemical alterations in the cells. Moreover, complex 2 induces cell death by p53-mediated apoptosis, caspase activation, increased Beclin-1 levels and decreased ROS levels. Therefore, complex 2 can be considered a suitable compound in antitumor treatment due to its cytotoxic mechanism.

In this work, we present the synthesis and characterization of five new ruthenium compounds with general formula [Ru(L)(dppb)(bipy)]PF 6 , where L = cinnamic acid derivatives, dppb = 1,4-bis(diphenylphosphino)butane and bipy = 2,2'-bipyridine. The cytotoxicity of the complexes was evaluated against human breast tumor cells from the lines MCF-7, MDA-MB-231 and in human (MCF-10A) or mouse (L929) non-tumor cells. Complexes Ru(L 4 )(dppb)(bipy)]PF 6 (4) (L 4  = 4-hydroxycinnamic acid) and [Ru(L 5 )(dppb)(bipy)]PF 6 (5) (L 5  = 3,4-dihydroxycinnamic acid) were the most selective, presenting the highest values of selectivity indexes besides inhibited some processes related to tumor progression in vitro, such as invasion, migration, and adhesion in the MDA-MB-231 cell line. In addition, the complexes 4 and 5 were able to interact with Bovine Serum Albumin (BSA) and complex 5 showed antioxidant activity., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Herein we discuss five ruthenium(ii) complexes with good cytotoxicity against cancer cells. These complexes are named [Ru(tzdt)(bipy)(dppb)]PF6 (1), [Ru(mmi)(bipy)(dppb)]PF6 (2), [Ru(dmp)(bipy)(dppb)]PF6 (3), [Ru(mpca)(bipy)(dppb)]PF6 (4) and [Ru(2mq)(bipy)(dppb)]PF6 (5), where tzdt = 1,3-thiazolidine-2-thione, mmi = mercapto-1-methyl-imidazole, dmp = 4,6-diamino-2-mercaptopyrimidine, mpca = 6-mercaptopyridine-3-carboxylic acid, 2mq = 2-mercapto-4(3H)-quinazolinone, bipy = 2,2'-bipyridine and dppb = 1,4-bis(diphenylphosphino)butane. In vitro cell culture experiments revealed significant cytotoxic activity for 1-5 against MDA-MB-231, MCF-7, A549, DU-145 and HepG2 tumor cells, higher than that for the standard anticancer drug cisplatin. Compound/DNA interaction studies were carried out showing that 1-5 interact with DNA by electrostatic force of attraction or by hydrogen bonding. Moreover, the complexes interact, moderately and spontaneously, with human serum albumin (HSA) through the hydrophobic region. The five complexes are able to inhibit the DNA supercoiled relaxation mediated by human topoisomerase IB (TopIB), and complex 1 is found to be the most efficient TopIB inhibitor among the five compounds. The inhibitory effect and analysis of different steps of the TopIB catalytic cycle indicate that complex 1 inhibits the cleavage reaction impeding the binding of the enzyme to DNA and has no effect on the religation step. Complexes 1, 2 and 3 did not show mutagenic activity when they were evaluated by the cytokinesis-block micronucleus cytome assay in HepG2 cells and the Ames test in the presence and absence of mouse liver S9 metabolic activation. Therefore, it is necessary to perform further in-depth analysis of the therapeutic potential of these promising ruthenium complexes as anticancer drugs.

Three new mixed and mononuclear Ru(II) complexes containing 1,3-thiazolidine-2-thione (tzdtH) were synthesized and characterized by spectroscopic analysis, molar conductivity, cyclic voltammetry, high-resolution electrospray ionization mass spectra and X-ray diffraction. The complexes presented unique stereochemistry and the proposed formulae are: [Ru(tzdt)(bipy)(dppb)]PF6 (1), cis-[Ru(tzdt)2(PPh3)2] (2) and trans-[Ru(tzdt)(PPh3)2(bipy)]PF6 (3), where dppb=1,4-bis(diphenylphosphino)butane and bipy=2,2'-bipyridine. These complexes demonstrated strong cytotoxicity against cancer cell lines when compared to cisplatin. Specifically, complex 2 was the most potent cytotoxic agent against MCF-7 breast cells, while complexes 1 and 3 were more active in DU-145 prostate cells. Binding of complexes to ctDNA was determined by UV-vis titration and viscosity measurements and revealed binding constant (Kb) values in range of 1.0-4.9×10(3)M(-1), which are characteristic of compounds possessing weak affinity to ctDNA. In addition, these complexes presented antiparasitic activity against Trypanosoma cruzi. Specifically, complex 3 demonstrated strong potency, moderate selectivity index and acted in synergism with the approved antiparasitic drug, benznidazole. Additionally, complex 3 caused parasite cell death through a necrotic process. In conclusion, we demonstrated that Ru(II) complexes have powerful pharmacological activity, while the metal-free tzdtH does not provoke the same outcome., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Herein we synthesized two new ruthenium(II) compounds [Ru(pySH)(bipy)(dppb)]PF6 (1) and [Ru(HSpym)(bipy)(dppb)]PF6 (2) that are analogs to an antitumor agent recently described, [Ru(SpymMe2)(bipy)(dppb)]PF6 (3), where [(Spy) = 2-mercaptopyridine anion; (Spym) = 2-mercaptopyrimidine anion and (SpymMe2) = 4,6-dimethyl-2-mercaptopyrimidine anion]. In vitro cell culture experiments revealed significant anti-proliferative activity for 1-3 against HepG2 and MDA-MB-231 tumor cells, higher than the standard anti-cancer drugs doxorubicin and cisplatin. No mutagenicity is detected when compounds are evaluated by cytokinesis-blocked micronucleus cytome and Ames test in the presence and absence of S9 metabolic activation from rat liver. Interaction studies show that compounds 1-3 can bind to DNA through electrostatic interactions and to albumin through hydrophobic interactions. The three compounds are able to inhibit the DNA supercoiled relaxation mediated by human topoisomerase IB (Top1). Compound 3 is the most efficient Top1 inhibitor and the inhibitory effect is enhanced upon pre-incubation with the enzyme. Analysis of different steps of Top1 catalytic cycle indicates that 3 inhibits the cleavage reaction impeding the binding of the enzyme to DNA and slows down the religation reaction. Molecular docking shows that 3 preferentially binds closer to the residues of the active site when Top1 is free and lies on the DNA groove downstream of the cleavage site in the Top1-DNA complex. Thus, 3 can be considered in further studies for a possible use as an anticancer agent.

This study describes the synthesis of a new ruthenium nitrosyl complex with the formula [RuCl(2)NO(BPA)] [BPA = (2-hydroxybenzyl)(2-methylpyridyl)amine ion], which was synthesized and characterized by spectroscopy, cyclic voltammetry, X-ray crystallography, and theoretical calculation data. The biological studies of this complex included in vitro cytotoxic assays, which revealed its activity against two different tumor cell lines (HeLa and Tm5), with efficacy comparable to that of cisplatin, a metal-based drug that is administered in clinical treatment. The in vivo studies showed that [RuCl(2)NO(BPA)]is effective in reducing tumor mass. Also, our results suggest that the mechanism of action of [RuCl(2)NO(BPA)] includes binding to DNA, causing fragmentation of this biological molecule, which leads to apoptosis., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)

The synthesis and characterization of ruthenium compounds of the type [RuCl(2)(NO)(dppp)(L)]PF(6) [dppp=1,3-bis(diphenylphosphino)propane; L=pyridine, 4-methylpyridine, 4-phenylpyridine and dimethyl sulfoxide] are described. The complexes were characterized by elemental analysis, UV/Vis and infrared spectroscopy, cyclic voltammetry, and X-ray crystallography for the complexes with the pyridine and 4-methylpyridine ligands. In vitro evaluation of these nitrosyl complexes revealed cytotoxic activity from 7.1 to 19.0 microM against the MDA-MB-231 breast tumor cells and showed that, in this case, they are more active than the reference metallodrug cisplatin. The 1,3-bis(diphenylphosphino)propane and the N-heterocyclic ligands alone failed to show cytotoxic activities at the concentrations tested (maximum concentration utilized=200 microM).

We have synthesized and characterized three new ruthenium(II) diphosphine complexes containing an acylthiourea ligand, with the general formula [Ru(DPEPhos)(O,S)(bipy)]PF6, where DPEPhos = bis(2-(diphenylphosphino)phenyl)ether, bipy = 2,2′-bipyridine, and O,S = N,N-dimethyl-N′-(benzoyl)thiourea (1), N,N-dimethyl-N′-(furoyl)thiourea (2), and N,N-dimethyl-N′-(thiophenyl)thiourea (3), by several physicochemical techniques. We evaluated the ruthenium complexes for their cytotoxicity against two human cancer cell lines, A549 (lung) and MDA-MB-231 (breast), and two corresponding lines of non-cancer cells, MRC-5 (lung) and MCF-10A (breast). All the complexes are cytotoxic against the cancer cell lines; the IC50 values lie in the micromolar range (0.07–0.70 μM). Ruthenium complex 1 is more selective (7 times more active) toward lung cancer cells (A549) than toward non-cancer cells (MRC-5) and is 160 times more cytotoxic than cisplatin against A549 cells. Investigations of the mechanism of action of complex 1 in A549 cells demonstrated that it inhibits colony formation and promotes cell cycle arrest in the G1 phase and apoptotic cell death. DNA binding studies revealed that complexes 1–3 interact with the biomolecule via minor grooves. These complexes also interact with human serum albumin (HSA) and have affinity for site I by hydrophobic forces. Therefore, this new class of ruthenium complexes can act as cytotoxic agents, mainly for lung cancer treatment. [ABSTRACT FROM AUTHOR]

Six new ruthenium(II) complexes with lapachol (Lap) and lawsone (Law) with the general formula [Ru(L)(P–P)(bipy)]PF6, where L = Lap or Law, P–P = 1,2′-bis(diphenylphosphino)ethane (dppe), 1,4′-bis(diphenylphosphino)butane (dppb), 1,1′-bis(diphenylphosphino)ferrocene (dppf) and bipy = 2,2′-bipyridine, were synthesized, fully characterized by elemental analysis, molar conductivity, NMR, cyclic voltammetry, UV-vis, IR spectroscopies and three of them by X-ray crystallography. All six complexes were active against breast (MCF-7 and MDA-MB-231) and prostate (DU-145) cancer cell lines with lower IC50 values than cisplatin. Complex [Ru(Lap)(dppe)(bipy)]PF6 (1a) showed significant selectivity for MDA-MB-231, a model of triple-negative breast cancer (TNBC), as compared to the "normal-like" human breast epithelial cell line, MCF-10A. Complex (1a) inhibited TNBC colony formation and induced loss of cellular adhesion. Furthermore, the complex (1a) induced mitochondrial dysfunction and generation of ROS, as is involved in the apoptotic cell death pathway. Preferential cellular uptake of complex (1a) was observed in MDA-MB-231 cells compared to MCF-10A cells, consistent with the observed selectivity for tumorigenic vs. non-tumorigenic cells. Taken together, these results indicate that ruthenium complexes containing lapachol and lawsone as ligands are promising candidates as chemotherapeutic agents. [ABSTRACT FROM AUTHOR]

Reaction of the precursor cis,fac-[RuCl2(dmso-S)3(dmso-O)] with three carbazate ligands led to new compounds of the type cis,fac-[RuCl2(dmso-S)3(L)] (L = benzylcarbazate (bc), 1; 4-methoxybenzylcarbazate (mc), 2; or 3,5-dimethoxy-α,α-dimethylbenzylcarbazate (mmc), 3). Complexes 1–3 have been characterized by elemental analysis (CHN), FTIR, UV–vis, and 1H and 13C{1H} NMR spectroscopy. Complex 1 was also analyzed by single-crystal X-ray diffraction and theoretical calculations were performed in order to better understand its spectroscopic data and electronic structure. All collected data were consistent with substitution of one dmso ligand by a monodentate carbazate ligand. Preliminary biological assays against breast and prostate human cancer cell lines were performed in order to evaluate the cytotoxic activity of these three new complexes. [ABSTRACT FROM AUTHOR]

Triple-negative breast cancer (TNBC) is a highly aggressive breast cancer subtype. The high rate of metastasis associated to the fact that these cells frequently display multidrug resistance, make the treatment of metastatic disease difficult. Development of antitumor metal-based drugs was started with the discovery of cisplatin, however, the severe side effects represent a limitation for its clinical use. Ruthenium (Ru) complexes with different ligands have been successfully studied as prospective antitumor drugs. In this work, we demonstrated the activity of a series of biphosphine bipyridine Ru complexes (1) [Ru(SO4)(dppb)(bipy)], (2) [Ru(CO3)(dppb)(bipy)], (3) [Ru(C2O4)(dppb)(bipy)] and (4) [Ru(CH3CO2)(dppb)(bipy)]PF6 [where dppb = 1,4-bis(diphenylphosphino)butane and bipy = 2,2’-bipyridine], on proliferation of TNBC (MDA-MB-231), estrogen-dependent breast tumor cells (MCF-7) and a non-tumor breast cell line (MCF-10A). Complex (4) was most effective among the complexes and was selected to be further investigated on effects on tumor cell adhesion, migration, invasion and in apoptosis. Moreover, DNA and HSA binding properties of this complex were also investigated. Results show that complex (4) was more efficient inhibiting proliferation of MDA-MB-231 cells over non-tumor cells. In addition, complex (4) was able to inhibit MDA-MB231 cells adhesion, migration and invasion and to induce apoptosis and inhibit MMP-9 secretion in TNBC cells. Complex (4) should be further investigated in vivo in order to stablish its potential to improve breast cancer treatment. [ABSTRACT FROM AUTHOR]

We herein report the synthesis and characterization of Ru(II)/amino acid complexes with general formula [Ru(AA-H)(dppb)(4-mebipy)](PF6), where AA-H means the deprotonated amino acids Gly, Ala, Val, Met, Trp, Tyr, and Ser; dppb is 1,4-bis(diphenylphosphino)butane and 4-mebipy = 4,4′-dimethyl-2,2′-bipyridine. The complexes were characterized by31P{1H},13C, and1H NMR spectroscopy, as well as X-ray crystallographic analysis of [Ru(DL-Ala-H)(dppb)(4-mebipy)]+, suggesting the presence of diastereoisomers. The complexes exhibit IC50values against breast tumor cells (MDA-MB-231) comparable with cisplatin. In addition, the Ru(II)-based complex with tryptophan inhibited tumor cell adhesion to collagen type I. Therefore, the use of ruthenium complexes containing amino acids can be an interesting tool for development of new therapeutic agents. [ABSTRACT FROM AUTHOR]

Over the past several decades, much attention has been focused on ruthenium complexes in antitumor therapy. Ruthenium is a transition metal that possesses several advantages for rational antitumor drug design and biological applications. In the present study, five ruthenium complexes containing amino acids were studied in vitro to determine their biological activity against sarcoma-180 tumor cells. The cytotoxicity of the complexes was evaluated by an MTT assay, and their mechanism of action was investigated. The results demonstrated that the five complexes inhibited the growth of the S180 tumor cell line, with IC50 values ranging from 22.53 µM to 50.18 µM, and showed low cytotoxicity against normal L929 fibroblast cells. Flow cytometric analysis revealed that the [Ru(gly)(bipy)(dppb)]PF6 complex (2) inhibited the growth of the tumor cells by inducing apoptosis, as evidenced by an increased number of Annexin V-positive cells and G0/G1 phase cell cycle arrest. Further investigation showed that complex 2 caused a loss of mitochondrial membrane potential; activated caspases 3, caspase-8, and caspase-9 and caused a change in the mRNA expression levels of caspase 3, caspase-9 as well as the bax genes. The levels of the pro-apoptotic Bcl-2 family protein Bak were increased. Thus, we demonstrated that ruthenium amino acid complexes are promising drugs against S180 tumor cells, and we recommend further investigations of their role as chemotherapeutic agents for sarcomas. [ABSTRACT FROM AUTHOR]

Tuberculosis is an ancient disease that is still present as a global public health problem. Our group has been investigating new molecules with anti-TB activity. In this context, inorganic chemistry has been a quite promising source of such molecules, with excellent results seen with ruthenium compounds. Nanostructured lipid systems may potentiate the action of drugs by reducing the required dosage and side effects and improving the antimicrobial effects. The aim of this study was to develop a nanostructured lipid system and then characterize and apply these encapsulated compounds (SCARs 1, 2 and 4) with the goal of improving their activity by decreasing the Minimum Inhibitory Concentration (MIC90) and reducing the cytotoxicity (IC50). The nanostructured system was composed of 10% phase oil (cholesterol), 10% surfactant (soy oleate, soy phosphatidylcholine and Eumulgin®) and 80% aqueous phase (phosphate buffer pH = 7.4). Good activity against Mycobacterium tuberculosis was maintained after the incorporation of the compounds into the nanostructured lipid system, while the cytotoxicity decreased dramatically, in some cases up to 20 times less toxic than the unencapsulated drug. [ABSTRACT FROM AUTHOR]

Abstract: N 4-Methyl-4-nitrobenzaldehyde thiosemicarbazone (H4NO2Fo4M), N 4-methyl-4-nitrobenzophenone thiosemicarbazone (H4NO2Bz4M) and their ruthenium(II) complexes [Ru(4NO2Fo4M)2(PPh3)2] (1), [Ru(4NO2Bz4M)2(PPh3)2] (2), [Ru(4NO2Fo4M)2(dppb)] (3) and [Ru(4NO2Bz4M)2(dppb)] (4) (dppb=1,4-bis(diphenylphospine)butane) were obtained and characterized. The crystal structure of H4NO2Fo4M has been determined. Electrochemical studies have shown that the nitro anion radical, one of the proposed intermediates in the mechanism of action of nitro-containing anti-trypanosomal drugs, is formed at approximately −1.00V in the free thiosemicarbazones as well as in their corresponding ruthenium(II) complexes, suggesting their potential to act as antitrypanosomal drugs. The natural fluorescence of H4NO2Fo4M, H4NO2Bz4M and complexes (1)–(4) provides a way to identify and to monitor their concentration in biological systems. [Copyright &y& Elsevier]

Examines ruthenium complexes containing chelating ditertiary phosphine ligands. Reaction of the ruthenium complex with chlorine; X-ray crystallographic analysis of the complexes; Cyclic voltammetric measurements of the complexes; Effective precursors for catalytic asymmetric halogenation.

Ruthenium(II) complexes with 6-methyl-2-thiouracil cis-[Ru(6m2tu)2(PPh3)2] (1) and [Ru(6m2tu)2(dppb)] (2) (where PPh3 = triphenylphosphine; dppb = 1,4-bis(diphenylphosphino)butane; and 6m2tu = 6-methyl-2-thiouracil) are potent cytotoxic agents and able to bind DNA. The aim of this study was to evaluate in vitro cellular underlying mechanism and in vivo effectiveness of these ruthenium(II) complexes in human acute promyelocytic leukemia HL-60 cells. Both complexes displayed potent and selective cytotoxicity in myeloid leukemia cell lines, and were detected into HL-60 cells. Reduction of the cell proliferation and augmented phosphatidylserine externalization, caspase-3, -8 and -9 activation and loss of mitochondrial transmembrane potential were observed in HL-60 cells treated with both complexes. Cotreatment with Z-VAD(OMe)-FMK, a pan-caspase inhibitor, reduced Ru(II) complexes-induced apoptosis. In addition, both metal complexes induced phosphorylation of histone H2AX (S139), JNK2 (T183/Y185) and p38α (T180/Y182), and cotreatment with JNK/SAPK and p38 MAPK inhibitors reduced complexes-induced apoptosis, indicating DNA double-strand break and activation of caspase-mediated apoptosis through JNK/p38 pathways. Complex 1 also reduced HL-60 cell growth in xenograft model. Overall, the outcome indicated the ruthenium(II) complexes with 6-methyl-2-thiouracil as a novel promising antileukemic drug candidates. [ABSTRACT FROM AUTHOR]

The efficacy of organoruthenium complexes containing ergosterol biosynthesis inhibitors (CTZ: clotrimazole, KTZ: ketoconazole and FCZ: fluconazole) against tumor cells, and their interaction with important macro-biomolecules such as human serum albumin and DNA have been investigated here. Our experimental results indicated that these ruthenium(II) complexes present spontaneous electrostatic interactions with albumin, and act as minor groove binders with the DNA. The ability of these Ru(II)–azole complexes to inhibit the proliferation of selected human tumor and non-tumor cell lines was determined by MTT assay. Complexes [RuCl(CTZ)(η6-p-cymene)(PPh3)]PF6 (3) and [RuCl(KTZ)(η6-p-cymene)(PPh3)]PF6 (4) were shown to be between 3- and 40-fold more cytotoxic than the free ligands and the positive control cisplatin. Complex 3 was selected to continue studies on the triple negative breast tumor cell line MDA-MB-231, inducing morphological changes, loss of adhesion, inhibition of colony formation, and migration through Boyden chambers, cell cycle arrest in the sub-G1 phase, and a mechanism of cell death by apoptosis. All these interesting results show the potential of this class of organometallic Ru(II) complexes as an antiproliferative agent. [ABSTRACT FROM AUTHOR]

Ruthenium-based compounds represent a class of potential antineoplastic drugs. Recently, we designed, synthesized, and identified the Ru(II)-thymine complex [Ru(PPh3)2(Thy)(bipy)]PF6 (where PPh = triphenylphosphine, Thy = thymine and bipy = 2,2′-bipyridine) as a potent cytotoxic agent with the ability to bind to DNA and human and bovine serum albumins. In this study, the underlying cytotoxic mechanism of the [Ru(PPh3)2(Thy)(bipy)]PF6 complex was assessed. This complex displayed potent cytotoxicity in different cancer cell lines; the morphology that is associated with apoptotic cell death, increased internucleosomal DNA fragmentation without cell membrane permeability, loss of the mitochondrial transmembrane potential, increased phosphatidylserine externalization, and caspase-3 activation were observed in human promyelocytic leukemia HL-60 cells that were treated with the complex. Moreover, pretreatment of HL-60 cells with Z-VAD(OMe)-FMK, a pan-caspase inhibitor, partially reduced the apoptosis that was induced by the complex, indicating that the apoptotic cell death occurred through a caspase-mediated pathway. In conclusion, the [Ru(PPh3)2(Thy)(bipy)]PF6 complex displays potent cytotoxicity to different cancer cells and induces caspase-mediated apoptosis in HL-60 cells. [ABSTRACT FROM AUTHOR]

Hepatic cancer is one of the main causes of cancer-related death worldwide. Cancer stem cells (CSCs) are a unique subset of cancer cells that promote tumour growth, maintenance, and therapeutic resistance, leading to recurrence. In the present work, the ability of a ruthenium complex containing 1,3-thiazolidine-2-thione (RCT), with the chemical formula [Ru(tzdt)(bipy)(dppb)]PF 6 , to inhibit hepatic CSCs was explored in human hepatocellular carcinoma HepG2 cells. RCT exhibited potent cytotoxicity to solid and haematological cancer cell lines and reduced the clonogenic potential, CD133+ and CD44high cell percentages and tumour spheroid growth of HepG2 cells. RCT also inhibited cell motility, as observed in the wound healing assay and transwell cell migration assay. RCT reduced the levels of Akt1, phospho-Akt (Ser473), phospho-Akt (Thr308), phospho-mTOR (Ser2448), and phospho-S6 (Ser235/Ser236) in HepG2 cells, indicating that interfering with Akt/mTOR signalling is a mechanism of action of RCT. The levels of active caspase-3 and cleaved PARP (Asp214) were increased in RCT-treated HepG2 cells, indicating the induction of apoptotic cell death. In addition, RCT modulated the autophagy markers LC3B and p62/SQSTM1 in HepG2 cells and increased mitophagy in a mt-Keima-transfected mouse embryonic fibroblast (MEF) cell model, and RCT-induced cytotoxicity was partially prevented by autophagy inhibitors. Furthermore, mutant Atg5-/- MEFs and PentaKO HeLa cells (human cervical adenocarcinoma with five autophagy receptor knockouts) were less sensitive to RCT cytotoxicity than their parental cell lines, indicating that RCT induces autophagy-mediated cell death. Taken together, these data indicate that RCT is a novel potential anti-liver cancer drug with a suppressive effect on CSCs. [Display omitted] • RCT exhibits potent cytotoxicity to solid and haematological cancer cells. • RCT causes elimination of hepatic CSCs from HCC HepG2 cells. • RCT inhibits HCC HepG2 cell motility. • RCT suppresses Akt/mTOR signalling in HCC HepG2 cells. • RCT induces apoptotic and autophagic cell death in HCC HepG2 cells. [ABSTRACT FROM AUTHOR]

Abstract: Phosphine ruthenate complexes containing the non-innocent ligands 4-chloro-1,2-phenylenediamine (opda-Cl) and 3,3′,4,4′-tetraamminebiphenyl (diopda) were synthesized and characterized by means of X-ray diffraction, electrochemistry, 31P{1H} NMR and electronic spectroscopies. Crystals of cis-[RuCl2(dppb)(bqdi-Cl)] complex were isolated as a mixture of two conformational isomers due to different positions of the chlorine atoms of the o-phenylene ligand in relation to the P1 atom of the phosphine moiety. [Copyright &y& Elsevier]

Graphical abstract Highlights • A series of novel ruthenium complexes containing lawsone were synthesized. • The complexes showed potent anticancer activity against several tumor cells. • Complex (4) exhibited remarkable anticancer activity against prostate tumor spheroids. • Complex (4) inhibits DU-145 cell adhesion and migration potential. • Complex (4) induced DU-145 cell apoptosis through elevated intracellular ROS. Abstract This study describes a series of newly synthesized phosphine/diimine ruthenium complexes containing the lawsone as bioligand with enhanced cytotoxicity against different cancer cells, and apoptosis induction in prostatic cancer cells DU-145. The complexes [Ru(law)(N-N) 2 ]PF 6 where N-N is 2,2′-bipyridine (1) or 1,10-phenanthroline (2) and [Ru(law)(dppm)(N-N)]PF 6 , where dppm means bis (diphenylphosphino)methane, N-N is 2,2′-bipyridine (3) or 1,10-phenanthroline (4), and law is lawsone, were synthesized and fully characterized by elemental analysis, molar conductivity, NMR, UV–vis, IR spectroscopies and cyclic voltammetry. The interaction of the complexes (1 – 4) with DNA was evaluated by circular dichroism, gel electrophoresis, and fluorescence, and the complexes presented interactions by the minor grooves DNA. The phosphinic series of complexes exhibited a remarkably broad spectrum of anticancer activity with approximately 34-fold higher than cisplatin and 5-fold higher than doxorubicin, inhibiting the growth of 3D tumor spheroids and the ability to retain the colony survival of DU-145 cells. Also, the complex (4) inhibits DU-145 cell adhesion and migration potential indicating antimetastatic properties. The mechanism of its anticancer activity was found to be related to increased reactive oxygen species (ROS) generation, increased the BAX/BCL-2 ratio and subsequent apoptosis induction. Overall, these findings suggested that the complex (4) could be a promising candidate for further evaluation as a chemotherapeutic agent in the prostate cancer treatment. [ABSTRACT FROM AUTHOR]

Graphical abstract A new Ru(η6- p -cymene) bearing the naproxen-pyridineamide (Npxpya) is synthesized and characterized by ESI-MS, NMR, ATR/FT-IR, UV/VIS and DFT computational calculations. Photophysical properties, antiproliferative activity, effects on mitochondrial membrane potential and cell cycle arrest in lung cancer cells are reported. All data are compared with those of Ru(II)- p -cymene-naproxenate, and the Npxpya and naproxen drugs. Highlights • The new Ru(II)- p -cymene bearing naproxen-pyridineamide (Npxpya) is synthesized. • Characterization is performed by ESI-MS, NMR, ATR/FT-IR, UV/VIS, DFT calculations. • Photophysical properties are described. • Biological properties in lung cancer cells are reported. • Comparative data for Ru(II)- p -cymene-naproxenate, Npxpya and naproxen are provided. 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)-η6- p -cymene framework with naproxen-pyridineamide (Npxpya, L1), a structurally modified form of the naproxen (HNpx, HL2) drug, to give the new organometallic [Ru(η6- p -cymene)(L1)Cl 2 ] (1) bearing the Npxpya ligand. The reported naproxenate-derived, [Ru(η6- p -cymene)(L2)Cl] (2) , is re-prepared, also from the precursor [Ru(η6- 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 1H 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(η6- 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 L1 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 IC 50 close to the IC 50 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 1H 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. [ABSTRACT FROM AUTHOR]

[Display omitted] • The chemistry of ruthenium/acylthiourea ligands is reviewed. • The coordination properties of acylthiourea ligands are highlighted. • This review covers anticancer activity, in vitro , of Ru(II)/acylthiourea complexes. • Structure-activity relationships and trends are discussed. This review outlines research on the development of ruthenium complexes containing acylthiourea ligands with potential antitumor activity, which have been leveraged in recent years. Also, this review sheds light on the fact that the coordination of biologically active acylthiourea molecules has been yielding a variety of complexes with superior biological activity to their precursor complexes and free ligands. The structure–activity relationships for several structure scaffolds of ruthenium complexes with different coordination modes of both, N-mono- and disubstituted acylthiourea ligands, are discussed here in relation to in vitro cytotoxic properties and in vivo antitumor activity. Another insight gained from this review is the understanding of the correlation between the nature of the substituents on the amide and thioamide moieties of the acylthiourea ligands, and the cytotoxic activity of their respective complexes. Furthermore, the mode of binding of Ru-acylthiourea complexes to DNA is explored to provide information on whether the biomolecule is a possible primary target of these compounds, and thus, whether it is a justification for the cytotoxic action of the complexes. [ABSTRACT FROM AUTHOR]

Thirteen new ruthenium amino acid complexes were synthesized and characterized. They were obtained by the reaction of α-amino acids (AA) with [RuCl 2 (P-P)(N-N)], where P-P = 1,4-bis(diphenylphosphino)butane (dppb) or 1,3-bis(diphenylphosphino)propane (dppp) and N-N = 4,4′-dimethyl-2,2′-bipyridine (4′-Mebipy), 5,5′-dimethyl-2,2′-bipyridine (5′-Mebipy) or 4,4′-Methoxy-2-2′-bipyridine (4′-MeObipy). This afforded a family of complexes formulated as [Ru(AA-H)(P-P)(N-N)]PF 6 , where AA = glycine (Gly), L-alanine (Ala), L-valine (Val), L-tyrosine (Tyr), L-tryptophan (Trp), L-histidine (His) and L-methionine (Met). All compounds were characterized by elemental analysis, spectroscopic and electrochemical techniques. The [Ru(AA-H)(P-P)(N-N)]PF 6 complexes are octahedral (the AA-H ligand binding involves N-amine and O-carboxylate), diamagnetic (low-spin d 6 , S = 0) and present bands due to electronic transitions in the visible region. 1 H, 13 C{ 1 H} and 31 P{ 1 H} NMR spectra of the complexes indicate the presence of C 2 symmetry, and the identification of diastereoisomers. In vitro cytotoxicity assays of the compounds and cisplatin were carried out using MDA-MB-231 (human breast) tumor cell line and a non-tumor breast cell line (MCF-10A). Most complexes present promising results with IC 50 values comparable with the reference drug cisplatin and high selectivity indexes were found for the complexes containing L-Trp. The binding of two Ru-precursors of the type [RuCl 2 (dppb)(N N)] (N-N = 4′-MeObipy or 4′-Mebipy) to the blood transporter protein human serum albumin (HSA) was evaluated by fluorescence and circular dichroism spectroscopy. Both complexes bind HSA, probably in the hydrophobic pocket near Trp214, and the Ru-complex containing 4′-MeObipy shows higher affinity for HSA than the 4′-Mebipy one. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

We report here on three new ruthenium(II) complexes, [Ru(DPEPhos)(mtz)(bipy)]PF 6 (Ru1), [Ru(DPEPhos)(mmi)(bipy)]PF 6 (Ru2) and [Ru(DPEPhos)(dmp)(bipy)]PF 6 (Ru3). DPEPhos = bis -[(2-diphenylphosphino)phenyl]ether, mtz = 2-mercapto-2-thiazoline, mmi = 2-mercapto-1-methylimidazole, dmp = 4,6-diamino-2-mercaptopyrimidine and bipy = 2,2′-bipyridine. The compounds were characterized by several spectroscopic techniques, and the molecular structure of Ru1 complex was determined by single-crystal X-ray diffraction. The cytotoxicity of Ru1 – Ru3 complexes were tested against the A549 (human lung) and the MDA-MB-231 (human breast) cancer cell lines and against MRC-5 (non-tumor lung) and MCF-10A (non-tumor breast) cell lines through the MTT assay. All three complexes are cytotoxic against the cell lines studied, with IC 50 values lower than those found for the cisplatin. Among them, the Ru2 complex has shown the best selectivity against MDA-MB-231 cancer cell lines, with an IC 50 value 12 times lower than that on MCF-10A. The complex Ru2 was capable to induce changes in MDA-MB-231 cells morphology, with loss of cellular adhesion, inhibited colony formation and induce an accumulation of cells at the sub-G1 phase, with an increase in S-phase and decrease of cells at G2 phase. Viscosity, electrochemical and Hoechst 33258 displacement experiments for Ru1 – Ru3 complexes with calf thymus DNA (CT-DNA) showed an electrostatic and groove binding mode of interaction. Additionally, the complexes interact with the protein Human Serum Albumin (HSA) by static mechanism. The negative values for ΔH and ΔS indicate that van der Waals forces and hydrogen bonding may occurs between the complexes and HSA. Therefore, this class of complexes are promising anticancer candidates and may be selected to further detailed studies. N,S-mercapto ligands can form new ruthenium compounds with promising cytotoxic activity against cancer cell lines. [Display omitted] • Ru(II)/N,S-mercapto complexes with promising anticancer properties. • Cytotoxic activity against breast and lung cancer cells. • Selectivity is reported against breast cancer cells. • Complexes interact with CT-DNA and Human Serum Albumin (HSA). • Complex inhibited colony formation and induce an accumulation of cells at the sub-G1 phase. [ABSTRACT FROM AUTHOR]

• Three new Ru(II) complexes were prepared. • Full characterization is reported. • Single-crystal X-ray diffraction confirm the molecular structures. • DFT are in agreement with experimental data. Reactions of cis -[RuCl 2 (P-P)(bipy)] precursors with the SpymMe 2 ligand (4,6-dimethyl-2-pyrimidinethiol) yielded complexes of the [Ru(SpymMe 2)(P-P)(bipy)]PF 6 type, where P-P = 1,2-bis(diphenylphosphino)ethane (dppe - for complex 1), 1,3-bis(diphenylphosphino)propane (dppp - for complex 2) and 1,1'-bis(diphenylphosphino)ferrocene (dppf - for complex 3) and bipy = 2,2'-bipyridine. The new compounds were obtained by displacing the chlorido ligands from the precursors and coordination of one monoanionic 4,6-dimethyl-2-pyrimidinethiol ligand. All complexes were characterized by spectroscopic, electrochemical and elemental analysis techniques, as well as single-crystal X-ray diffraction, where the structures of complexes 1, 2 and 3 showed that the SpymMe 2 ligand coordinates to the ruthenium(II) center as bidentated, yielding complexes with the sulfur atom trans positioned to the nitrogen atom from the bipy ligand. A theoretical study of the structures of the complexes was performed using the DFT/B3LYP method. Distances and angles of optimized structures agree with X-ray experimental data. Furthermore, the calculated IR and UV-Vis spectra are compatible with experimental data. Charge decomposition analysis (CDA) and NBO (natural bond orbitals) charges showed that there was an overall charge transfer from bipy and P-P ligands to the ruthenium centers. Higher electrochemical stability and 1H and 31P{1H} NMR shifts of 1, 2 and 3 compared with precursors could be explained by the lower values of calculated molecular orbital energies, NBO charge on atoms and CDA data. Finally, the structure of the isomers of complexes 1, 2 and 3, considering the sulfur atom trans positioned to the phosphorus atom, were optimized, showing that they are slightly less stable, presenting total energy higher, 10.4, 31.5 and 60.5 kJ/mol than 1, 2 and 3 , where nitrogen is trans to the phosphorus atom. [ABSTRACT FROM AUTHOR]

Six new complexes of Ru(II)/phenanthroline/1,4-bis(diphenylphosphino)butane containing amino acids (Glycine, l -Alanine, l -Valine, l -Tyrosine, l -Methionine or l -Tryptophan) were synthesized and characterized by IR, 31 P{ 1 H}, 13 C and 1 H NMR spectroscopies and cyclic voltammetry experiments. These data suggest the presence of diastereoisomers, except for the complex with glycine, amino acid that does not exhibit chiral carbon. The compounds are active against the MDA-MB-231 tumor cells and against Mycobacterium tuberculosis . The cationic ruthenium complexes with amino acids, reported here, show similar cytotoxicity against the MDA-MB-231 tumor cells. When compared with analogs complexes containing 2,2′-bipyridine as ligands, instead of 1,10-phenatroline, the new complexes studied here are, in general, roughly twice more active than the 2,2′-bipyridine ones and their IC 50 values comparable with the cisplatin. In addition, low MICs values were obtained against Mycobacterium tuberculosis compared with the reference drugs, cycloserine and ethambutol. [ABSTRACT FROM AUTHOR]

In this work we present the synthesis and characterization of six new ruthenium compounds with general formulae [Ru(L)(dppb)(bipy)]PF 6 and [Ru(L)(dppe) 2 ]PF 6 where L = salicylic acid (Sal), 4-aminosalicylic acid (AmSal) or 2,4-dihydroxybenzoic acid (DiSal), dppb = 1,4- bis (diphenylphosphino)butane, dppe = 1,2- bis (diphenylphosphino)ethane and bipy = 2,2′-bipyridine. The complexes were characterized by elemental analysis, molar conductivity, cyclic voltammetry, NMR, UV–vis and IR spectroscopies, and two by X-ray crystallography. The 31P{1H} NMR spectra of the complexes with the general formula [Ru(L)(dppe) 2 ]PF 6 showed that the phosphorus signals are solvent-dependent. Aprotic solvents, which form strong hydrogen bonds with the complexes, inhibit the free rotation of the salicylic acid-based, modifying the diphosphine cone angles, leading to distortion of the phosphorus signals in the NMR spectra. The cytotoxicity of the complexes was evaluated in MCF-7, MDA-MB-231, SKBR3 human breast tumor cells, and MCF-10 non-tumor cell lines. The complexes with the structural formula [Ru(L)(dppe) 2 ]PF 6 were the most cytotoxic, and the complex [Ru(AmSal)(dppe) 2 ]PF 6 with L = 4-aminosalicylic acid ligand was the most selective for the MDA-MB-231 cell line. This complex interacts with the transferrin and induces apoptosis through the intrinsic pathway, as demonstrated by increased levels of proteins involved in apoptotic cell death. [Display omitted] • Six Ru(II) complexes of salicylic acid and derivatives were synthesized. • Complex [Ru(AmSal)(dppe) 2 ]PF 6 – Ru(5) was the most selective against TNBC. • Ru(5) inhibited colony formation by acting as a cytotoxic and cytostatic agent. • Ru(5) induced tumor cells apoptosis, altering the mitochondrial membrane potential. • Ru (5) induced cell death through intrinsic apoptotic pathway signaling. [ABSTRACT FROM AUTHOR]

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 (1H, 13C), 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. Two new Ru(II) complexes with bipyridine or phenanthroline and lapachol as ligands were synthesized, characterized, and their properties were evaluated against several cancer cells, showing anti-cancer activity in vitro by inducing ROSmediated cytotoxicity. Genotoxicity studies were also performed using the Ames test, which attested that both complexes do not induce gene mutations. [Display omitted] • Novel Ru(II)-bipyridine/phenanthroline complexes containing lapachol were synthesized. • The complexes showed cytotoxic activity against several cancer cells. • The cytotoxicity of the complexes is related to the ROS-mediated pathway. • Complexes may bind to DNA via a minor groove. • None of the complexes induce DNA significant mutations. [ABSTRACT FROM AUTHOR]

Four ruthenium(II)-based complexes with N -(acyl)- N ′, N ′-(disubstituted)thiourea derivatives (Th) were obtained. The compounds, with the general formula trans -[Ru(PPh 3 ) 2 (Th)(bipy)]PF 6 , interact with bovine serum albumin (BSA) and DNA. BSA-binding constants, which were in the range of 3.3–6.5 × 10 4 M − 1 , and the thermodynamic parameters (ΔG, ΔH and ΔS), suggest spontaneous interactions with this protein by electrostatic forces due to the positive charge of the complexes. Also, binding constant by spectrophotometric DNA titration (Kb = 0.8–1.8 × 10 4 M − 1 ) and viscosity studies indicate weak interactions between the complexes and DNA. Cytotoxicity assays against DU-145 (prostate cancer) and A549 (lung cancer) tumour cells revealed that the complexes are more active in tumour cells than in normal (L929) cells, and that they present high cytotoxicity (low IC 50 values) compared with the reference metallodrug, cisplatin. [ABSTRACT FROM AUTHOR]

Three promising antimycobacterium tuberculosis ruthenium(II) complexes with the deprotonated ligands 2-hydroxynicotinic acid (2-OHnicH), 6-hydroxynicotinic acid (6-OHnicH) and 3-hydroxypicolinic acid (3-OHpicH) were synthesized and characterized. Structural analysis revealed three different coordination modes depending of the hydroxypyridinecarboxylate ligand. In the complex [Ru(2-OHnic)(dppb)(bipy)]PF 6 ( 1 ), the 2-OHnic anion is coordinated by the O,O-chelating mode (via carboxylate group and phenolate oxygen), in the [Ru(6-OHnic)(dppb)(bipy)]PF 6 ( 2 ) a O–O chelation by the carboxylate group is observed for the 6-OHnic ligand and for the complex [Ru(3-OHpic)(dppb)(bipy)]PF 6 ( 3 ) a N,O-chelating mode (via carboxylate) occurs to the 3-OHpic anion. The compounds were evaluated for activity against Mycobacterium tuberculosis H 37 Rv ATCC 27294 using Resazurin Microtitre Assay (REMA) plate method and cytotoxicity in VERO CCL-81 cell line. All the synthesized compounds exhibited good antimycobacterial activity and a completely lack of cytotoxicity activity, indicating a good selectivity index. [ABSTRACT FROM AUTHOR]

Amino acid/diphosphine ruthenium complexes, of general formula [Ru(AA-H)(dppb)(bipy)]PF 6 [AA = amino acid: glycine (gly), l -alanine (ala), l -tyrosine (tyr), l -methionine (met), l -leucine (leu), l -valine (val), l -serine (ser), l -tryptophan (trp), and l -lysine(lys); dppb = 1,4-bis(diphenylphosphino)butane; bipy = 2,2′-bipyridine], were synthesized and characterized. The X-ray structures of the glycine and leucine complexes showed that the amino acids are coordinated to the metal center through the carboxylate and amine groups. The complexes, except for the glycine ligand, form two different conformational isomers, as suggested by X-ray structure determination of the complex with leucine, and shown by 31 P{ 1 H} NMR analysis. The cyclic and differential pulse voltammograms of the complexes exhibited an oxidation potential (Ru II /Ru III ) close to 1.0 V, against Ag/AgCl. Toxicity tests against the MDA-MB-231 and DU 145 human tumor cell lines and the Ehrlich mouse cell line indicated a high degree of cytotoxicity for the amino acid complexes. The intrinsic binding constants ( K b ) for the amino acid complexes were determined and found to be in the range of 1.40 × 10 4 –1.80 × 10 4 M −1 , suggesting weak interactions of the complexes with DNA. [ABSTRACT FROM AUTHOR]

Abstract: This work links aspects of non-covalent interaction among gold nanoparticles (AuNPs) and ruthenium complexes, which were used to modify the surface of the glassy carbon electrode (GCE), without the necessity of a sulfur substrate with a covalent bond between gold–sulfur (Au–S), to keep the AuNPs onto the surface of the electrode. The AuNPs were synthesized by the method of encapsulation by citrate conferring on them a negative charge. The ruthenium complex [RuCl(dppb)(bipy)(4-vpy]+ was synthesized by ligand exchange in its coordination sphere, giving it a positive charge. A thin film of [RuCl(dppb)(bipy)(4-vpy)]+ was generated onto the surface of glassy carbon electrode (GCE), using cyclic voltammetry, under potential cycling between −0.9 and −2.4V, to produce the CGE–Ru+ electrode. Afterward, the GCE–Ru+ electrode was kept in a colloidal suspension of AuNPs for 1h to incorporate them onto the surface of GCE–Ru+ by electrostatic interaction. The resulting electrode GCE–Ru–AuNPs was finally washed with water to remove the excess of AuNPs and it was used to acetaminophen detection by cyclic voltammetry. To find the optimum analysis conditions of the modified electrode, studies were conducted to understand; which were: the number of cyclic voltammograms to produce the film, dip-coating time in AuNPs, pH, scan rate and repeatability. The Ru–AuNPs aggregates were analyzed by UV–Vis spectroscopy (UV–Vis), Fourier transform infrared spectroscopy–attenuated total reflectance (FTIR–ATR), nuclear magnetic resonance of phosphorus (31P{1H} NMR), cyclic voltammetry (CV); scanning electron microscopy with energy dispersive spectroscopy (SEM–EDS) and transmission electron microscopy with energy dispersive spectroscopy (TEM–EDS). The X-ray structure of [RuCl(dppb)(5,5′-Me-bipy)(4-vpy)](PF6) was determinate. [Copyright &y& Elsevier]

Highlights: [•] Two solvate forms of fac-[RuCl3(NO)(dppb)] were obtained. [•] Guest acetone and chloroform were identified by XRD and FT-IR analysis. [•] Solvent inclusion affects the molecular structure of the complex. [•] Weak intermolecular interactions kept the solvent caged. [ABSTRACT FROM AUTHOR]

Abstract: The arene–ruthenium complex [Ru(η6-C10H14)(dppf)Cl]PF6 (1) was used as a precursor for the syntheses of the [Ru(η6-C10H14)(dppf)Br]PF6 (2), [Ru(η6-C10H14)(dppf)I]PF6 (3), [Ru(η6-C10H14)(dppf)SnF3]PF6 (4) and [Ru(η6-C10H14)(dppf)Cl][SnCl3]·0.45CH2Cl2 (5) complexes by its reactions with KBr, KI, SnF2 and SnCl2, respectively. All of the compounds were characterized by NMR, IR, 57Fe and 119Sn-Mössbauer spectroscopy, and cyclic voltammetry. The single-crystal X-ray structure analysis of the [Ru(η6-C10H14)(dppf)Cl][SnCl3]·0.45CH2Cl2 complex revealed the expected piano-stool geometry. Cyclic voltammograms of the complexes showed only one quasi-reversible electrochemical process, involving the oxidation of Fe(II) and Ru(II) at the same potential, which was confirmed by exhaustive electrolysis experiments. 57Fe-Mössbauer parameters obtained for the complexes (1–5) were fitted with one doublet corresponding to a site of one iron(II). The 119Sn-Mössbauer parameters of the complex (4) indicate that tin is tetra covalent. [Copyright &y& Elsevier]

Abstract: This paper describes the synthesis and characterization of four new ruthenium complexes containing 1,4 bis(diphenylphosphino)butane (dppb), 2-pyridinecarboxylic acid anion (pic) and the diimines [(2,2′-bipyridine (bipy), 4,4′-dimethyl-2,2′-bipyridine (Me-bipy), 4,4′-dichloro-2,2′-bipyridine (Cl-bipy) and 1,10-phenanthroline (phen) as ligands, with formulae [Ru(pic)(dppb)(bipy)]PF6 (SCAR01), [Ru(pic)(dppb)(Me-bipy)]PF6 (SCAR02), [Ru(pic)(dppb)(Cl-bipy)]PF6 (SCAR03) and [Ru(pic)(dppb)(phen)]PF6 (SCAR04). Additionally, the in vitro anti-Mycobacterium tuberculosis (MTB) activity, cytotoxicity and activity against in vitro infection of these complexes and two more complexes, cis-[Ru(pic)(dppe)2]PF6 (SCAR05) and cis-[RuCl2(dppb)(bipy)] (SCAR06), and their free ligands are described and discussed. All compounds showed excellent MIC against MTB, low cytotoxicity and a selectivity index higher than 10. Also, all compounds showed significant intracellular inhibition and the compound SCAR05 showed a better activity than rifampin and SQ109. This is the first report of activity against in vitro infection of ruthenium compounds. [Copyright &y& Elsevier]

Abstract: The synthesis and characterization of ruthenium compounds of the type [RuCl2(NO)(dppp)(L)]PF6 [dppp=1,3-bis(diphenylphosphino)propane; L=pyridine, 4-methylpyridine, 4-phenylpyridine and dimethyl sulfoxide] are described. The complexes were characterized by elemental analysis, UV/Vis and infrared spectroscopy, cyclic voltammetry, and X-ray crystallography for the complexes with the pyridine and 4-methylpyridine ligands. In vitro evaluation of these nitrosyl complexes revealed cytotoxic activity from 7.1 to 19.0μM against the MDA-MB-231 breast tumor cells and showed that, in this case, they are more active than the reference metallodrug cisplatin. The 1,3-bis(diphenylphosphino)propane and the N-heterocyclic ligands alone failed to show cytotoxic activities at the concentrations tested (maximum concentration utilized=200μM). [Copyright &y& Elsevier]

Abstract: The synthesis, characterization and the anti-Mycobacterium tuberculosis (MTB) activities of three ruthenium complexes containing the 2-pyridinecarboxylic acid anion (picolinate), with formulae cis- [Ru(pic)(dppm)2]PF6 (1), cis- [Ru(pic)(dppe)2]PF6 (2) and [Ru(pic)2(PPh3)2] (3) [pic=2-pyridinecarboxylate; dppm=bis(diphenylphosphino)methane; dppe=1,2-bis(diphenylphosphino)ethane; PPh3 =triphenylphosphine] are reported in this article. The complexes were characterized by elemental analysis, spectroscopic and electrochemical techniques. Their in vitro antimycobacterial activity was determinated as the Minimum Inhibitory Concentration (MIC) for MTB cell growth, measured by the REMA method. The best MICs were found for complexes (1) and (2), with values of 0.78 and 0.26μg/mL, respectively. The results are comparable to or better than “first line” or “second line” drugs commonly used in the treatment of TB. [Copyright &y& Elsevier]

Abstract: The reaction of cis-[RuCl2(P–P)(N–N)] type complexes (P–P=1,4-bis(diphenylphosphino)butane or (1,1′-diphenylphosphino)ferrocene; N–N=2,2′-bipyridine or 1,10-phenantroline) with monodentate ligands (L), such as 4-methylpyridine, 4-phenylpyridine and benzonitrile forms [RuCl(L)(P–P)(N–N)]+ species. Upon characterization of the isolated compounds by elemental analysis, 31P{1H} NMR and X-ray crystallography it was found out that the type of the L ligand determines its position in relation to the phosphorus atom. While pyridine derivatives like 4-methylpyridine and 4-phenylpyridine coordinate trans to the phosphorus atom, the benzonitrile ligand (bzCN), a good π acceptor, coordinates trans to the nitrogen atom. A 31P{1H} NMR experiment following the reaction of the precursor cis-[RuCl2(dppb)(phen)] with the benzonitrile ligand shows that the final position of the entering ligand in the complex is better defined as a consequence of the competitive effect between the phosphorus atom and the cyano-group from the benzonitrile moiety and not by the trans effect. In this case, the benzonitrile group is stabilized trans to one of the nitrogen atoms of the N–N ligand. A differential pulse voltammetry experiment confirms this statement. In both experiments the [RuCl(bzCN)(dppb)(phen)]PF6 species with the bzCN ligand positioned trans to a phosphorus atom of the dppb ligand was detected as an intermediate complex. [Copyright &y& Elsevier]

Abstract: The chemistry of Ru(III) complexes containing dmso as a ligand has become an interesting area in the cancer treatment field. Because of this, structural knowledge and chemistry of the moiety Ru(III)–dmso have become important to cancer research. The crystal structures of the compounds mer-[RuCl3(dms)3] (1) and mer-[RuCl3(dms)2(dmso)]:mer-[RuCl3(dms)3] (2) were determined by X-ray crystallography and a speciation of the presence of intramolecular hydrogen bond in these structures has been studied. Compound (1) crystallizes in the orthorhombic space group, Pna21; a =16.591(8)Å, b =8.724(2)Å, c =10.547(3)Å; Z =12 and (2) crystallizes in the space group, P21/C; a =11.9930(2)Å, b =7.9390(2) Å, c =15.8700(3)Å, β =93.266(1)°, Z =2. From the X-ray structures solved in this work, were possible to suggest an interpretation for the broad lines observed in the EPR spectra of the Ru(III) compounds explored here. Also, the exchange interactions detected by EPR spectroscopy in solid state and in solution, confirm the presence of van der Waals interactions such as C–H…Cl in the compounds (1), (2) and (3). The use of techniques such as IR, UV–vis, 1H NMR and EPR Spectroscopy and Cyclic Voltammetry were applied in this work to analyze the behavior of these metallocompounds. [Copyright &y& Elsevier]

Abstract: The reaction of cis-[RuCl2(dppb)(N–N)], dppb=1,4-bis(diphenylphosphino)butane, complexes with the ligand HSpymMe2, 4,6-dimethyl-2-mercaptopyrimidine, yielded the cationic complexes [Ru(SpymMe2)(dppb)(N–N)]PF6, N–N=bipy (1) and Me-bipy (2), bipy=2,2′-bipyridine and Me-bipy=4,4′-dimethyl-2,2′-bipyridine, which were characterized by spectroscopic and electrochemical techniques and X-ray crystallography and elemental analysis. Additionally, preliminary in vitro tests for antimycobacterial activity against Mycobacterium tuberculosis H37Rv ATCC 27264 and antitumor activity against the MDA-MB-231 human breast tumor cell line were carried out on the new complexes and also on the precursors cis-[RuCl2(dppb)(N–N)], N–N=bipy (3) and Me-bipy (4) and the free ligands dppb, bipy, Me-bipy and SpymMe2. The minimal inhibitory concentration (MIC) of compounds needed to kill 90% of mycobacterial cells and the IC50 values for the antitumor activity were determined. Compounds 1–4 exhibited good in vitro activity against M. tuberculosis, with MIC values ranging between 0.78 and 6.25μg/mL, compared to the free ligands (MIC of 25 to >50μg/mL) and the drugs used to treat tuberculosis. Complexes 1 and 2 also showed promising antitumor activity, with IC50 values of 0.46±0.02 and 0.43±0.08μM, respectively, against MDA-MB-231 breast tumor cells. [Copyright &y& Elsevier]

Abstract: Complex fac-[RuCl3(NO)(P–N)] was synthesized from [RuCl3(H2O)2(NO)] in methanol solution under reflux. The orange solid obtained was characterized by NMR (31P{1H}, 1H, 13C) and, cyclic voltammetry, ESI-MS, IR, elemental analysis and X-ray diffraction structure determination. The 31P{1H} reveals the presence of singlet at 36ppm. IR N–O stretching as KBr pellets or CH2Cl2 solution presented 1866cm−1 and 1872cm−1, respectively. [Copyright &y& Elsevier]

Abstract: The [Ru(dppb)(mbt)2], mbt=2-mercaptobenzothiazole, complex, isolated from the reaction of the mer-[RuCl3(dppb)(OH2)] complex with the 2,2′-dithiobis(benzothiazole), mbts, was characterized by spectroscopic and electrochemical techniques (E 1/2 =0.78V versus NHE) and its structure was determined by crystal X-ray analysis. The structural analysis suggests that the S–S bond of the mbts ligand is cleaved, thus forming two four-membered chelate rings coordinated to the ruthenium through the N,S-donor atoms of the mbt reduced ligands, with an average bite angle of 67.295(11)°. The 1H and 13C NMR signals observed for mbts ligand coordinated to the metal center, the changes in the vibrational spectra, and the appearance of a MLCT band in the electronic spectrum of the complex point for the reduced state of the ruthenium metal center, RuII. These reducing processes are suggested to be due to the methanol interference, which is observed to be strongly affected by N-methylmorpholine. The cytochrome c electrochemistry was analyzed by using the SAMs formed by the mbts and the [Ru(dppb)(mbt)2] complex on gold, with only the former presenting electroactivity. [Copyright &y& Elsevier]

The fac-[RuCl3(NO)(dppb)] complex I has been prepared from solution of the correspondent mer isomer in refluxing methanol (dppb=1,4-bis(diphenylphosphino)butane). The mer-[RuCl3(NO)(diop)] (II) has been obtained from the mer-[RuCl3(diop)(H2O)] by bubbling NO for 1 h in dichloromethane (diop=2S,3S-O-isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino)butane). The complexes have been characterized by microanalysis, cyclic voltammetry (CV), IR and 31P{1H} NMR spectroscopies. The crystal and molecular structures of these two compounds have been determined from X-ray studies. The mer-[RuCl3(NO)(dppb)] isomer III was characterized in solution by NMR spectra (31P{1H}, 1H{31P}, 31P&z.sbnd;1H HETCORR, COSY 1H&z.sbnd;1H, HMQC 1H&z.sbnd;13C and HMBC 1H&z.sbnd;13C). [Copyright &y& Elsevier]

The use of natural products as potential ligands has been explored as a strategy in the development of metal-based chemotherapy. Since ruthenium complexes are promising alternatives to traditional antitumor agents, this study evaluated the anti-melanoma potential of two ruthenium(II) complexes containing the naphthoquinone ligands lapachol (lap), [Ru(lap)(dppm) 2 ]PF 6 , and lawsone (law), [Ru(law)(dppm) 2 ]PF 6 , in addition to the bis (diphenylphosphino)methane (dppm) ligand, referred to as complexes (1) and (2), respectively, using a syngeneic murine melanoma model. Activation of the apoptotic pathway by the treatments was assessed by immunohistochemistry in tumor tissue. Additionally, toxicity of the treatments was evaluated by variation in body and organ weight, quantification of biochemical indicators of renal damage, and genotoxicity in bone marrow and hepatocytes. First, the antiproliferative activity of (1) and (2) was observed in B16F10 cells, with IC 50 values of 2.78 and 1.68 μM, respectively. The results obtained in mice showed that, unlike complex (1), (2) possesses significant anti-melanoma activity demonstrated by a reduction in tumor volume and mass (88.42%), as well as in mitosis frequency (83.86%). Additionally, complex (2) increased the levels of cleaved caspase-3, inducing tumor cell apoptosis. When compared to the metallodrug cisplatin, complex (2) exhibited similar anti-melanoma activity and lower toxicity considering all parameters evaluated. In silico studies demonstrated no difference in the binding energy of the naphthoquinone complex between complexes (1) and (2). However, the complex containing the lawsone ligand has a lower molar volume, which may be important for interactions with minor DNA grooves. The present results demonstrate the antitumor efficiency of complex (2) and a significantly lower systemic toxicity compared to cisplatin. Ruthenium complex containing the lawsone (Ru-Law) ligand significant exhibited anti-melanoma activity, unlike complex containing the lapachol. Ru-Law increased the levels of cleaved caspase-3, inducing tumor cell apoptosis. Ru-Law has a lower molar volume, which may be important for interactions with minor DNA grooves. Ru-Law showed lower systemic toxicity than cisplatin. [Display omitted] • Ru(law)(dppm) 2 ]PF 6 [Ru-Law; Law, lawsone; dppm, bis (diphenylphosphino)methane] prepared. • Ru-Law exhibited anti-melanoma activity. • Ru-Law increased the levels of cleaved caspase-3, inducing tumor cell apoptosis. • Ru-Law showed significantly lower systemic toxicity compared to cisplatin. [ABSTRACT FROM AUTHOR]

The complexes [Ru(Tyr-)(dppe) 2 ]Cl (1) and [Ru(Ser-)(dppe) 2 ]Cl (2) [Tyr = 8tyrosinate; Ser = 8serinate; dppe = 81,2-bis(diphenylphosphino)ethane] were synthesized and their in vitro cytotoxicities against the MDA-MB-231 cell line were determined by MTT assay. In vivo toxicity assessment on zebrafish embryos showed that although the higher concentration of complex (1) has caused lethality of embryos, the effects of the concentration equivalent to the IC 50 of complex (1) and cisplatin were similar in the hatching rate, mortality rate and morphological changes. [Display omitted] Reaction of α-amino acids (HL) with the precursor cis -[RuCl 2 (dppe) 2 ] [HL = tyrosine (Tyr) or serine (Ser); dppe = 1,2-bis(diphenylphosphino)ethane] afforded the complexes [Ru(L−)(dppe) 2 ]Cl {[Ru(Tyr-)(dppe) 2 ]Cl (1) and [Ru(Ser-)(dppe) 2 ]Cl (2)}. The new ruthenium complexes, with formulae [Ru(Tyr-)(dppe) 2 ]Cl (1) and [Ru(Ser-)(dppe) 2 ]Cl (2) were synthesized and characterized on the basis of elemental analysis, molar conductivity, IR/UV–Vis and 31P{1H} NMR spectra. The in vitro cytotoxicities of the complexes against the MDA-MB-231 (breast adenocarcinoma) cell line were determined by the MTT assay. Complexes (1) and (2) show good cytotoxicity profiles against the MDA-MB-231 cell line with IC 50 values of 2.05 ± 0.71 μM and 5.64 ± 0.72 μM, respectively, which are in the same order of values obtained for the metallodrug cisplatin (2.44 ± 0.20 μM) in the same assay. The selectivity indexes were significant for both complexes, showing lower cytotoxicity activity against the non-tumor breast cell line MCF-10A, with SI of 5.0 and 3.2, respectively. In addition, the lipophilicities of these complexes were determined and their interactions with human serum albumin (HSA) protein were investigated by fluorescence. The lipophilicities of the complexes suggest that this property has a significant effect on their cytotoxicity and the interaction measurements of the complexes with HSA indicate that the static fluorescence quenching mechanism is the main one involved in the formation of (1)-HSA and (2)-HSA adducts. Moreover, Van der Waalś interactions and hydrogen bonds in (1)-HSA and electrostatic interaction in (2)-HSA are the predominant intermolecular forces between the complexes and the biomolecule. Furthermore, the antioxidant activity of the complexes was determined using the superoxide radical scavenging method, in vitro. Complex (1) was found to present a higher antioxidative activity, showing to be better than the standard antioxidant, vitamin C. In vivo toxicity assessment on zebrafish embryos showed that although the higher concentration of complex (1) has caused lethality of embryos, the effects of the concentration equivalent to the IC 50 of complex (1) and cisplatin were similar in the hatching rate, mortality rate and morphological changes, showing a potential of complex (1) as a new anticancer agent. [ABSTRACT FROM AUTHOR]