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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]

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]

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]

The success of a classic inorganic coordination compound, Cisplatin, cis -[Pt(NH 3) 2 Cl 2 ], as the first anticancer metallodrug started a field of research dedicated to discovering coordination compounds with antitumor activity, encompassing various metals. Among these, copper complexes have emerged as interesting candidates to develop drugs to treat cancer. In this work, mixed ligand complexes of Cu(II) with diimines (phenanthroline or 4-methylphenanthroline) and 3-(4-hydroxyphenyl)propanoate, phenylcarboxylate or phenylacetate were synthesized. They were characterized in the solid state, including a new crystal structure of [Cu 2 (3-(4-hydroxyphenyl)propanoate) 3 (phenanthroline) 2 ]Cl·H 2 O. The obtained complexes presented a variety of stoichiometries. In solution, complexes were partially dissociated in the corresponding Cu-diimine complex. The complexes bound to the DNA by partial intercalation and groove binding, as assessed by Circular Dichroism, relative viscosity change and UV–Vis titration. The cytotoxicity of the complexes was determined in vitro on MDA-MB-231, MCF-7 (human metastatic breast adenocarcinomas, the first triple negative), MCF-10A (breast nontumoral), A549 (human lung epithelial carcinoma), and MRC-5 (human nontumoral lung epithelial cells), finding an activity higher than that of Cisplatin, although with less selectivity. Six copper complexes with diimines and phenylcarboxylates as ligands were characterized. Their DNA binding and cytotoxic activity were assessed, and they were found to present high cytotoxic activity. [Display omitted] • Six copper complexes with diimines and phenylcarboxylates as ligands were characterized. • The crystal structure of [Cu 2 (3-(4-hydroxyphenyl)propanoate) 3 (phen) 2 ]Cl·H 2 O is reported. • Cu-diimine-phenylcarboxylate complexes are highly cytotoxic to cancer cells. [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]

New Ru(II) complexes with lawsone (law) characterized as trans- [Ru(law)(PPh 3 ) 2 (N-N)]PF 6 , where PPh 3 means triphenylphosphine and N-N is 2,2′-bipyridine ( 1 ), 4,4′-dimethyl-2,2′-bipyridine ( 2 ), 4,4′-dimethoxy-2,2′-bipyridine ( 3 ), 1,10-phenanthroline ( 4 ) or 4,7-diphenyl-1,10-phenanthroline ( 5 ), induce apoptosis in tumor cells. Cytotoxicity of the complexes against the tumor cell lines DU-145 (prostate cancer cells), MCF-7 (breast cancer cells), A549 (lung cancer cells) and lung non-tumor cell line MRC-5 demonstrated promising IC 50 values, lower than those found for the cisplatin, a drug used as a reference. Due to the high cytotoxic activity and selectivity against A549 cells line, complex ( 5 ) was selected for detailed assays. The complex ( 5 ) inhibits cells migration in concentrations in a nanomolar range, inducing tumor cell death by apoptosis, as confirmed by flow cytometry experiments. Furthermore, the antiproliferative activity of complex ( 5 ) on A549 tumor cells is attributed to a cell cycle arrest at the Sub G1 phase, followed by a decrease in the number of cells at the S phase. In addition, the interaction of the complexes ( 1 – 5 ) with CT-DNA was evaluated by circular dichroism, in which no changes in the secondary structure of DNA were observed, suggesting a weak interaction of the complexes with the biomolecule. On the other hand, complexes ( 1 – 5 ) showed a higher interaction with human serum albumin (HSA) by non-covalent van der Waals forces and hydrogen bonding, resulting in static quenching. [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]

This study reports on the synthesis of a new ruthenium(II) complex, cis -[Ru(PPh 3 ) 2 (lap) 2 ] ( 1 ) with two molecules of the natural product known as lapachol [lap = (2-hydroxy-3-(3-methyl-2-buthenyl)-1,4-naphthoquinone)] coordinated as bidentated by oxygen atoms and two monodentate PPh 3 (triphenylphosphine) in a cis configuration. This neutral complex was characterized by spectroscopic analysis, single-crystal X-ray diffraction, elemental analysis, molar conductivity and cyclic voltammetry. In this study, ruthenium complex trans -[Ru(lap)(PPh 3 ) 2 (phen)]PF 6 ( 2 ) was used for comparison purposes. The interaction of ruthenium complexes ( 1 ) and ( 2 ) with CT-DNA was evaluated by UV–Vis and circular dichroism and it was observed that the complexes interact weakly with the CT-DNA. The fluorescence measurements suggest that complex ( 1 ) shows stronger interaction with HSA and BSA proteins compared to complex ( 2 ). Cytotoxicity assays against A549 (lung cancer), MDA-MB-231 (breast cancer) and V79 (non-tumoral lung) revealed that complex ( 2 ) is more active (lower IC 50 values) than complex ( 1 ) and the cisplatin, used as a reference. [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]

Gallium and indium octahedral complexes with isoniazid derivative ligands were successfully prepared. The ligands, isonicotinoyl benzoylacetone (H 2 L 1 ) and 4-chlorobenzoylacetone isonicotinoyl hydrazone (H 2 L 2 ), and their respective coordination compounds with gallium and indium [GaL1(HL1)] (GaL 1 ) , [GaL2(HL2)] (GaL 2 ), [InL1(HL1)] (InL 1 ) and [InL2(HL2)] (InL 2 ) were investigated by NMR, ESI-MS, UV–Vis, IR, single-crystal X-ray diffraction and elemental analysis. In vitro interaction studies with human serum albumin (HSA) evidenced a moderate affinity of all complexes with HSA through spontaneous hydrophobic interactions. The greatest suppression of HSA fluorescence was caused by GaL 2 and InL 2 , which was associated to the higher lipophilicity of H 2 L 2 . In vitro interaction studies with CT-DNA indicated weak interactions of the biomolecule with all complexes. Cytotoxicity assays with MCF-7 (breast carcinoma), PC-3 (prostate carcinoma) and RWPE-1 (healthy human prostate epithelial) cell lines showed that complexes with H 2 L 2 are more active and selective against MCF-7, with the greatest cytotoxicity observed for InL 2 (IC 50 = 10.34 ± 1.69 μM). H 2 L 1 and H 2 L 2 were labelled with gallium-67, and it was verified that 67 GaL 2 has a greater lipophilicity than 67 GaL 1 , as well as higher stability in human serum or in the presence of apo -transferrin. Cellular uptake assays with 67 GaL 1 and 67 GaL 2 evidenced that the H 2 L 2 -containing radiocomplex has a higher accumulation in MCF-7 and PC-3 cells than the non-halogenated congener 67 GaL 1 . The anti- Mycobacterium tuberculosis assays revealed that both ligands and metal complexes are potent growth inhibitors, with MIC 90 (μg mL−1) values observed from 0.419 ± 0.05 to 1.378 ± 0.21. Bioactive gallium and indium complexes with isoniazid-derived ligands. [Display omitted] • Gallium and indium complexes with isoniazid-derived ligands were prepared and characterized. • Challenge assays with apo -tf and human serum were performed in aqueous solutions. • Metal complex interactions with human serum albumin and CT-DNA were evaluated. • Cytotoxicity assays were carried out against tumor and healthy cell lines. • In vitro assays showed all compounds as potent growth inhibitors of MTB (H 37 Rv). [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]

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 (PPh 3 ) 2 ] ( 2 ) and trans -[Ru(tzdt)(PPh 3 ) 2 (bipy)]PF 6 ( 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 (K b ) 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. [ABSTRACT FROM AUTHOR]

Tuberculosis is a top infectious disease killer worldwide, caused by the bacteria Mycobacterium tuberculosis . Increasing incidences of multiple drug-resistance (MDR) strains are emerging as one of the major public health threats. However, the drugs in use are still incapable of controlling the appalling upsurge of MDR. In recent years a marked number of research groups have devoted their attention toward the development of specific and cost-effective antimicrobial agents against targeted MDR-Tuberculosis. In previous studies, ruthenium(II) complexes (SCAR) have shown a promising activity against MDR-Tuberculosis although few studies have indeed considered ruthenium toxicity. Therefore, within the preclinical requirements, we have sought to determine the cyto-genotoxicity of three SCAR complexes in this present study. The treatment with the SCARs induced a concentration-dependent decrease in cell viability in CHO-K1 and HepG2 cells. Based on the clonogenic survival, SCAR 5 was found to be more cytotoxic while SCAR 6 exhibited selectivity action on tumor cells. Although SCAR 4 and 5 did not indicate any mutagenic activity as evidenced by the Ames and Cytokinesis block micronucleus cytome assays, the complex SCAR 6 was found to engender a frameshift mutation detected by Salmonella typhimurium in the presence of S9. Similarly, we observed a chromosomal damage in HepG2 cells with significant increases of micronuclei and nucleoplasmic bridges. These data indicate that SCAR 4 and 5 complexes did not show genotoxicity in our models while SCAR 6 was considered mutagenic. This study presented a comprehensive genotoxic evaluation of SCAR complexes were shown to be genotoxic in vitro . All in all, further studies are required to fully elucidate how the properties can affect human health. [ABSTRACT FROM AUTHOR]

The synthesis and spectroscopic characterization of nine π-arene piano–stool ruthenium (II) complexes with aromatic dinitrogen chelating ligands or containing chloroquine (CQ), are described in this study: [Ru(η 6 -C 10 H 14 )(phen)Cl]PF 6 ( 1 ), [Ru(η 6 -C 10 H 14 )(dphphen)Cl]PF 6 ( 2 ), [Ru(η 6 -C 10 H 14 )(bipy)Cl]PF 6 ( 3 ), [Ru(η 6 -C 10 H 14 )(dmebipy)Cl]PF 6 ( 4 ) and [Ru(η 6 -C 10 H 14 )(bdutbipy)Cl]PF 6 ( 5 ), [Ru(η 6 -C 10 H 14 )(phen)CQ](PF 6 ) 2 ( 6 ), [Ru(η 6 -C 10 H 14 )(dphphen)CQ](PF 6 ) 2 ( 7 ), [Ru(η 6 -C 10 H 14 )(bipy)CQ](PF 6 ) 2 ( 8 ), [Ru(η 6 -C 10 H 14 )(dmebipy)CQ](PF 6 ) 2 ( 9 ): [1,10-phenanthroline (phen), 4,7-diphenyl-1,10-phenanthroline (dphphen), 2,2′-bipyridine (bipy), 5,5′-dimethyl-2,2′-bipyridine (dmebipy), and 4,4′-di-t-butyl-2,2′-bipyridine (dbutbipy)]. The solid state structures of five ruthenium complexes ( 1 – 5 ) were determined by X-ray crystallography. Electrochemical experiments were performed by cyclic voltammetry to estimate the redox potential of the Ru II /Ru III couple in each case. Their interactions with DNA and BSA, and activity against four cell lines (L929, A549, MDA-MB-231 and MCF-7) were evaluated. Compounds 2 , 6 through 9 , interact with DNA which was comparable to the one observed for free chloroquine. The results of fluorescence titration revealed that these complexes strongly quenched the intrinsic fluorescence of BSA following a static quenching procedure. Binding constants (K b ) and the number of binding sites (n ~ 1) were calculated using modified Stern–Volmer equations. The thermodynamic parameters ΔG at different temperatures were calculated and subsequently the values of ΔH and ΔS were also calculated, which revealed that hydrophobic and electrostatic interactions play a major role in the BSA–complex association. The MTT assay results indicated that complexes 2 , 5 and 7 showed cytostatic effects at appreciably lower concentrations than those needed for cisplatin, chloroquine and doxorubicin. [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: The present study describes the synthesis, characterization, antileishmanial and antiplasmodial activities of novel diimine/(2,2′-bipyridine (bipy), 1,10-phenanthroline (phen), 4,4′-methylbipyridine (Me-bipy) and 4,4′-methoxybipyridine (MeO-bipy)/phosphine/ruthenium(II) complexes containing lapachol (Lap, 2-hydroxy-3-(3-33 methyl-2-buthenyl)-1,4-naphthoquinone) as bidentate ligand. The [Ru(Lap)(PPh3)2(bipy)]PF6 (1), [Ru(Lap)(PPh3)2(Me-bipy)]PF6 (2), [Ru(Lap)(PPh3)2(MeO-bipy)]PF6 (3) and[Ru(Lap)(PPh3)2(phen)]PF6 (4) complexes, PPh3 =triphenylphospine, were synthesized from the reactions of cis-[RuCl2(PPh3)2(X-bipy)] or cis-[RuCl2(PPh3)2(phen)], with lapachol. The [RuCl2(Lap)(dppb)] (5) [dppb=1,4-bis(diphenylphosphine)butane] was synthesized from the mer-[RuCl3(dppb)(H2O)] complex. The complexes were characterized by elemental analysis, molar conductivity, infrared and UV–vis spectroscopy, 31P{1H} and 1H NMR, and cyclic voltammetry. The Ru(III) complex, [RuCl2(Lap)(dppb)], was also characterized by the EPR technique. The structure of the complexes [Ru(Lap)(PPh3)2(bipy)]PF6 and [RuCl2(Lap)(dppb)] was elucidated by X-ray diffraction. The evaluation of the antiparasitic activities of the complexes against Leishmania amazonensis and Plasmodium falciparum demonstrated that lapachol–ruthenium complexes are more potent than the free lapachol. The [RuCl2(Lap)(dppb)] complex is the most potent and selective antiparasitic compound among the five new ruthenium complexes studied in this work, exhibiting an activity comparable to the reference drugs. [Copyright &y& Elsevier]

Abstract: The rational design of anticancer drugs is one of the most promising strategies for increasing their cytotoxicity and for minimizing their toxicity. Manipulation of the structure of ligands or of complexes represents a strategy for which is possible to modify the potential mechanism of their action against the cancer cells. Here we present the cytotoxicity of some new palladium complexes and our intention is to show the importance of non-coordinated atoms of the ligands in the cytotoxicity of the complexes. New complexes of palladium (II), with general formulae [Pd(PPh3)2(L)]PF6 or [PdCl(PPh3)(L)], where L=N,N-disubstituted-N′-acyl thioureas, were synthesized and characterized by elemental analysis, molar conductivity, melting points, IR, NMR(1H, 13C and 31P{1H}) spectroscopy. The spectroscopic data are consistent with the complexes containing an O, S chelated ligand. The structures of complexes with N,N-dimethyl-N′-benzoylthiourea, N,N-diphenyl-N′-benzoylthiourea, N,N-diethyl-N′-furoylthiourea, and N,N-diphenyl-N′-furoylthiourea were determined by X-ray crystallography, confirming the coordination of the ligands with the metal through sulfur and oxygen atoms, forming distorted square-planar structures. The N,N-disubstituted-N′-acyl thioureas and their complexes were screened with respect to their antitumor cytotoxicity against DU-145 (human prostate cancer cells), MDA-MB-231 (human breast cancer cells) and their toxicity against the L929 cell line (health cell line from mouse). [Copyright &y& Elsevier]

Abstract: The complexes [RuCl(SpymMe2-N,S)2(NO)] (1) and [Ru(dppb)(SpymMe2-N,S)2] (2) (dppb=1,4-bis(diphenylphosphino)butane, SpymMe2 =deprotonated 4,6-dimethyl-2-mercaptopyrimidine) were obtained and characterized by elemental analysis, spectroscopic techniques including X-ray crystallography, conductimetry and cyclic voltammetry. Energy Decomposition Analysis (EDA) calculation indicated strong intermolecular interaction between monomers of complex 1, as suggested by the 1H NMR spectrum of this complex, in chloroform solution. Additionally, preliminary tests were carried out, in order to evaluate the cytotoxicity activity on cancer cell lines of the new complexes, and the free ligands, against MDA-MB-231 (breast cancer), Hela (cervical cancer), U251 (glioma cancer) tumor cell lines and the V79 (Chinese lung fibroblast hamster) cell line. The best result was obtained for the complex 1 with IC50 value of 0.11±0.02, against MDA-MB-231 tumor cells. [Copyright &y& Elsevier]

Abstract: This study describes the synthesis of a new ruthenium nitrosyl complex with the formula [RuCl2NO(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 [RuCl2NO(BPA)]is effective in reducing tumor mass. Also, our results suggest that the mechanism of action of [RuCl2NO(BPA)] includes binding to DNA, causing fragmentation of this biological molecule, which leads to apoptosis. [Copyright &y& Elsevier]

Abstract: The aim of this study was to identify a candidate drug for the development of anti-tuberculosis therapy from previously synthesized compounds based on the thiosemicarbazones, semicarbazones, dithiocarbazates and hydrazide/hydrazones compounds. The minimal inhibitory concentration (MIC) of these compounds against Mycobacterium tuberculosis was determined. Their in vitro cytotoxicity to J774 cells (IC50) was determined to establish a selectivity index (SI) (SI=IC50/MIC). The best compounds were the thiosemicarbazones (2, 3 and 4) and the hydrazide/hydrazones (14, 15, 16 and 18). The results are comparable to or better than those of “first line” or “second line” drugs commonly used to treat TB, suggesting these compounds as anti-TB drug candidates. [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]

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]

This paper highlights the structural and biological aspects of seven Pd(II) complexes with acylthioureas. Interestingly, we observed that the S,N-chelation mode occurs when monosubstituted acylthioureas are used as ligands, while disubstituted acylthioureas give a S,O-coordination mode to the metal center. Seven new complexes (1 – 7) of Pd(II) with N- alkyl- and N , N -dialkyl- N ′-acylthioureas were prepared and characterized by elemental analysis and spectroscopic techniques. The crystal structures of the coordination compounds [PdCl(PPh 3)(5- cloropiridyl- N ′-benzoylthioureato-k2N,S)] (2), cis -[Pd(PPh 3) 2 (N -morpholyn- N ′-benzoylthioureato-k2O,S)]PF 6 (4) and cis -[Pd(PPh 3) 2 (N , N -diphenyl- N ′-thiophenylthioureato-k2O,S)]PF 6 (7) were determined by X-ray crystallography. The present study reports on an interesting contribution on the chemistry of Pd(II)/acylthiourea complexes, where the use of monosubstituted acylthiourea conducts to formation of neutral complexes with general formula [Pd(Cl)(PPh 3)(acylthiourea)], with a N,S-coordination mode. On the other hand, cationic complexes with formula [Pd(PPh 3) 2 (acylthiourea)]+, with O,S bidentately coordinated to the metal, are obtained by using a disubstituted acylthiourea derivative. The antitumor activity of the N -alkyl- and N , N -dialkyl- N ′-acylthiourea ligands and their palladium (II) complexes with synthesized triphenylphosphine were evaluated against the growth of the DU-145 tumor cells (prostate cancer cells), (MDA-MB-231 (breast cancer cells), L929 (healthy mouse cells). The ligands are not cytotoxic, but the complexes showed good cytotoxicity against the tumor cells tested in this work, and were even better, when compared to the IC 50 reported for the cisplatin. The complexes showed better activity results in MDA-MB-231 tumor cells, than for the DU-145 tumor cells. Complexes 1 and 6 showed high cytotoxic activity at low micromolar concentrations (IC 50 = 1.93 ± 0.45, 0.62 ± 0.08 μM) against MDA-MB-231 (human breast cancer cells). This result indicated that the binding of the ligands to the metal center increases their antitumor activity. [ABSTRACT FROM AUTHOR]

Ruthenium complexes are being considered as novel chemotherapeutic alternatives for cancer treatment. In our study, we assessed the antitumoral activities of novel ruthenium complexes coupled to the amino acids proline (RuPro) and threonine (RuThr) in prostate tumor cell lines (DU145) and breast (MCF7), and normal cell lines of the lung fibroblast (GM07492A). Our results revealed that the EC 50 of the complexes for DU145 and MCF7 was two times lower than that GM07492A. Moreover, RuPro and RuThr were not able to induce significant genomic instability, cell cycle arrest or cell death in GM07492A, but could induce DNA damage, arrest in G2/M and apoptosis in DU145 and MCF7. Furthermore, BAX, TP53 and ATM were found to be upregulated in DU145 and MCF7 treated with RuPro and RuThr, in which, a higher ASCT2 gene expression was also observed. Using molecular docking, RuPro and RuThr interact with ASCT2, suggesting that this transporter might have a pivotal role in the execution of their activities. Hence, our results with RuPro and RuThr are capable of selectively inducing genetic damage, cell cycle arrest and apoptosis in DU145 and MCF7. We suggest that the selective action of the RuPro and RuThr complexes is related to the higher expression of ASCT2 in the tumor cells. Unlabelled Image • Ruthenium (II) complexes with ligands N, O-chelating proline or threonine are cytotoxic to tumor cells. • EC 50 values in the range of 30 to 40 μM were determined in tumor cells. • The complexes also exhibit a genotoxic effect, cell cycle arrest and induce cell death by apoptosis. [ABSTRACT FROM AUTHOR]