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Abstract: Complexes [RuCl(H4NO2Fo4M)(bipy)(dppb)]PF6 (1), [RuCl(H4NO2Fo4M)(Mebipy)(dppb)]PF6 (2), [RuCl(H4NO2Fo4M)(phen)(dppb)]PF6 (3), [RuCl(H4NO2Ac4M)(bipy)(dppb)]PF6 (4), [RuCl(H4NO2Ac4M)(Mebipy)(dppb)]PF6 (5) and [RuCl(H4NO2Ac4M)(phen)(dppb)]PF6 (6) with N4 -methyl-4-nitrobenzaldehyde thiosemicarbazone (H4NO2Fo4M) and N4 -methyl-4-nitroacetophenone thiosemicarbazone (H4NO2Ac4M) were obtained from [RuCl2(bipy)(dppb)], [RuCl2(Mebipy)(dppb)], and [RuCl2(phen)(dppb)], (dppb = 1,4-bis(diphenylphospine)butane; bipy = 2,2′-bipyridine; Mebipy = 4,4′-dimethyl-2,2′-bipyridine; phen = 1,10-phenanthroline). In all cases the thiosemicarbazone is attached to the metal center through the sulfur atom. Complexes (1–6), together with the corresponding ligands and the Ru precursors were evaluated for their ability to in vitro suppress the growth of Trypanosoma cruzi. All complexes were more active than their corresponding ligands and precursors. Complexes (1–3) and (5) revealed to be the most active among all studied compounds with ID50 = 0.6–0.8 μM. In all cases the association of the thiosemicarbazone with ruthenium, dppb and bipyridine or phenanthroline in one same complex proved to be an excellent strategy for activity improvement. [Copyright &y& Elsevier]

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]

Abstract: [RuCl(L)(PPh3)2] complexes with 2-benzoylpyridine- and 2-pyridineformamide-derived thiosemicarbazones (HL) were obtained and fully characterized. The complexes form cis–trans isomers. The cis isomer is disfavored by the sterical effect of two bulky groups close to each other whereas the trans isomer is disfavored by the electronic effect of competition of two phosphorous for π-bonding d orbitals of the metal. Our results suggest that, although both factors may be operating simultaneously, in CH2Cl2 solution the balance of these counterpoising effects favors the formation of the trans isomer. [Copyright &y& Elsevier]

Abstract: The reaction product of fac-[RuCl3(NO)(dppm)], dppm=bis(diphenylphosphino)methane with the 2-mercaptopyridine ligand (pyS) in methanol, in the presence of triethylamine, is the nitrosyl derivative [Ru(pyS)2(NO)(dppmO-P)]PF6 (1). In this reaction the ‘pyS’ ligand displaces one of the phosphorus atoms of the dppm moiety and this dangling phosphorus is oxidized in the experimental conditions generating a mono–hapto dppmO. The X-ray crystal structure of the complex (2) shows sulfur atoms mutually trans and NO and P ligands trans to the pyridinic nitrogens. The ν NO band in the IR spectrum is at 1882cm−1 and in the cyclic voltammogram two processes at −0.45 and −1.15V (vs Ag/AgCl) are observed indicating a nitrosonium character for the coordinated NO. [Copyright &y& Elsevier]

Abstract: The reaction products of fac-[RuCl3(NO)(P–P)], [P–P=dppe (1) and c-dppen (2)] with the 4,6-dimethyl-2-mercaptopyrimidine ligand in methanol are the correspondent nitrosyl derivatives [Ru(‘SpymMe2’,-N,-S)(‘SpymMe2’,-S)(NO)(P–P)](PF6). These are the first reported ruthenium complexes containing both, nitrosyl and a pyrimidinethiol derivative. The X-ray crystal structure of complex 1 is reported. The intense ν NO bands in the IR spectra (KBr pellets) of complexes 1 and 2 are at 1850 and 1860 cm−1, respectively. The cyclic voltammetry of both complexes shows two reduction waves centered at the NO+ ligand. [Copyright &y& Elsevier]

Abstract: Ruthenium (II) complexes with the hemilabile ligand Ph2PCH2P(O)Ph2 (dppmO) were obtained and characterized by 31P{1H} NMR, IR and cyclic voltammetry. The reaction of the compound tcc-[RuCl2(η2-dppmO)2] with carbon monoxide yielded the complexes [RuCl2(CO)(η1,η2-dppmO)2] and [RuCl(CO)(η2-dppmO)2]PF6. For the tcc-[RuCl2(η2-dppmO)2] and [RuCl2(CO)(η1,η2-dppmO)2] species, two dimensional NMR analyses 31P–31P gCOSY, 13C–1H HSQC, 1H–31P HMBC were performed. Based on the resulting chemical shifts, coupling constants and correlations between 1H, 13C and 31P spectra it was possible to reveal the structures of these complexes in solution. The structure of the tcc-[RuCl2(η2-dppmO)2] complex was determined by X-ray diffraction, confirming the NMR results. The mer-[RuCl3(η1,η2-dppmO)2] complex was characterized by EPR and its crystal structure was also established by X-ray diffraction. The isomerization of tcc-[RuCl2(η2-dppmO)2] into cct-[RuCl2(η2-dppmO)2] was followed by UV–Vis spectroscopy and 31P{1H} NMR. [Copyright &y& Elsevier]

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]

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]

Abstract: 2-(Diphenylphosphinomethyl)aniline, H2L1, reacts with [RuCl2(PPh3)3] to yield the monomeric complexes [RuCl2(H2L1)(PPh3)(CH3CN)], [RuCl2(H2L1)2] and the chloro-bridged dimer [(H2L1)(PPh3)Ru(μ-Cl)2Ru(PPh3)(H2L1)] depending on the conditions applied. Exclusively the monochelate [RuCl2(H2L1)(dmso)2] is formed during reactions of H2L1 with [RuCl2(dmso)4]. H2L1 acts as a neutral, bidentate ligand in all complexes. The products are studied spectroscopically and by X-ray diffraction. [Copyright &y& Elsevier]

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]

Abstract: N 4-Methyl-4-nitroacetophenone thiosemicarbazone (H4NO2Ac4M, 1), N 4,N 4-dimethyl-4-nitroacetophenone thiosemicarbazone (H4NO2Ac4DM, 2) and N 4-piperidyl-4-nitroacetophenone thiosemicarbazone (H4NO2Ac4Pip, 3) and their copper(II) complexes [Cu(4NO2Ac4M)2] (4), [Cu(4NO2Ac4DM)2] (5) and [Cu(4NO2Ac4Pip)2] (6) were tested for their in vitro ability to inhibit the growth of Trypanosoma cruzi epimastigote forms. H4NO2Ac4DM (2), [Cu(4NO2Ac4M)2] (4) and [Cu(4NO2Ac4DM)2] (5) proved to be as active as the clinical reference drugs nifurtimox and benznidazol. Taking into consideration the serious side effects and the poor efficacy of the reference drugs, as well as the appearance of resistance during treatment, the studied compounds could constitute a new class of anti-trypanosomal drug candidates. [Copyright &y& Elsevier]

Abstract: The iron(III) complexes [Fe(2Am4DH)2]Cl (1), [Fe(2Am4Me)2]Cl (2) and [Fe(2Am4Et)2]Cl (3) with 2-pyridineformamide thiosemicarbazone (H2Am4DH) and its N(4)-methyl (H2Am4Me) and N(4)-ethyl (H2Am4Et) derivatives were obtained and characterized by means microanalyses, infrared and EPR spectra. The electrochemical behavior of the complexes was investigated. The thiosemicarbazones and complexes (1) and (2) presented toxicity against Artemia salina at low concentrations. Since this bioassay has a good correlation with cytotoxic activity in human solid tumors, the studied compounds present potential pharmacological applications. [Copyright &y& Elsevier]

Trans-[RuCl(NO)(dppe)2]2+ species were prepared. The complexes have been characterized by microanalysis, IR and 31P{1H} NMR spectroscopy and cyclic voltammetry. The trans-[RuCl(NO)(dppe)2](ClO4)2 complex shows a reversible one-electron-reduction process at E1/2 = 0.200 V and another one-electron-reduction irreversible process at −0.620 V, both centered at the NO+ group. The dissociation of the NO group from the trans-[RuCl(NO)(dppe)2]2+ after two one-electron reductions results in the formation of the trans- and cis-[RuCl2(dppe)2] isomers. The product of an electrolyzed solution of the same complex at −0.300 V shows an EPR signal consistent with the presence of the [RuCl(NO0)(dppe)2]+ complex. Crystal data for trans-[RuCl(NO)(dppe)2]2+·[RuCl4(NO)(H2O)]·1/2[RuCl6]4−·2[H2O] (I) and trans-[RuCl(NO)(dppe)2]2+·2[RuCl4(NO)(CH3O)]−·3[CH3OH] (II) are as follow: (I) Space group P-1, a=10.4040(3) A˚, b=12.3470(4) A˚, c=23.5620(8) A˚, α=95.885(2)°, β=99.608(2)°, γ=104.378(2)°, R=0.0521; (II) space group P-1, a=10.9769(2) A˚, b=13.2753(3) A˚, c=24.0287(4) A˚, α=99.743(1)°, β=95.847(1)°, γ=97.549(1)°; R=0.0496. The fac-[RuCl3(NO)(dppe)] (III) complex has been also prepared; its crystal data are: space group P21/n (No. 14), a=11.841(2) A˚, b=13.775(2) A˚, c=16.295(4) A˚, β=92.81(2)°; R1=0.0395. [Copyright &y& Elsevier]

Two cobalt(III) complexes containing different β-ketoesters, namely [CoIII(L1)(py 2 en)](ClO 4) 2 ·H 2 O (1) and [CoIII(L2)(py 2 en)](ClO 4) 2 (2) (py 2 en = N,N′ -bis(pyridin-2-ylmethyl)ethylenediamine; L1 − = methylacetoacetate; L2 − = ethyl 4-chloroacetoacetate) have been prepared and investigated as prototypes of bioreductive prodrugs. The presence of β-ketoester and py 2 en ligands in 1 and 2 , as well as the perchlorate counterions, was supported by IR spectroscopy and CHN elemental analysis. The composition molecular structure of both complexes was confirmed by NMR spectroscopy and ESI mass spectrometry. Structural information was also obtained for 2 via X-ray diffraction analysis. The redox properties indicate that 1 and 2 are suitable for reduction under biological conditions. Investigation of DNA-interacting suggest that 1 and 2 bind DNA via electrostatic forces. Both complexes may be employed as possible platforms for the delivery of biologically active compounds, since their reaction with ascorbic acid in PBS at pH 6.2 and 7.4 at 37°C results in the release of the β-ketoester ligands upon Co(III)/Co(II) reduction. O 2 -dependent redox activation of a cobalto(III) complex with release of β-ketoester drug prototypes. [Display omitted] • CoIII complexes have been designed for hypoxia-selective anticancer drug delivery. • Redox potential of CoIII-β-ketoesters complexes has been tuned by ancillary ligands. • Biological redox activation was successfully simulated using ascorbate reducing agent. • O 2 -dependent dissociation of the β-ketoesters has been achieved upon Co3+/Co2+ reduction. • DNA-interaction assays suggest that 1 and 2 bind DNA via electrostatic forces. [ABSTRACT FROM AUTHOR]

Abstract The rational design of anticancer agents that acts in specific biological targets is one of the most effective strategies for developing chemotherapeutic agents. Aiming at obtaining new ruthenium (II) compounds with good cytotoxicity against tumor cells, a series of new complexes of general formula [RuCl(PPh 3)(Hdpa)(N N)]Cl [PPh 3 = triphenylphosphine, N-N = 2,2′-dipyridylamine (Hdpa) (1), 1,2-diaminoethane (en) (2), 2,2′-bipyridine (bipy) (3), 5,5′-dimethyl-2,2′-bipyridine (dmbipy) (4), 1,10-phenanthroline (phen) (5) and 4,7-diphenyl-1,10-phenanthroline (dphphen) (6)] were synthesized. The complexes were characterized by elemental analysis and spectroscopic techniques (IR, UV/Visible, and 1D and 2D NMR) and three of their X-ray structures were determined: [RuCl(PPh 3)(Hdpa) 2 ]Cl, [RuCl(PPh 3)(Hdpa)(en)]Cl and [RuCl(PPh 3)(Hdpa)(dmbipy)]Cl. All the complexes are more cytotoxic against the cancer cell line than against the non-tumor cell line, highlighting complexes 1 and 5, which have an index selectivity of 18 and 15, respectively. The binding constants of compounds 1 – 6 with human serum albumin (HSA) were determined by tryptophan fluorescence quenching, indicating moderate to strong interactions. The binding mode of the complexes to calf thymus (CT) DNA was explored by several techniques, which reveal that only the dphphen compound 6 causes distortions in the secondary and tertiary structures of DNA. The studies demonstrated that the nature of the N N co-ligand and the presence of the PPh 3 and Hdpa ligands are features that can influence the binding affinity of the complexes by the biomolecules and in the cytotoxic activity of the complexes. Overall, the complexes with diimine co-ligand are much more cytotoxic than compound 2 with the aliphatic diamine. Graphical abstract The studies demonstrated that the nature of the N N (diamine or diimine) co-ligand in the new complexes, [RuCl(PPh 3)(Hdpa)(N N)]Cl (Hdpa = 2,2′-dipyridylamine), can influence the binding affinity by the human serum albumin (HSA) and DNA. Overall, the complexes with diimine co-ligand are much more cytotoxic than compound with the aliphatic diamine. Unlabelled Image Highlights • Ru (II)/phosphine complexes with low IC 50 values against the tumor cell lines MDA-MB-231; • The complexes are more cytotoxic against the cancer cell line than against the non-tumor cell line. • The complexes with diimine co-ligand are much more cytotoxicity than compound with the aliphatic diamine. • The interactions of the new compounds with DNA and human serum albumin (HSA) were studied. • The nature of the N N (diamine or diimine) co-ligand can influence the binding affinity of the complexes by the HSA and DNA. [ABSTRACT FROM AUTHOR]