Synthesis, structural characteristics, DNA binding properties and cytotoxicity studies of a series of Ru(III) complexes

Four related ruthenium(III) complexes, with the formula mer-[RuCl₃(dmso)(N−N)] (dmso = dimethyl sulfoxide; N−N = 2,2′-bipyridine (1), 1,10-phenantroline (2), dipyrido[3,2-f:2′,3′-h]quinoxaline (3) and dipyrido[3,2-a:2′,3′-c]phenazine (4)), have been reported. Complexes 3 and 4 are newly synthesized and characterized by X-ray diffraction. The hydrolysis process of 1-4 has been studied by UV-vis measurement, and it has been found that the extension of the N−N ligands can increase the stability of the complexes. The binding of these complexes with DNA has been investigated by plasmid cleavage assay, competitive binding with ethidium bromide (EB), DNA melting experiments and viscosity measurements. The DNA binding affinity is increased with the extension of the planar area of the N−N ligands, and complex 4 shows an intercalative mode of interaction with DNA. The in vitro anticancer activities of these compounds are moderate on the five human cancer cell lines screened.     

Hydrolysis and cytotoxic properties of osmium(II)/(III)-DMSO-azole complexes. Short communication

The antiproliferative properties of the osmium(II) complexes cis,fac-[Os(II)Cl(2)(DMSO)(3)(L)] and trans,cis,cis-[Os(II)Cl(2)(DMSO)(2)(L)(2)] (L = 1H-pyrazole, 1H-imidazole) were studied in three human cancer cell lines, namely 41M (ovary), SK-BR-3 (breast), and SW480 (colon). Their activities were compared with those of osmium(III) and ruthenium(III) NAMI-A type complexes on HT-29 (colon) and SK-BR-3 cancer cell lines. While IC(50) values of all the Os(II) complexes were found to be >1000 microM in all cell lines, Os and Ru-NAMI-A type complexes showed remarkable antiproliferative activity. The marginal in vitro cytotoxicity of the Os(II) compounds is presumably attributed to their resistance to hydrolysis. However, the Os-NAMI-A complexes, which are also kinetically stable in aqueous solution, showed reasonable antiproliferative activity in vitro when compared with the analogous Ru compounds and with the Os(II)-DMSO-azole species, indicating that hydrolysis might be not a prerequisite for the antitumor activity of Os-NAMI-A type complexes.     

X-ray crystallographic investigation and biological activities of Ru(III) complexes containing Schiff base and triphenyl phosphine/arsine

The crystal structures of the complexes [RuCl(Nap-o-phd)(AsPh₃)] and [RuBr(Nap-o-phd)(PPh₃)] (where H₂-Nap-o-phd = N,N′-bis(2-hydroxy-1-naphthaldehyde) o-phenylenediamine) have been determined by single crystal X-ray diffraction techniques. The antibacterial properties of the complexes have also been examined.     

Differences in structure, physiological stability, electrochemistry, cytotoxicity, DNA and protein binding properties between two Ru(III) complexes

A novel Ru(III) complex, mer-[RuCl(3)(CH(3)CN)(dpq)] (1), has been synthesized and characterized by X-ray diffraction, where dpq=dipyrido[3,2-d:2',3'-f]quinoxaline. Its chemical and biological properties have been intensively compared with those of mer-[RuCl(3)(DMSO)(dpq)] (DMSO=dimethyl sulfoxide) (2). It has been found that the stability in buffered solutions and the reduction potential for the Ru(III)/Ru(II) couple can be modulated by changing the small molecule bonded to the Ru(III) center. Interactions of 1 with DNA have been investigated by DNA melting experiments, DNA competitive binding with EB (ethidium bromide), plasmid DNA cleavage experiments and viscosity measurements. The interaction of 1 and 2 with BSA (bovine serum albumin) has also been studied using fluorescent quenching method. The experimental results show that 1 exerts higher affinity towards DNA and BSA than 2 does. The cytotoxicity of 1 has been evaluated by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) method, and 2 shows slightly higher anticancer potency than 1 does against all the cell lines screened. Attempts are made to clarify the possible antitumor mechanisms of these two complexes by analyzing the experimental results presented.     

Organogallium(III) complexes as apoptosis promoting anticancer agents for head and neck squamous cell carcinoma (HNSCC) cell lines

Organogallium(III) dinuclear (1-9) and tetranuclear (10) complexes present potential therapeutic agents for the treatment of various types of cancer. The antiproliferative activity of 1-10 was evaluated with cell lines of head and neck squamous cell carcinomas, e.g. HN (soft palate), Cal27, Cal33 (tongue) and FaDu (hypopharynx) cell lines. The activity of compound 8 is comparable with that of cisplatin on cell line Cal27 (IC₅₀ 4.6 μM for both compounds). The mode of cell death induced, caspase activity and cell cycle analysis were evaluated for potential hit compounds 3, 5 and 8 Potential hit compounds 3, 5 and 8 were further evaluated for the mode of cell death, caspase activity and cell cycle analysis. Apoptosis induced by compounds 3, 5 and 8 on Cal27 and FaDu cells was confirmed by DNA laddering , as well as acridine orange (AO) and ethidium bromide (EB) double staining. These compounds (3, 5 and 8) induced caspase-independent apoptosis (within 4 h of action) in cell line Cal27. Extrinsic-mediated apoptosis associated with caspase 8 and 3 activation is the main mode of cytotoxicity induced on FaDu cells by compounds 3, 5 and 8. Cell cycle perturbations caused by these compounds are also observed. Our data suggest that compounds 3, 5 and 8 should be studied further for the treatment of head and neck cancer.     

Differential effects of Co(III), Ni(II), and Ru(III) amine complexes on Sindbis virus

Transition metal complexes [Co(cyclen)(NH₃)₂](ClO₄)₃⋅H₂O (cyclen = 1,4,7,10-tetraazacyclododecane) (2), [Co(NH₃)₅(OH₂)](CF₃SO₃)₃ (3) [Ni(NH₃)₆]Br₂ (4) and [Ru(NH₃)₆]Cl₃ (5) were tested against Sindbis infected baby hamster kidney (BHK) cells and show differential effects from the previously reported anti-viral complex [Co(NH₃)₆]Cl₃ (1). The macrocyclic complex 2 and labile aqua complex 3 show either no or little effect on the survival on Sindbis virus-infected cells as compared to that for 1, which show a monotonic increase in % BHK cell survival. Nickel and ruthenium ammine complexes 4 and 5 had a moderate influence of cell survival. While the results showed some anti-viral activity for some of the structural variations, it appears that 1, with its potential to be a broad-spectrum anti-viral compound, occupies a unique position in its ability to both significantly enhance cell survival and to decrease viral expression of infected cells. We also show that 1 also shows anti-viral activity against Adenovirus lending support to the broad-spectrum potential of this complex.     

Structure,properties and in vitro cytotoxic activity of hexakis(2-cyanoethyl)ditin(III)

The structure of the tin(III) complex [Sn₂(CH₂CH₂CN)₆] has been determined. There are two independent molecules in the crystal, both adopt distorted eclipsed conformation. The molecular and electronic structures of this compound have been studied both at the semiempirical level and with the use of non-empirical ab initio methods. The calculated Sn–Sn distances agree well with those found crystallographically. The results of calculations showed that the eclipsed conformation of complex is more stable as compared with staggered conformation. The compound show modest cytotoxic activity against A549 and HSMC cells.     

Gold(III) compounds as anticancer agents: relevance of gold-protein interactions for their mechanism of action

Gold(III) compounds constitute an emerging class of biologically active substances, of special interest as potential anticancer agents. During the past decade a number of structurally diverse gold(III) complexes were reported to be acceptably stable under physiological-like conditions and to manifest very promising cytotoxic effects against selected human tumour cell lines, making them good candidates as anti-tumour drugs. Some representative examples will be described in detail. There is considerable interest in understanding the precise biochemical mechanisms of these novel cytotoxic agents. Based on experimental evidence collected so far we hypothesize that these metallodrugs, at variance with classical platinum(II) drugs, produce in most cases their growth inhibition effects through a variety of "DNA-independent" mechanisms. Notably, strong inhibition of the selenoenzyme thioredoxin reductase and associated disregulation of mitochondrial functions were clearly documented in some selected cases, thus providing a solid biochemical basis for the pronounced proapoptotic effects. These observations led us to investigate in detail the reactions of gold(III) compounds with a few model proteins in order to gain molecular-level information on the possible interaction modes with possible protein targets. Valuable insight on the formation and the nature of gold-protein adducts was gained through ESI MS (electrospray ionization mass spectrometry) and spectrophotometric studies of appropriate model systems as it is exemplified here by the reactions of two representative gold(III) compounds with cytochrome c and ubiquitin. The mechanistic relevance of gold(III)-induced oxidative protein damage and of direct gold coordination to protein sidechains is specifically assessed. Perspectives for the future of this topics are briefly outlined.     

A Novel Cytotoxic Cerium Complex: Aquatrichloridobis(1,10‐phenanthroline)cerium(III) (KP776). Synthesis,Characterization, Behavior in H2O,Binding towards Biomolecules,and Antiproliferative Activity

The lanthanide complex aquatrichloridobis(1,10‐phenanthroline)cerium(III) [Ce(phen)₂(H₂O)Cl₃] (KP776) was fully characterized by elemental analysis, IR‐, and ¹H‐ and ¹³C‐NMR spectroscopy, as well as TG/DTA measurements, and its behavior in H₂O, important for the application as a chemotherapeutic, was studied. In addition, the binding of KP776 to nucleotides and single serum proteins was investigated by capillary electrophoresis, whereas binding to proteins in human plasma was observed by ICP‐MS. The compound shows promising anticancer properties in vitro: proliferation of human cancer cell lines is strongly inhibited with IC₅₀ values in the very low micromolar range.     

Structural studies on novel Ru(II)-Binap complexes

The solid-state structures for two complexes, 7 and 8, are reported. Complex 7 was prepared by treating Ru(OAc)₂(Binap) with two equivalents of HBArF in toluene solution, and represents only the second solid-state structure of a Binap complex, in which the Binap is a 6e donor to the Ru(II). The bonding is maintained in solution as shown via ¹³C NMR studies. The unusual cation 8, as an salt, arises from prolonged reaction of Ru(OAc)₂(Binap) with wet HBF₄ (and, subsequently, added HSbF₆) in 1,2-dichloroethane.     

Synthesis, structure and properties of di- and mononuclear ruthenium(III) complexes with N-(benzoyl)-N′-(salicylidene)hydrazine and its derivatives

The reactions of [Ru(PPh₃)₃Cl₂], N-(benzoyl)-N′-(5-R-salicylidene)hydrazines (H₂bhsR, R = H, OCH₃, Cl, Br and NO₂) and triethylamine (1:1:2 mole ratio) in methanol afford mononuclear ruthenium(III) complexes having the general formula trans-[Ru(bhsR)(PPh₃)₂Cl]. In the case of R = H, a dinuclear ruthenium(III) complex of formula [Ru₂(μ-OCH₃)₂(bhsH)₂(PPh₃)₂] has been isolated as a minor product. The complexes are characterized by elemental analysis, magnetic, spectroscopic and electrochemical measurements. The crystal structures of the dinuclear complex and two mononuclear complexes have been determined. In the dinuclear complex, each metal centre is in distorted octahedral NO₄P coordination sphere constituted by the two bridging methoxide groups, one PPh₃ molecule and the meridionally spanning phenolate-O, imine-N and amide-O donor bhsH²⁻. The terminal PPh₃ ligands are trans to each other. In the mononuclear complexes, bhsR²⁻ and the chlorine atom form an NO₂Cl square-plane around the metal centre and the P-atoms of the two PPh₃ molecules occupy the remaining two axial sites to complete a distorted octahedral NO₂ClP₂ coordination sphere. All the complexes display ligand-to-metal charge transfer bands in the visible region of the electronic spectra. The cryomagnetic measurements reveal the antiferromagnetic character of the diruthenium(III) complex. The low-spin mononuclear ruthenium(III) complexes as well as the diruthenium(III) complex display rhombic EPR spectra in frozen solutions. All the complexes are redox active in CH₂Cl₂ solutions. Two successive metal centred oxidations at 0.69 and 1.20 V (versus Ag/AgCl) are observed for the dinuclear complex. The mononuclear complexes display a metal centred reduction in the potential range −0.53 to −0.27 V. The trend in these potential values reflects the polar effect of the substituents on the salicylidene moiety of the tridentate ligand.     

DNA binding properties of novel cytotoxic gold(III) complexes of terpyridine ligands: the impact of steric and electrostatic effects

Four gold(III) complexes of terpyridine derivatives 1–4 have been synthesized and characterized by spectroscopic methods. In vitro data demonstrated that all of them showed higher cytotoxicity than cisplatin against the human non-small-cell lung cancer cell line (A-549), the human stomach carcinoma cell line (SGC-7901), the human cervix carcinoma cell line (HELA), the human colon carcinoma cell line (HCT-116), the human liver carcinoma cell line (BEL-7402), the murine leukemia cell line (P-388) and the human acute promyelocytic leukemia cell line (HL-60). Complex 3 exhibits the highest activity, with growth inhibition rates of over 80% at 10⁻⁸ mol L⁻¹ against the A-549, HCT-116 and HELA tumor cell lines. Interestingly, ligands L1–L4 are also very cytotoxic against the cell lines tested. Complexes 1–4 are stable in aqueous solution for 2 days in the presence of the biological reducing agent glutathione. The inductively coupled plasma mass spectrometry data showed that DNA isolated from cells treated with complexes 1 and 3 contained gold with gold-to-nucleotide ratios of approximately 1:6,400 and 1:4,900, respectively. Fluorescence titration, UV and circular dichroism analyses proved that the steric and electrostatic effects of the ligand remarkably influence the interactions of their gold(III) complexes with DNA. The DNA binding ability of the complexes has been correlated with their cytotoxicity, which could potentially provide a new rationale for the future design of terpyridine-based metal complexes with antitumor potential.Electronic Supplementary Material Supplementary material is available to authorized users in the online version of this article at .     

Bismuth(III) complexes with 2-acetylpyridine- and 2-benzoylpyridine-derived hydrazones: Antimicrobial and cytotoxic activities and effects on the clonogenic survival of human solid tumor cells

Complexes [Bi(2AcPh)Cl₂]·0.5H₂O (1), [Bi(2AcpClPh)Cl₂] (2), [Bi(2AcpNO₂Ph)Cl₂] (3), [Bi(2AcpOHPh)Cl₂]·2H₂O (4), [Bi(H2BzPh)Cl₃]·2H₂O (5), [Bi(H2BzpClPh)Cl₃] (6), [Bi(2BzpNO₂Ph)Cl₂]·2H₂O (7) and [Bi(H2BzpOHPh)Cl₃]·2H₂O (8) were obtained with 2-acetylpyridine phenylhydrazone (H2AcPh), its -para-chloro-phenyl- (H2AcpClPh), -para-nitro-phenyl (H2AcpNO₂Ph) and -para-hydroxy-phenyl (H2AcpOHPh) derivatives, as well as with the 2-benzoylpyridine phenylhydrazone analogues (H2BzPh, H2BzpClPh, H2BzpNO₂Ph, H2BzpOHPh).Upon coordination to bismuth(III) antibacterial activity against Gram-positive and Gram-negative bacterial strains significantly improved except for complex (4).The cytotoxic effects of the compounds under study were evaluated on HL-60, Jurkat and THP-1 leukemia, and on MCF-7 and HCT-116 solid tumor cells, as well as on non-malignant Vero cells. In general, 2-acetylpyridine-derived hydrazones proved to be more potent and more selective as cytotoxic agents than the corresponding 2-benzoylpyridine-derived counterparts.Exposure of HCT-116 cells to H2AcpClPh, H2AcpNO₂Ph and complex (3) led to 99% decrease of the clonogenic survival. The IC₅₀ values of these compounds were three-fold smaller when cells were cultured in soft-agar (3D) than when cells were cultured in monolayer (2D), suggesting that they constitute interesting scaffolds, which should be considered in further studies aiming to develop new drug candidates for the treatment of colon cancer.     

Electron transfer. Part 165: Oxidations of Ti(II)(aq) with ligated iron(III) and ruthenium(III)

Titanium(II) solutions, prepared by dissolving titanium wire in triflic acid + HF, contain equimolar quantities of Ti(IV). Treatment of such solutions with excess Fe(III) or Ru(III) complexes yield Ti(IV), but reactions with Ti(II) in excess give Ti(III). Oxidations by (NH₃)₅Ru(III) complexes, but not by Fe(III) species, are catalyzed by titanium(IV) and by fluoride. Stoichiometry is unchanged. The observed rate law for the Ru(III)-Ti(II)-Ti(IV) reactions in fluoride media points to competing reaction paths differing by a single F⁻, with both routes involving a Ti(II)-Ti(IV) complex which is activated by deprotonation. It is suggested that coordination of Ti(IV) to Ti^II(aq) minimizes the mismatch of Jahn-Teller distortions which would be expected to lower the Ti(II,III) self-exchange rate.     

Effect of substituents on complex stability aimed at designing new iron(III) and aluminum(III) chelators

The solution equilibria of iron(III) and aluminum(III) with two classes of hard ligands (catechol, salicylic acid and their nitro-derivatives) have been reliably studied by potentiometric, spectrophotometric and NMR spectroscopy. The effect of the nitro substituent on the binding properties of catechol and salicylic acid has been examined thoroughly. The inductive and resonance properties of the substituent that, as expected, lower the basicity of the phenolic and carboxylic groups, lead to a general decrease in both protonation and complex formation constants. This decrease causes an increase in pM of between 0.2 and 1.1 pM units for the nitro-substituted salicylates and of about 4 units for 4-nitrocatechol, with a significantly higher chelating efficacy. The influence of the substituent on catechol and salicylic acid is discussed in detail on the basis of conditional constants at pH 7.4.     

Anti-tubercular Activity of Ruthenium (II) Complexes with Polypyridines

A series of nine polypyridyl-ruthenium (II) complexes (N-ligands = 2,2′-bipyridines; 2,2′-6′,2′-terpyridines, di-alkyloxy-2,2′-6,2-bipyridine-3,3′-di-carboxylates), were tested against Mycobacterium tuberculosis (MBT). The complex (11) showed remarkable activity against MBT as compared to other complexes, (1–10). The aquo ligand of complex (11), as opposed to other chloro and acetonitrile derivatives, appears to play a key role in the antitubercular potency of this new class of metal-based compounds.     

In vitro studies on the DNA impairments induced by Cr(III) complexes with cellular reductants

The influence of Cr(III) complexes with ascorbic acid, cysteine and glutathione on DNA has been studied spectrophotometrically and chromatographically. The toxic and genotoxic activities of these complexes were also investigated. It was found that these complexes bind to DNA weaker than hexaaqua Cr(III) complexes. It could be explained through the greater strength of the bi- and tridentate ligands coordinated to chromium in comparison to water molecules. The formation of DNA-DNA intermolecular bonds and DNA interstrand cross-linking has been also observed. These complexes were found to be non-toxic and non-genotoxic in the bacterial test.     

In vitro and in vivo biological activity screening of Ru(III) complexes involving 6-benzylaminopurine derivatives with higher pro-apoptotic activity than NAMI-A

A series of novel octahedral ruthenium(III) complexes involving 6-benzylaminopurine (L) derivatives as N-donor ligands has been prepared by the reaction of [(DMSO)₂H][trans-RuCl₄(DMSO)₂] with the corresponding L derivative. The complexes 1-12 have the general compositions trans-[RuCl₄(DMSO)(n-Cl-LH)] ⋅ xSol (1-3), trans-[RuCl₄(DMSO)(n-Br-LH)] · xSol (4-6), trans-[RuCl₄(DMSO)(n-OMe-LH)] · xSol (7-9) and trans-[RuCl₄(DMSO)(n-OH-LH)] · xSol (10-12); n = 2, 3, and 4, x = 0-1.5; and Sol = H₂O, DMSO, EtOH and/or (Me)₂CO. The complexes have been thoroughly characterized by elemental analysis, UV-visible, FTIR, Raman, and EPR spectroscopy, ES + (positive ionization electrospray) mass spectrometry, thermal analysis, cyclic voltammetry, magnetic and conductivity measurements. The X-ray molecular structure of trans-[RuCl₄(DMSO)(3-Br-LH)] ⋅ (Me)₂CO (5) revealed the distorted octahedral coordination in the vicinity of the central atom, and also confirmed that the 3-Br-L ligand is present as the N3-protonated N7-H tautomer and is coordinated to Ru(III) through the N9 atom of the purine moiety. The tested complexes have been found to be in vitro non-cytotoxic against K562, G361, HOS and MCF7 human cancer cell lines with IC₅₀ > 100 μM in contrast to the moderate results regarding the antiradical activity with IC₅₀ ≈ 10^− 3 M. On the contrary, in vivo antitumor activity screening showed that the prepared Ru(III) complexes possess higher pro-apoptotic activity than NAMI-A. The reduction of Ru(III) to Ru(II) and Ru(II)-species formation in tumor tissues was confirmed by means of a simple method of detection and visualization of intracellular Ru(II) by fluorescence microscopy. The originality of this method is based on the preparation of a Ru(II)-bipyridine complex in situ.     

Synthesis,spectral characterization,in vitro microbial and cytotoxic studies of lanthanum(III) and thorium(IV) complexes with 1,2,4-triazole Schiff bases

A series of metal complexes of La(III) and Th(IV) have been synthesized with newly derived biologically active ligands. These ligands were synthesized by the condensation of 3-substituted-4-amino-5-hydrazino-1,2,4-triazole with 8-formyl-7-hydroxy- 4-methylcoumarin. The structure of the complexes has been proposed by elemental analyses, spectroscopic data i.e. i.r., ¹H nmr, Uv-Vis, FAB-mass and thermal studies. The elemental analyses of the complexes conform to the stoichiometry of the type [La(L)·3H₂O]·2H₂O and [Th(L)(NO₃)·2H₂O]·2H₂O where (L = L^I-L^IV). All the complexes are soluble in DMF and DMSO and are non-electrolytes in DMF and DMSO. All these ligands and their complexes have also been screened for their antibacterial (Escherichia coli, Staphylococcus aureus, Staphylococcus pyogenes and Pseudomonas aeruginosa) and antifungal activities (Aspergillus niger, Aspergillus flavus and cladosporium) by the MIC method. The brine shrimp bioassay was also carried out to study their invitro cytotoxic properties.     

From hydrolytically labile to hydrolytically stable Ru(II)-arene anticancer complexes with carbohydrate-derived co-ligands

The synthesis, characterization, reactivity and in vitro anticancer activity of a series of Ru^II-arene complexes with carbohydrate-derived phosphite and biscarboxylato co-ligands are reported. The compounds were characterized by NMR spectroscopy and electrospray ionization (ESI) mass spectrometry, and the molecular structures of oxalato(η⁶-p-cymene)(3,5,6-bicyclophosphite-1,2-O-isopropylidene-α-D-glucofuranoside)ruthenium(II) and oxalato(η⁶-p-cymene)(3,5,6-bicyclophosphite-1,2-O-cyclohexylidene-α-D-glucofuranoside)ruthenium(II) were determined by X-ray diffraction analysis. In contrast to their dichlorido counterparts, the biscarboxylato complexes did not exhibit significant reactivity towards biomolecules, such as cysteine, methionine, ubiquitin or the DNA model 5′-GMP, and resist hydrolysis; no hydrolytic species were detected by ¹H and ³¹P{¹H} NMR spectroscopy over several days. These structural alterations led to a decrease in the tumor-inhibiting potency of the compounds in human cancer cell lines.