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 .     

Electronic and steric effects in cobalt Schiff bases complexes: Synthesis, characterization and catalytic activity of some cobalt(II) tetra-halogens-dimethyl salen complexes

The synthesis, characterization and catalytic activity of a series of tetra-halogeno-dimethyl salen cobalt (II) complexes are reported in this paper. The investigated complexes of cobalt (II) with Schiff bases are: αα′-di-methyl Salen cobalt (II) [Co(dMeSalen)], 3,3′,5,5′-tetra chloro α,α′-di-methyl Salen cobalt (II), [Co(tCldMeSalen)], 3,3′-di-bromo 5,5′-di-chloro α,α′-di-methyl Salen cobalt (II), [Co(tBrdMeSalen)], 3,3′,5,5′-tetra bromo α,α′-di-methyl Salen cobalt (II), [Co(tBrdMeSalen)] and 3,3′,5,5′-tetra iodo α,α′-di-methyl Salen cobalt (II), [Co(tIdMeSalen)] (where Salen is bis(salicylaldehyde)ethylenediamine). The characterization of the complexes was performed by elemental analysis, cyclic voltammetry, UV-Vis, IR and EPR spectroscopies. The study was made in DMF, and pyridine was used for coordination as axial base. The redox potential is influenced by the substituent grafted on aromatic ring and in the azomethynic position and also by the molecules coordinating in axial position (solvent, DMF, or pyridine). The catalytic oxygenation of 2,6-di-tert-butylphenol by these complexes leads to the obtention of benzoquinone and diphenoquinone products. The cobalt (II) complexes form reversible adducts with molecular oxygen.     

Neuropharmacological actions of some binuclear lanthanide(III) complexes

Binuclear lanthanide(III) compounds are of great interest because of the potential of their mutual Ln(3+)-Ln(3+) electronic couplings to produce unusually sharp images in magnetic resonance and fluorescence imaging of biological tissue. The toxicity and neuropharmacological properties of the water soluble and stable neutral binuclear complex [La(api)](2) were compared with those of binuclear complexes with lower water stability, and the components used in their syntheses. The order of the 24-h LD(50) (mg/kg body wt.) of the compounds in mice was: salicylaldehyde (2.24)160). These compounds induced convulsions, urination and defecation in mice. Due to the relatively very low toxicity of [La(api)](2), its mode of action was explored. Its proconvulsant action may possibly involve an interaction of undissociated complex with muscarinic receptors, and is reversed by atropine.     

Interaction of hexacyanoferrate(III) with some copper(II) complexes

The interaction between hexacyanoferrate(III) and some copper complexes of different geometry was studied. In solution, and in the presence of coordination unsaturation of copper, 1:1 and 2:1 Cu:Fe adducts formed and were characterized by the absence of any copper electron paramagnetic resonance (EPR) signal. The magnetic susceptibility of the 1:1 adducts is essentially equal to the sum of those due to the parent compounds. Solid state studies confirm the solution data. In the light of the present results the absence of the EPR signal of [Fe(CN)₆]^3?-treated galactose oxidase is discussed.     

UV-Vis absorption study of some tetragonal chromium (III) complexes

A UV-Vis absorption study was performed in order to elucidate the electronic energy levels of three tetragonal chromium (III) complexes, namely trans-[Cr(en)₂(CN)₂]ClO₄, trans-[Cr(cyclam)(CN)₂]ClO₄, and trans-[Cr(NH₃)₄(CN)₂]ClO₄. The absorption spectra of the preceding complexes have been analyzed via Gaussian analysis to locate the quartet band maxima of the tetragonal components. The deconvoluted band maxima were then fitted with the tetragonal energy matrices of d³ configuration with full configuration interaction, neglecting spin-orbit interaction. The ligand field parameters D_q, D_t, and D_s along with the electron correlation parameters have been extracted via the fitting procedure. The significance of these parameters and the translated angular overlap model parameters has been discussed. We have also uncovered in the spectrum of the ethylenediamine complex the low intensity doublet absorption bands and a high intensity charge transfer band which have been tentatively assigned.     

Low energy vibronic transitions of some tetrahalogenocobalt(II) complexes

Near-infrared absorption spectra of A₂CoX₄ (A = Cs, ethyl₄N; X = Cl, Br) single crystals and from KBr pellets at low temperature are recorded by the Fourier transform technique. At 2 K a rich fine structure of v₁(⁴A₂→⁴T₂) and v₂(⁴A₂→⁴T₁) ligand field spectra is detected which can be assigned to low symmetry level splittings due to actual site symmetries superimposed by vibrational fine structure. Comparison of fundamental frequencies obtained from far-infrared spectra allows an assignment of all peaks measured in the vibronic spectra to vibrational modes of the MX₄ complex. Zero-phonon bands are identified using the assistance of angular overlap calculations.     

An unexpected influence of the nature of the amine on the crystal structure of some Co(III)-Bi(III) heterobimetallic complexes

Two novel cobalt(III)-bismuth(III) heterometallic compounds [Co(NxH)₂(An)₂]₂[Bi(EDTA)(H₂O)]₂ · 7H₂O (1) and [Co(NxH)₂(p-Tol)₂][Bi(EDTA)] · 4H₂O (2) [An-aniline, p-Tol-para-toluidine, NxH-1,2-cyclohexanedionedioximate-ion, EDTA-ethylenediaminetetraacetate-ion] have been synthesized and characterized by NMR, thermogravimetry and single X-ray crystallography. Substitution of the aniline by para-toluidine molecules leads to radical changes in the anionic sub-lattice: from monomeric form to polymeric one. The coordination number of bismuth is 7+1 in 1, and 8 in 2; Bi coordination polyhedron in 1 can be described as a two-capped trigonal prism, while in 2 as a dodecahedron. The Co atoms in 1 and 2 have an octahedral coordination. NMR spectroscopy in DMSO solution confirms the trans-configuration of the complex cations in 1 and 2 by observation of a broad singlet of two symmetric hydrogen bonds. The NCH₂CH₂N component of EDTA ligand is in the domain of the fast exchange and the signal from this group is a singlet, while four acetate methylene protons give rise to an AB quartet system. It was shown that thermolysis of 1 and 2 occurs in three successive stages, via the dehydration, pyrolysis of the ligands and, finally, the formation of a sillenite-type phase Bi_26−xCo_xO_40−δ and small quantities of Co₃O₄.     

Action cross sections of two-photon excited luminescence of some Eu(III) and Tb(III) complexes.

Four different luminescent lanthanide complexes have been studied with respect to multiphoton excitation using near-infrared femtosecond pulses. The method for measuring action cross sections of two-photon excited fluorescence in solution relative to a known standard is reviewed. Two refractive index-related corrections are necessary in this method: one for the multiphoton excitation process, the other for the collection of the emitted light. It has been found that (2,4,6-trimethoxyphenyl)dipicolinic acid and Michler's ketone are reasonable sensitisers of two-photon excited lanthanide luminescence in solution, whereas dipicolinic acid and carbostyril-124 do not give rise to any detectable two-photon excited lanthanide luminescence using modest excitation powers (<20 mW focused at the sample) in the 700-1000 nm range.     

Heavy-atom effects on energy transfer from polynucleotides to terbium (III)

Energy transfer in nucleic acids or polynucleotides at room temperature can be studied by using the fluorescence of complexed terbium (III) as a tool. Complexing the heavy atom thallium (I) enhances energy transfer from poly(G) to terbium (III). Thallium has no effect on transfer from GMP to terbium and a small negative effect on the transfer from single-stranded DNA to terbium. Use of the Medinger-Wilkinson model to analyze the poly(G) results provides an estimate of the room-temperature intersystem crossing constant.     

Chiral metal complexes. 25. Cobalt(III) complexes of some linear mesomeric tetramine ligands

The complexes of Λ-α-[Co(R,S-picbn)Cl₂] ClO₄ (where R,S-picbn is 3R,4S-dimethyl-1,6-di(2-pyridyl)-2,5-diazahexane) together with its Δ-Λ-α and Δ,Λ-β exo congeners,Δ-Λ-β-exo-[Co(picchmn)Cl₂] ClO₄ (where picchmn is N,N'-di(2-picolyl)-1R, 2S-diaminocyclohexane) as well as Δ,Λ-β-endo-[Co(R,S-picstien)Cl₂] ClO₄·2H₂O, [Co(R,S-picstien)(ox)] ClO₄·0.5H₂O and [Co(R,S-picstien)(mal)] ClO₄·3H₂O (where picstien is 3R,4S-diphenyl-1,6-di(2-pyridyl)-2,5-diazahexane, ox is the oxalate dianion and mal is the malonate dianion) have been synthesised. The nature of the compounds was determined using a combination of ¹H NMR and, for certain chiral species, chiroptical techniques. In the various β complexes, the tetradentate is observed to adopt either the exo or endo geometry, specifically. Factors which influence coordination geometry include steric interactions and hydrophobic bonding effects.A number of chemical transformations between dinitro and dichloro complexes of Co(III) with R,S- picbn have been examined, as has the reaction of Δ,Λ-β-exo-[Co(R,S-picbn)Cl₂]⁺ with S-alanine in aqueous solution. The resulting product mixture contains eight of the sixteen possible β diastereoisomers, of which three have been isolated and characterised. The eight are composed of four β₁ and four β₂ isomers, however, and it is noted that isomerisation at the inplane amine nitrogen atom is restricted by the overall geometry of the complexes formed. Discriminatory forces in these complexes are small in magnitude, and exo/endo isomerisation is somewhat dependent upon the choice of ligand(s) used to complete the coordination sphere.     

Rhodium(III) complexes as genotoxic agents: photochemical effects and their implications

The genetic toxicology of coordination compounds of transition metals has been of considerable interest since the application of cis-platinum(II) to the therapy of solid tumors. The nature of reactions of such compounds with DNA is still unclear, despite intensive investigation. In this study, several coordination compounds of rhodium(III) were tested for DNA-damaging activity and mutagenicity in bacterial assays in an attempt to understand both the chemical species involved in interactions with DNA and any structural requirements for such interactions. For several complexes it appears that dissociation of a ligand from the complex precedes reactions with DNA. This conclusion stems from the finding that photosensitive complexes of rhodium(III) are often many times more toxic to repair-deficient bacterial stains of E. coli K12 when incubated in the light than when incubated in the dark. Similar responses were seen for mutagenicity in S. typhimurium strain TA100. However, reversion of strain TA102 was largely independent of light exposure. Comparisons between mutagenicity and DNA-damaging activity revealed that the 3 activities measured sorted with some independence among the different compounds tested. Thus, the profiles for crosslink formation and/or generation of oxidative mutagens (mutagenicity in S. typhimurium strain TA102), mutagenicity in TA100 and DNA-damaging activity for the various groups of complexes showed many of the theoretically possible combinations of response in the assays. It is possible, then, that there are different structural requirements for DNA-damaging activity and mutagenicity respectively. This may indicate that synthesis of coordination compounds with specific genotoxic properties is possible. Such syntheses may provide complexes for study of DNA-metal interactions and could, later, direct an approach to the design of new antitumor agents.     

Mechanistic informations from trans-effect in the anation reactions of some bis(dimethylglyoximato)Rh(III) complexes

The parallel lability trend for the anation reactions of RRh(DH)₂H₂O (RCH₃, CH₃CH₂, CF₃CH₂, ClCH₂) and RCo(DH)₂H₂O complexes suggests a dissociative activation process for the reactions of the organorhodoximes. The high lability of these complexes, arising from the stabilization of the transition state, is not entirely due to the trans-effect of the R group, but, at least partially, to the labilizing effect of the equatorial macrocycle.     

A comparative DFT study on aquation and nucleobase binding of ruthenium (II) and osmium (II) arene complexes

The potential energy surfaces of the reactions of organometallic arene complexes of the type [(η ⁶-arene)M^II(pic)Cl] (where pic = 2-picolinic acid, M = Ru or Os) were examined by a DFT computational study. Among the seven density functional methods, hybrid exchange functional B3LYP outperforms the others to explain the aquation of the complexes. The reactions and binding energies of Ru^II and Os^II arene complexes with both 9EtG and 9EtA were studied to gain insight into the reactivity of these types of organometallic complexes with DNA. The obtained data rationalize experimental observation, contributing to partly understanding the potential biological and medical applications of organometallic complexes.

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.     

Studies on some iridium(III) complexes with Schiff bases derived from amino carboxylic acids

The reactions of iridium(III) chloride with different Schiff bases gave complexes of types [Ir(SB)3], [Ir(SB')Cl(H2O)2], [Ir(SB')Cl2]n, [Ir(SB' ')Cl(H2O)]n (SBH = Schiff bases derived from anthranilic acid and benzaldehyde, acetophenone, vanillin, cinnamaldehyde or m-hydroxyacetophenone; SB'H2 = Schiff bases derived from anthranilic acid and salicylaldehyde or o-hydroxyacetophenone; SB'H = Schiff bases derived from p-aminobenzoic acid and benzaldehyde, acetophenone, vanillin, cinnamaldehyde, or m-hydroxyacetophenone; SB' 'H2 = Schiff bases derived from p-aminobenzoic acid and salicylaldehyde or o-hydroxyacetophenone). These complexes have been characterized on the basis of elemental analyses, conductance, magnetic moment, and spectral (electronic, i.r., and 1H n.m.r.) data. The electronic spectra reveals octahedral geometry for these complexes except for [Ir(SB')Cl2]n, which is trigonal bipyramidal. The thermal behavior of these complexes has also been studied by TG, DTG, and DSC techniques. The different kinetic parameters, viz., order of reaction, activation of energy, and heat of reaction were calculated. The antifungal and antiviral activities of the complexes with Schiff bases derived from anthranilic acid have also been investigated.     

(Catecholato)iron(III) complexes: structural and functional models for the catechol-bound iron(III) form of catechol dioxygenases

Catechol dioxygenases are mononuclear non-heme iron enzymes that catalyze the oxygenation of catechols to aliphatic acids via the cleavage of aromatic rings. In the last 20 years, a number of (catecholato)iron(III) complexes have been synthesized and characterized as structural and functional models for the catechol-bound iron(III) form of catechol dioxygenases. This review focuses on the structural and spectroscopic characteristics and oxygenation activity of the title complexes.     

Antileukemic activity and cellular effects of rhodium(III) crown thiaether complexes

The cytostatic properties of novel rhodium(III) thiacrown ether complexes [RhCl(LL)([9]aneS₃)]ⁿ⁺ with either aromatic κ² N ligands (n = 2) or anionic chelate ligands (n = 1) have been investigated for the human cancer cell lines HT-29 and MCF-7 and for immortalized HEK-293 cells. Taken together with literature IC₅₀ values for analogous complexes with polypyridyl ligands or 1,4-dithiane, the in vitro assays indicate that dicationic complexes with soft κ² N (imino) or κ² S (thiaether) ligands exhibit significantly higher antiproliferative effects than those with hard κ² N (amino) ligands. Dicationic complexes are more active than monocationic complexes with similar ligands. Pronounced apoptosis-inducing properties towards Jurkat cells were established for complexes with LL = bpm, dpq, and 1,4-dithiane. The order of activity (bpm > 1,4-dithiane > dpq > bpy) contrasts to that observed for adhesive cancer cells (bpm > bpy, 1,4-dithiane > dpq). Necrosis is insignificant in all cases. The percentage of Jurkat cells exhibiting apoptosis after 24 or 48 h incubation periods is directly correlated to the percentage of cells exhibiting high levels of reactive oxygen species. As established by online monitoring with a sensor chip system, treatment of MCF-7 cells with the bpm and 1,4-dithiane complexes leads to a significant and permanent concentration-dependent decrease in oxygen consumption and cellular adhesion.