X-ray absorption spectroscopy studies of the adducts formed between cytotoxic gold compounds and two major serum proteins

Gold metallodrugs form a class of promising antiproliferative agents showing a high propensity to react with proteins. We exploit here X-ray absorption spectroscopy (XAS) methods [both X-ray absorption near-edge spectroscopy (XANES) and extended X-ray absorption fine structure (EXAFS)] to gain insight into the nature of the adducts formed between three representative gold(I, III) metallodrugs (i.e., auranofin, [Au(2,2′-bipyridine)(OH)₂](PF₆), Aubipy, and dinuclear [Au₂(6,6′-dimethyl-2,2′-bipyridine)₂(μ-O)₂](PF₆)₂, Auoxo6) and two major plasma proteins, namely, bovine serum albumin (BSA) and human serum apotransferrin (apoTf). The following metallodrug–protein systems were investigated in depth: auranofin/apoTf, Aubipy/BSA, and Auoxo6/apoTf. XANES spectra revealed that auranofin, upon protein binding, conserves its gold(I) oxidation state. Protein binding most probably takes place through release of the thiosugar ligand and its subsequent replacement by a thiol (or a thioether) from the protein. This hypothesis is independently supported by EXAFS results. In contrast, the reactions of Aubipy with serum albumin and of Auoxo6 with serum apoTf invariantly result in gold(III) to gold(I) reduction. Gold(III) reduction, clearly documented by XANES, is accompanied, in both cases, by release of the bipyridyl ligands; for Auoxo6 cleavage of the gold–gold dioxo bridge is also observed. Gold(III) reduction leads to formation of protein-bound gold(I) species, with deeply modified metal coordination environments, as evidenced by EXAFS. In these adducts, the gold(I) centers are probably anchored to the protein through nitrogen donors. In general, these two XAS methods, i.e., XANES and EXAFS, used here jointly, allowed us to gain independent structural information on metallodrug/protein systems; detailed insight into the gold oxidation state and the local environment of protein-bound metal atoms was achieved in the various cases.     

Protein metalation by metal-based drugs: reactions of cytotoxic gold compounds with cytochrome?c and lysozyme

Protein metalation processes are crucial for the mechanism of action of several anticancer metallodrugs and warrant deeper characterisation. We have explored the reactions of three cytotoxic gold(III) compounds??namely [(bipy^2Me)₂Au₂(??-O)₂][PF₆]₂ (where bipy^2Me is 6,6??-dimethyl-2,2??-bipyridine) (Auoxo6), [(phen^2Me)₂Au₂(??-O)₂][PF₆]₂ (where phen^2Me is 2,9-dimethyl-1,10-phenanthroline) (Au₂phen) and [(bipy^dmb-H)Au(OH)][PF₆] [where bipy^dmb-H is deprotonated 6-(1,1-dimethylbenzyl)-2,2??-bipyridine] (Aubipyc)??with two representative model proteins, i.e. horse heart cytochrome?c and hen egg white lysozyme, through UV?Cvisible absorption spectroscopy and electrospray ionisation mass spectrometry (ESI MS) to characterise the inherent protein metalation processes. Notably, Auoxo6 and Au₂phen produced stable protein adducts where one or more ??naked?? gold(I) ions are protein-coordinated; very characteristic is the case of cytochrome?c, which upon reaction with Auoxo6 or Au₂phen preferentially forms ??tetragold?? adducts with four protein-bound gold(I) ions. In turn, Aubipyc afforded monometalated protein adducts where the structural core of the gold(III) centre and its +3 oxidation state are conserved. Auranofin yielded protein derivatives containing the intact auranofin molecule. Additional studies were performed to assess the role played by a reducing environment in protein metalation. Overall, the approach adopted provides detailed insight into the formation of metallodrug?Cprotein derivatives and permits trends, peculiarities and mechanistic details of the underlying processes to be highlighted. In this respect, electrospray ionisation mass spectrometry is a very straightforward and informative research tool. The protein metalation processes investigated critically depend on the nature of both the metal compound and the interacting protein and also on the solution conditions used; thus, predicting with accuracy the nature and the amounts of the adducts formed for a given metallodrug?Cprotein pair is currently extremely difficult.     

Combined chelation of bi-functional bis-hydroxypiridinone and mono-hydroxypiridinone: Synthesis, solution and in vivo evaluation

3-Hydroxy-4-pyridinones (3,4-HP) are well known iron-chelators with applications in medicinal chemistry, mainly associated with their high affinity towards trivalent hard metal ions (e.g. M³⁺, M = Fe, Al, Ga) and use as decorporating agents in situations of metal accumulation. The polydenticity and the extra-functionality of 3,4-HP derivatives have been explored, aimed at improving the chelating efficacy and the selectivity of the interaction with specific biological receptors. However, the ideal conjugation of both features in one molecular unity usually leads to high molecular weight compounds which can have crossing-membrane limitations.Herein, a different approach is used combining a arylpiperazine-containing bis-hydroxypyridone (H₂L¹) with a biomimetic mono-hydroxypyridinone, ornithine-derivative (HL²), to assess the potential coadjuvating effect that could result from the administration of both compounds for the decorporation of hard metal ions. This work reports the results of solution and in vivo studies on their chelating efficacy either as a simple binary or a ternary system (H₂L¹:HL²:M³⁺), using potentiometric and spectrophotometric methods. The solution complexation studies with Fe(III) indicate that the solubility of the complexes is considerably increased in the ternary system, an important feature for the metal complex excretion, upon the metal sequestration. The results of the in vivo studies with ⁶⁷Ga-injected mice show differences on the biodistribution profiles of the radiotracer, upon the administration of each chelating agent, that are mainly ascribed to the differences of their extra-functional groups and lipo/hydrophilic character. However, administration of both chelating agents leads to a more steady metal mobilization, which may be attributed to an improved access to different cellular compartments.     

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.     

Cd(II) and Cu(II) complexes of polydentate Schiff base ligands: synthesis, characterization, properties and biological activity

We report the synthesis of the Schiff base ligands, 4-[(4-bromo-phenylimino)-methyl]-benzene-1,2,3-triol (A₁), 4-[(3,5-di-tert-butyl-4-hydroxy-phenylimino)-methyl]-benzene-1,2,3-triol (A₂), 3-(p-tolylimino-methyl)-benzene-1,2-diol (A₃), 3-[(4-bromo-phenylimino)-methyl]-benzene-1,2-diol (A₄), and 4-[(3,5-di-tert-butyl-4-hydroxy-phenylimino)-methyl]-benzene-1,3-diol (A₅), and their Cd(II) and Cu(II) metal complexes, stability constants and potentiometric studies. The structure of the ligands and their complexes was investigated using elemental analysis, FT-IR, UV-Vis, ¹H and ¹³C NMR, mass spectra, magnetic susceptibility and conductance measurements. In the complexes, all the ligands behave as bidentate ligands, the oxygen in the ortho position and azomethine nitrogen atoms of the ligands coordinate to the metal ions. The keto-enol tautomeric forms of the Schiff base ligands A₁-A₅ have been investigated in polar and non-polar organic solvents. Antimicrobial activity of the ligands and metal complexes were tested using the disc diffusion method and the strains Bacillus megaterium and Candida tropicalis.Protonation constants of the triol and diol Schiff bases and stability constants of their Cu²⁺ and Cd²⁺ complexes were determined by potentiometric titration method in 50% DMSO-water media at 25.00 ± 0.02 °C under nitrogen atmosphere and ionic strength of 0.1 M sodium perchlorate. It has been observed that all the Schiff base ligands titrated here have two protonation constants. The variation of protonation constant of these compounds was interpreted on the basis of structural effects associated with the substituents. The divalent metal ions of Cu²⁺ and Cd²⁺ form stable 1:2 complexes with Schiff bases.The Schiff base complexes of cadmium inhibit the intense chemiluminescence reaction in dimethylsulfoxide (DMSO) solution between luminol and dioxygen in the presence of a strong base. This effect is significantly correlated with the stability constants K_CdL of the complexes and the protonation constants K_OH of the ligands; it also has a nonsignificant association with antibacterial activity.     

Synthesis and characterization of mixed-ligand ruthenium(III) complexes with oxalate and acetylacetonate ions

Two mononuclear mixed-ligand ruthenium(III) complexes with oxalate dianion (ox²⁻) and acetylacetonate ion (2,4-pentanedionate, acac⁻), K₂[Ru(ox)₂(acac)] (1) and K[Ru(ox)(acac)₂] (2), were prepared as a candidate for a building block. In fact, reaction of complex 2 with manganese(II) sulfate gave a heterometallic tetranuclear complex, TBA[Mn^II{(μ-ox)Ru^III(acac)₂}₃] (5) in the presence of tetrabutylammonium (TBA) bromide. The ¹H NMR, UV-Vis, selected IR and FAB mass spectral data of these complexes are presented. Both mixed-ligand ruthenium(III) complexes gave a Nernstian one-electron reduction step in 0.1 mol dm⁻³ Na₂SO₄ aqueous solution on a mercury electrode at 25 °C. Comparison of observed reversible half-wave potentials with calculated values for a series of [Ru(ox)_n(acac)_3 − n]ⁿ⁻ (n=0-3) complexes by using Lever’s ligand electrochemical parameters is presented.     

Analysis and Optimum Design of Hybrid Plasmonic Slab Waveguides

Propagation properties of hybrid plasmonic slab waveguides are studied in detail using transfer matrix method considering structural and material aspects. Hybrid metal–insulator, hybrid metal–insulator–metal, and hybrid insulator–metal–insulator waveguides are considered. Propagation length (L _p), spatial length (L _s), and mode length (L _m) are utilized as three common figures of merit to compare and optimize the waveguides according to the layer thicknesses and metal/dielectric materials. The effect of constituting materials including metals (such as silver, gold, copper, and aluminum) and dielectrics (common dielectric materials used in photonic integrated circuit technologies such as silicon and silicon compounds, III–V compounds, and polymers) are discussed. It is found that hybrid waveguides are partially to completely superior to conventional plasmonic waveguides, providing a better balance between confinement and loss.     

Syntheses and crystal structures of the first iridium complexes with m- and p-terphenyl (tp). {[Ir2(p-tp)(cod)2](BF4)2 · 2CH2Cl2}3 and [Ir(m-tp)(η-C5Me5)](BF4)2

Novel two iridium terphenyl complexes were prepared and their structures were characterized crystallographically. The reaction of [Ir(cod)₂]BF₄ with p-terphenyl (p-tp) in CH₂Cl₂ was carried out to afford dinuclear Ir(I) complex {[Ir₂(p-tp)(cod)₂](BF₄)₂ · 2CH₂Cl₂}₃ (cod=1,5-cyclooctadiene) (1 · 2CH₂Cl₂), whereas the reaction of the intermediate [Ir(η⁵-C₅Me₅)(Me₂CO)₃]³⁺ in Me₂CO with m-terphenyl (m-tp) was done to provide mononuclear Ir(III) complex [Ir(m-tp)(η⁵-C₅Me₅)](BF₄)₂ (2). In complex 1 · 2CH₂Cl₂, two Ir atoms are η⁶-coordinated to both sides of terminal benzene rings from the upper and lower sides in the p-tp ligand, while one Ir atom is η⁶-coordinated to one side of the terminal benzene ring in the m-tp ligand in complex 2. Each crystal structure describes the first coordination mode found in metal complexes with the m- and p-tp ligands.     

Synthesis of 2-(nitromethyl)ornithine from ornithine mediated by cobalt(III)

Rac.-p-(tris(2-aminoethyl)amine-2-(nitromethyl)ornithine)cobalt(III) trichloride (2d) was obtained by a simple three-step procedure from ornithine using cobalt template chemistry. p-(Tris(2-aminoethyl)amine-ornithine)cobalt(III) trichloride (2a) was obtained from tris(2-aminoethyl)amine (tren) and (S)-ornithine in the presence of cobalt(II), which was oxidised to cobalt(III) during the reaction. Complex 2a was selectively oxidised with thionyl chloride-dimethyl formamide to p-(tris(2-aminoethyl)amine-dehydro-ornithine)cobalt(III) trichloride 2b. Complex 2c, in which reaction of thionyl chloride-dimethyl formamide has also occurred at the δ-amine of ornithine, was obtained at longer reaction times. Complex 2b reacted with nitromethane anion to give rac.-p-(tris(2-aminoethyl)amino-2-(nitromethyl)ornithine)cobalt(III) trichloride (2d). The amino acid rac.-2-(nitromethyl)ornithine (1b) was released by reducing complex 2d with aqueous ammonium sulfide. Complex 2d was expected to release 2-(nitromethyl)ornithine (1b) in hypoxic cells, where the amino acid could act as an inhibitor of ornithine decarboxylase. Preliminary data indicated that complex 2d was weakly cytotoxic in one cell type studied.     

Two new mononuclear gold(I)-nitrogen [N,N′-di(2,6-methyl)phenylformamidine] complexes: Syntheses and crystal structures

Two gold(I) mononuclear complexes have been prepared by reacting gold(I) tetrahydrothiophene with N,N′-di(2,6-methyl)phenylformamidine. The neutral complex [N,N′-di(2,6-methyl)phenylformamidine)-gold(I) chloride (C₁₇H₂₀AuClN₂) (1), crystallizes in the triclinic group while the cationic [N,N′-di(2,6-methyl)phenylformamidine](tetrahydrothiophene)-gold(I) (C₂₁H₂₈AuN₂S) (2) crystallizes with a nitrate anion in the monoclinic group P2(1)/n. Both compounds are good starting materials for synthetic gold chemistry.     

Synthesis, structural and electrochemical features of alicyclic and aromatic α,α′-N2- and-S2-dioximate macrobicyclic cobalt(II,III) and ruthenium(II) tris-complexes

The triribbed-functionalized cobalt(II,III) and ruthenium(II) clathrochelate derivatives of the vic-dioximes with two nitrogen or sulfur atoms in α-positions to π-conjugated diazomethine chelate fragments of a macrobicyclic framework were obtained in moderate yields under mild and high dilution conditions by nucleophilic substitution of six reactive chlorine atoms of the boron-capped macrobicyclic cobalt and ruthenium(II) precursors with N₂- and S₂-dinucleophiles (ethylenediamine and the corresponding α-dithiols in the presence of triethylamine, respectively). The complexes obtained were characterized using elemental analysis, MALDI-TOF mass spectrometry, IR, UV-Vis, ¹H and ¹³C{¹H} NMR and EPR spectroscopies, magnetochemistry and X-ray crystallography. The MN₆-coordination polyhedra of all the X-ray studied clathrochelates possess a slightly distorted trigonal prismatic geometry. The encapsulated cobalt(II) ions are shifted from the centers of the cavities formed by the macrobicyclic ligand due to the Jahn-Teller distortion, while the ruthenium and iron(II) ions in their clathrochelate analogs do occupy these centers. The main geometrical parameters of the macrobicyclic frameworks vary with Shannon radius of an encapsulated metal ion. In the case of the tris-ethylenediamine cobalt(III) clathrochelate, the field strength of the macrobicyclic amine ligand is essentially lower than those for their aromatic and aliphatic analogs because of the negative σ_para-effect of the ribbed alkylamine substituents. The magnetometry and EPR data confirmed the low-spin character of the cobalt(II) complexes synthesized. The electrochemically generated oxidized cobalt clathrochelates are stable in the CVA time scale, whereas their ruthenium- and iron-containing analogs as well as the reduced forms of all the cobalt, ruthenium and iron complexes obtained are unstable.     

Synthesis and structural characterization of dinuclear complexes of trivalent aluminum, gallium, indium and chromium derived from pyrazole-2-ethanol

The reaction of 1-(2-hydroxyethyl)-3,5-dimethylpyrazole (HL) with anhydrous metal(III) halides (M = Al, Ga, In and Cr) results in the isolation of four novel dinuclear complexes [Al(μ-L)Cl₂]₂ (1), [Ga(μ-L)Cl₂]₂ (2), [In(μ-L)Br₂(H₂O)]₂·2thf (3) and [Cr(μ-L)Cl₂(H₂O)]₂·1.5thf (4) in good yields. The new complexes have been characterized with the aid of analytical and spectroscopic studies. A single crystal X-ray structure determination in each case confirms the dimeric structure for all the complexes in the solid-state. The pyrazole ethanol ligand binds to the metal through both pyrazole nitrogen and bridging alkoxide oxygen terminals with the formation of a central M₂O₂ core involving the ethoxide anion. The metal(III) center is pentacoordinated in compounds 1 and 2, while it is hexacoordinated in compounds 3 and 4.     

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.     

Syntheses, crystal structure, spectroscopic characterization and antifungal activity of new N-R-sulfonyldithiocarbimate metal complexes

Five new compounds with the general formula of (Bu₄N)₂[M(RSO₂NCS₂)₂], where Bu₄N = tetrabutylammonium cation, (M = Ni, R = 4-FC₆H₄) (1), (M = Zn, R = 4-FC₆H₄, 4-ClC₆H₄, 4-BrC₆H₄, 4-IC₆H₄), (2), (3), (4) and (5), respectively, were obtained by the reaction of the appropriate potassium N-R-sulfonyldithiocarbimate (RSO₂NCS₂K₂) with nickel(II) chloride hexahydrate or zinc(II) acetate dihydrate in metanol:water 1:1. The elemental analyses and the IR data are consistent with the formation of the expected bis(dithiocarbimato)metal(II) complexes. The ¹H and ¹³C NMR spectra showed the signals for the tetrabutylammonium cation and the dithiocarbimate moieties. The compounds 1, 2 and 5 were also characterized by X-ray diffraction techniques. The nickel(II) is coordinated by two N-4-fluorophenylsulphonyldithiocarbimato(2-) ligands forming a planar coordination. The zinc(II) exhibits distorted tetrahedral configuration in compounds 2 and 5 due to the chelation effect of two sulfur atoms of the N-R-sulfonyldithiocarbimate ligands. The antifungal activities of the compounds were tested in vitro against Colletotrichum gloeosporioides, an important fungus that causes the plant disease known as anthracnose in fruit trees. All the complexes were active.     

6-Halogenopyridin-2-olato complexes with the diruthenium(2+) core: Equilibria between head-to-head and head-to-tail structures

The dinuclear bis(6-X-pyridin-2-olato) ruthenium complexes [Ru₂(μ-XpyO)₂(CO)₄(PPh₃)₂] (X = Cl (4B) and Br (5B)), [Ru₂(μ-XpyO)₂(CO)₄(CH₃CN)₂] (X = Cl (6B), Br (7B) and F (8B)) and [Ru₂(μ-ClpyO)₂(CO)₄(PhCN)₂] (9B) were prepared from the corresponding tetranuclear coordination dimers [Ru₂(μ-XpyO)₂(CO)₄]₂ (1: X = Cl; 2: X = Br) and [Ru₂(μ-FpyO)₂(CO)₆]₂ (3) by treatment with an excess of triphenylphosphane, acetonitrile and benzonitrile, respectively. In the solid state, complexes 4B-9B all have a head-to-tail arrangement of the two pyridonate ligands, as evidenced by X-ray crystal structure analyses of 4B, 6B and 9B, in contrast to the head-to-head arrangement in the precursors 1-3. A temperature- and solvent-dependent equilibrium between the yellow head-to-tail complexes and the red head-to-head complexes 4A-7A and 9A, bearing an axial ligand only at the O,O-substituted ruthenium atom, exists in solution and was studied by NMR spectroscopy. Full ¹H and ¹³C NMR assignments were made in each case. Treatment of 1 and 2 with the N-heterocyclic carbene (NHC) 1-butyl-3-methylimidazolin-2-ylidene provided the complexes [Ru₂(μ-XpyO)₂(CO)₄(NHC)], X = Cl (11A) or Br (12A). An XRD analysis revealed the head-to-head arrangement of the pyridonate ligands and axial coordination of the carbene ligand at the O,O-substituted ruthenium atom. The conversion of 11A and 12A into the corresponding head-to-tail complexes was not possible.     

A spectroscopic study of the reaction of NAMI, a novel ruthenium(III)anti-neoplastic complex, with bovine serum albumin.

The reaction of Na[transRuCl4Me2SO(Im)] (NAMI; where Im is imidazole), a novel anti-neoplastic ruthenium(III) complex, with BSA, was studied in detail by various physico-chemical techniques. It is shown that NAMI, following chloride hydrolysis, binds bovine serum albumin tightly; spectrophotometric and atomic absorption data point out that up to five ruthenium ions are bound per albumin molecule when BSA is incubated for 24 h with an eightfold excess of NAMI. CD and electronic absorption results show that the various ruthenium centers bound to albumin exhibit well distinct spectroscopic features. The first ruthenium equivalent produces a characteristic positive CD band at 415 nm whereas the following NAMI equivalents produce less specific and less marked spectral effects. At high NAMI/BSA molar ratios a broad negative CD band develops at 590 nm. Evidence is provided that the bound ruthenium centers remain in the oxidation state +3. By analogy with the case of transferrins it is proposed that the BSA-bound ruthenium ions are ligated to surface histidines of the protein; results from chemical modification experiments with diethylpyrocarbonate seem to favor this view. Spectral patterns similar to those shown by NAMI are observed when BSA is reacted with two strictly related ruthenium(III) complexes Na[transRuCl4(Me2SO)2] and H(Im)[transRuCl4(Im)2] (ICR), implying a similar mechanism of interaction in all cases. It is suggested that the described NAMI-BSA adducts may form in vivo and may be relevant for the biological properties of this complex; alternatively NAMI/BSA adducts may be tested as specific carriers of the ruthenium complex to cancer cells. Implications of these findings for the mechanism of action of NAMI and of related ruthenium(III) complexes are discussed.     

The influence of inductive ligand electronics on the metrical parameters and redox potentials of a series of manganese(II) compounds

In order to assess the changes in the redox activity of a metal ion that result from inductive effects, three electronically modified derivatives of the ligand, N-benzyl-N,N′-bis(2-pyridylmethyl)-1,2-ethanediamine (L^H), have been prepared: N-(4-nitro)benzyl-N,N′-bis(2-pyridylmethyl)-1,2-ethanediamine (L^NO2), N-(4-chloro)benzyl-N,N′-bis(2-pyridylmethyl)-1,2-ethanediamine (L^Cl), and N-(4-methoxy)benzyl-N,N′-bis(2-pyridylmethyl)-1,2-ethanediamine (L^OMe). Due to the lack of a fully conjugated π-system between the 4-benzyl substituent and the N-donors, the electronic perturbation should influence a bound metal ion’s redox properties through primarily inductive pathways. The organic ligands react with MnCl₂ to form mononuclear complexes with the general formula [Mn(L^R)Cl₂]. The parent ligand, L^H, and its three derivatives each coordinate Mn(II) ions in a cis-α conformation, with the amine N-donors installed trans to the Mn-Cl bonds. Despite its distance from the metal ion, the electron-donating or - withdrawing group has a notable impact on both the metrical parameters of the Mn(II) compounds and the Mn(III/II) reduction potential. A single inductive perturbation can vary the reduction potential by as much as 50 mV.     

Ruthenium(II) thiacrown complexes: Synthetic, spectroscopic, electrochemical, DFT, and single crystal X-ray structural studies of [Ru([15]aneS5)Cl](PF6)

We wish to report the synthesis of the Ru(II) crown thioether complex, (1,4,7,10,13-pentathiacyclopentadecane)chlororuthenium(II) hexafluorophosphate, [Ru([15]aneS₅)Cl](PF₆), and a study of its properties utilizing single crystal X-ray diffraction, electronic spectroscopy, NMR spectroscopy, density functional theory calculations and cyclic voltammetry. The crystal structure shows a single [15]aneS₅ macrocycle and a chloro ligand coordinated in a distorted octahedral fashion around the ruthenium(II) center. A significant shortening (0.15 Å) of the trans Ru-S bond length occurs in this complex compared to the related PPh₃ complex (2.4458(10) to 2.283(1) Å) due to the differences in the trans influence of the two ligands. ¹³C NMR spectroscopy demonstrates that the structure of [Ru([15]aneS₅)Cl]⁺ is retained in solution. As expected for a Ru(II) complex, the electronic absorption spectrum shows two d-d transitions at 402 and 331 nm. These are red-shifted compared to hexakis(thioether)ruthenium(II) complexes and consistent with the weaker ligand field effect of the chloro ligand. The electrochemical behavior of the complex in acetonitrile shows a single one-electron reversible oxidation-reduction at +0.722 V versus Fc/Fc⁺ which is assigned as the Ru(II)/Ru(III) couple. DFT calculations for [Ru([15]aneS₅)Cl]⁺ show a HOMO with orbital contributions from a t_2g type orbital of the Ru ion, a π component from a p orbital of the axial S atom of [15]aneS₅, and a p orbital of the chloro ligand while the LUMO consists of orbital contributions of d_x²-y² orbital of the Ru center and p orbitals of the four equatorial S donors.     

Tumor cytotoxicity of 5,6-dimethyl-1,10-phenanthroline and its corresponding gold(III) complex

A gold(III) complex possessing 5,6-dimethyl-1,10-phenanthroline (5,6DMP) was synthesized and fully characterized using standard spectroscopic techniques, as well as X-ray crystallography and elemental analysis. The complex [(5,6DMP)AuCl₂][BF₄] (2) was found to possess a distorted square planar geometry about the gold(III) center, commonplace for d⁸ Au(III) cations possessing sterically un-hindered polypyridyl ligands. Compound 2 was evaluated for its potential use as an anticancer therapeutic. It was determined that the complex is stable in phosphate buffer over a 24-hour period, thought it does undergo rapid reduction in the presence of equimolar amounts of reduced glutathione (GSH) and ascorbic acid. The DNA binding and in vitro tumor cytotoxicity of the title compound 2 were also determined. It was found to undergo weak and reversible binding to calf thymus DNA, and was more cytotoxic towards a panel of human cancer cell lines than the commonly used chemotherapy agent cisplatin. Cytotoxicity experiments with the free 5,6DMP ligand indicate that the ligand has IC₅₀ values that are slightly lower than those observed for the gold complex (2), and coupled with the fact that the ligand appears to be released from the gold(III) metal center in reducing environments, this suggests the ligand itself may play an important role in the antitumor activity of the parent gold complex.