Evaluation of the activity of some water-soluble ferrocene and ferricenium compounds against carcinoma of the lung by the human tumor clonogenic assay

The two ferrocene compounds, ferrocenylacetic acid (3) and ferrocylthiomalic acid (4), as well as the ferricenium salts, ferricenium tetrachloroferrate (III) (1) and ferricenium trichloroacetate–trichloroacetic acid solvate (2), were investigated by the in vitro human tumor clonogenic assay for their inhibiting effects, in continuous exposure in a double-layer medium, on the colony formation of single-cell suspensions prepared from 30 selected fresh specimens of human adenocarcinoma, squamous cell carcinoma and large-cell carcinoma of the lung. At the high drug concentration level of 100 μg cm ^?3, good response ratios were observed for 3 (79%) and 4 (72%), followed by 1 (67%) and 2 (52%). At the low concentration level of 10 μg cm^?3 response ratios were below 25% for all compounds, best performance (24%) being shown by 1. In vitro experiments probing the schedule dependencies of the compounds' inhibiting effects against the lung carcinoma cell line PC-9 were also performed, as were experiments involving the combination of the ferricenium salt 1 and cisplatin, which showed the combination effect to be additive in both one-hour and continuous-exposure tests.     

Ferrocenylalkyl azoles: bioactivity,synthesis, structure

The toxicity of ferrocenylethyl benzotriazole ( 1 ) and other ferrocene compounds including ferrocenylmethyl benzimidazoles ( 4,5,6,11 ), ferricenium salts ( 3,9,10 ) and ferrocenylmethyl adenine ( 7 ), was studied. All ferrocene complexes under investigation showed low or medium toxicities. On the basis of an earlier model of chemical carcinogenesis, the antitumor activity of ferrocenylalkyl azoles 1, 8 and ferricenium salts 9, 10 was studied in vivo in the so‐called sub‐capsular test on human tumors. This effectiveness was compared with that of cisplatin. A series of ferrocenylalkyl azoles were synthesized by interacting azoles either with α‐hydroxyalkyl ferrocenes FcC(OH)R₁R₂ in organic solvent in the presence of aqueous HBF₄ in quantitative yields or with trimethyl(aminomethyl)ferrocene iodide in an aqueous‐basic medium in good yields. The X‐ray determinations of molecular and crystal structures of α‐(1‐benzotriazolyl)ethylferrocene ( 1 ) and α‐(1‐naphthatriazolyl)ethylferrocene ( 12 ) were performed. Copyright © 2008 John Wiley & Sons, Ltd.     

Antineoplastic activity of polyaspartamide–ferrocene conjugates

The ferrocene/ferricenium redox system plays a significant role in biological oxidation, reduction and free-radical reactions. Of particular interest are the findings of earlier investigations which showed certain water-soluble ferricenium salts to possess appreciable antiproliferative activity against various murine tumor lines and a xenografted human colorectal adenocarcinoma. Solubility in water, a prerequisite for efficacious transport and dissipation in central circulation, was then proposed as a principal requirement for the ferrocene complex system to exert antineoplastic activity irrespective of the oxidation state in which it is administered. In order to shed more light on this question, we decided to investigate the antiproliferative properties of polymer–ferrocene conjugates containing the metal complex in the non-oxidized (ferrocene) form while fulfilling the critical requirement of water solubility. To this end, five selected, water-soluble conjugates, synthesized by reversible coupling of 4-ferrocenylbutanoic acid to variously structured polyaspartamides featuring pendant primary amino groups as coupling sites, were tested in vitro against cultured HeLa cells at concentrations up to 50 µg Fe ml⁻¹. Optimal antiproliferative activities, with IC₅₀ in the range of 2–7 µg Fe ml⁻¹, were determined for three compounds possessing tertiary-amine functions susceptible to protonation at physiological pH. Lower activities (IC₅₀ = 45–60 µg Fe ml⁻¹) were demonstrated for two poly(ethylene oxide)-containing conjugates. However, no reasonable structure–performance relationships can be derived at this stage from the small number of compounds tested. Copyright © 1998 John Wiley & Sons, Ltd.     

Preparative and spectroscopic features of ferricenium tetrachloroferrate(III). Interconversion to diferricenium μ-oxo-bis[trichloroferrate(III)]

Summary Ferricenium tetrachloroferrate(III)(1), one of the more frequently cited ferricenium salts, has recently attracted biomedical interest because of its pronounced antineoplastic activity against Ehrlich ascites murine tumor. In this paper, synthetic methods are reinvestigated in an effort to prepare pure(1) free from a common contaminant, diferricenium-oxo-bis(trichloroferrate)(3). The oxodiferrate, or mixtures of this salt with(1), can readily be converted into pure(1) under acidic conditions. Conversely, dimerization of(1) with participation of water to give the oxodiferrate(3) is brought about by recrystallization of the former from moist acetonitrile/methanol in the presence of base; this reaction thus represents a simple procedure for the preparation of pure(3) from crude(1) readily obtainable by the long known interaction of ferrocene and iron(III) chloride in indifferent media. The i.r. and electronic absorption spectra of(1) are presented, as are the Mössbauer and x-ray photoelectron spectra. The room-temperature effective magnetic moment, 6.40 _B, of the salt is lower than would be expected on the basis of typical ferricenium cation (2.4 _B) and tetrachloroferrate(III) anion (5.9 _B) moments determined for related salts. This suggests the possibility of weak inter- or intra-molecular antiferromagnetic interaction in the crystal.     

Photochemical properties of ferrocene,cobaltocene and nickelocene and their complexes with 2,2,2-trichloroethanol in liquid phase

Summary Photochemical changes in the solutions of ferrocene, cobaltocene, nickelocene and their complexes with 2,2,2-trichloroethanol exposed to near u.v. and argon laser (=514.5 nm) radiation were investigated. The solutions of cobaltocene, nickelocene and their complexes were found to undergo photolysis, whereas ferrocene solutions are not sensitive to this kind of irradiation and the ferrocene bound in a complex undergoes photooxidation to give the ferricenium cation. The activating effect of laser irradiation of ferrocene was revealed as a tendency to complex formation. The quantum yield of the investigated photoreactions, equilibrium constant of complex formation,K, and their molar extinction coefficients, _c, were determined.     

Antitumor effects of binuclear ferrocene derivatives

On the basis of an earlier model of chemical carcinogenesis, the antitumor activity of the mono-, bi- and poly-nuclear ferrocene derivatives ferricenium tri-iodide (1), ferricenium tetrachloroferrate (2), 1, 1′-diethylferricenium triiodide: (3), N-(ferrocenylmethyl)hexamethylenetetramine tetrafluoroborate (4), bis(ferrocenylmethyl)benzotriazolium tetrafluoroborate (5), bis(ferrocenyl-α-ethyl)benzotriazolium tetrafluoroborate (6) and bis(ferrocenylmethyl)-2-methylbenzimidazolium tetrafluoroborate (7), and the oligomer (—Fc—CH₂—Fc^+˙—CH₂—)_7–8^? (PF₆)_7–8 (8) was studied in vivo (Fc?C₁₀H₈Fe). The tumor models studied included MCH-11 (mouse sarcoma induced by methylcholantrene), P-815 (mouse mastocytoma of DBA/2 origin) and virus-induced Raucher leukemia (RLV). The cytotoxic effects of these preparations were examined against in vitro cultured normal murine cells (line L-929). The binuclear ferrocene derivatives 5, 6 and 7 inhibited the development of experimental tumors in mice. Ferricenium tri-iodide (1) was effective in Rauscher leukemia. Kinetic dependencies for most complexes had a two-phase character: the region of inhibition of tumorogenesis was followed by a region in which the complexes accelerated the development of this process. The link between the structure of compounds 1–8 and their antitumor effects is discussed.     

Reaction of [α-(trimethylsilyl)benzyl]ferrocenes with α-ferrocenylbenzyl cations

Although methanolysis of [α-(trimethylsilyl)benzyl]ferrocene (I) and [p-methyl-α-(trimethylsilyl)benzyl]ferrocene (II) in the presence of anhydrous ferric chloride merely gave α-ferrocenylbenzyl methyl ether (III) and p-methyl-α-ferrocenylbenzyl methyl ether (IV), respectively, acid-catalyzed methanolysis of (I) and (II) in the presence of an equimolar amount of (III) or (IV) afforded 1,2-diferrocenyl-l,2-diarylethanes. It is suggested that one electron oxidation of [α-(trimethylsilyl)benzyl]ferrocene by α-ferrocenylbenzyl cation generated from α-ferrocenylbenzyl methyl ether, and subsequent methanolysis of the resulting substituted ferricenium ion may occur to give the two species of α-ferrocenylbenzyl radical, which in turn undergo an approximately statistical coupling.     

Synthesis and Mossbauer spectroscopic studies of chemically oxidized ferrocenyl(phenyl)phosphines

The electrochemical potentials of Fc3-xPPhx, (1-3, x = 0-2) and (FcPPh)n (4) indicate that iodine should oxidize ferrocenyl(phenyl)phosphines. The molar conductivity of solutions of 1-3 increases sharply when the solutions are titrated with iodine, leveling off after the addition of > 2 equiv of oxidant, consistent with formation of 1:1 electrolytes. Diamagnetic salts 6-9 are observed upon addition of a benzene solution of iodine to a benzene solution of 1-4 at ambient temperature in ratios of I2/metallocene ranging from 1:1 to 2:1. Well-resolved 1H and 31P NMR spectra are obtained for 6-8. Absorptions assigned to the I3- anion dominate the UV-vis spectrum of 6-8, whereas characteristic absorptions for [Fc][I3] are absent. Mossbauer spectra of 7-9 reveal isomer shifts consistent with low-spin iron(II) in ferrocene derivatives rather than those in ferricenium ions. Small amounts of low-spin FeIII appear to be present in 6. Taken together, the results suggest that 6-9 are iodophosphonium salts and not ferricenium salts. Diferrocenyl(phenyl)phosphine oxide (5) reacts with iodine to produce a diamagnetic, dark solid 10. Low-spin FeII is observed at 77 and 293 K in the Mossbauer spectra of 10 with no evidence for oxidation of FeII to FeIII. Compound 10 is proposed to be a neutral complex between 5 and I2. Reactions between 5 and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) yield [Fc2P(=O)][DDQ]2 (11). Mossbauer spectroscopy of 11 indicates the presence of a mixture of low-spin FeII and low-spin FeIII at 77 K, suggesting that some electron transfer occurs from 5 to DDQ. The fraction of low-spin FeIII increases at room temperature.     

Reaction of ferrocenylmethyl derivatives of silicon and germanium with methanol: Solvolysis of the metal-carbon bond in the presence of ferric ions

Nine ferrocenylmethyl derivatives of silicon and germanium were prepared and found to undergo methanolysis of their C---M (M = Si or Ge) bonds in the presence of ferric ions to give ferrocenylmethyl methyl ether. For this reaction, relative rate studies and polarographic studies of the pertinent ferrocene derivatives were carried out to obtain some insight into the reaction mechanism. The substituted ferricenium ion intermediate which is formed by oxidation with ferric ions can readily undergo nucleophilic attack by methanol on the metal (Si or Ge) atom. The observed higher reactivity of the germanium derivative relative to the silicon congener in this reaction is not that expected for the usual base-catalyzed attack at the metal atom, and may be reasonably interpreted in terms of a possible change in the transition state depending on the nature of the leaving group, viz. on the acidity of the corresponding hydrocarbon acid, in the solvolysis of the C---M bond.     

Kinetics of polyesterification. I. Dibasic acid and glycol systems

Polyesterification of diacid and diol in the absence of foreign acid is carried out under constant reaction temperatures from 140 to 180°C (rather than under constant oil bath temperature as is usually done) and molar ratios r of diol to diacid from 1 to 3.55. The experimental data obtained cannot fit conventional rate equations as they appear in the literature. Based on ion pair formation and considering additional proton transfer from acid to alcohol, we propose a reaction mechanism and rate equations. The rate equation is found to fit our experimental data very well except for r = 1. At r = 1, the kinetic plot shows two straight lines rather than one as predicted. This is attributed to unremoved water due to the higher molecular weight (and therefore higher viscosity) at r = 1 which causes a reverse reaction and slower apparent reaction rate.     

金属有机配合物对DNA的断链作用

过渡金属配合物催化DNA、RNA的断链反应研究是近年来最为活跃的前沿研究领域之一,因某些金属配合物具有核酸酶特异性催化DNA、RNA断链的功能,因而该研究对新型抗肿瘤、抗艾滋病化学药物的定向设计及其基因治疗和分子生物学研究中DNA、RNA的高度专一性定点断裂、染色体图谱分析及DNA定位诱变、基因工程中足迹技术(footprinting)以及DNA构象识别等方面均具有重要意义和应用前景,文献已报道了一些具有断裂DNA、RNA功能的金属配合物,但其中很少有含金属-碳σ键的金属有机化合物,本文首次报道了二茂铁鎓离子三氯乙酸盐和二氯二茂钛对DNA的断链作用。     

Electrochemical approach to direct homogeneous chemical cyanation of ferricenium salts: The complexing of system components

An unusual homogeneous chemical reaction of a direct cyanation of ferricenium salts by hydrocyanic acid is analyzed on the basis of an electrochemical approach and the notions of the chemistry of coordination compounds about an inner-sphere electron transfer. The complexing between a ferricenium cation and cyanide anion is confirmed experimentally using a potentiometric titration of aqueous solutions of ferricenium tetrafluoroborate by hydrocyanic acid. Variations of the mechanism of a rebound substitution of the CN group in the cyclopentadienyl ring for the hydrogen atom are considered. The mechanism is based on the notion about an inner-sphere redox reaction between the Fe(III) atom of a ferricenium cation and the CN^- anion. The magnitude and sign of the difference between standard potentials of systems [(C₅H₅)₂M)]⁺/(C₅H₅)₂M and CN⁺/CN^- are found to represent a thermodynamic criterion indicating whether cations of metallocenes [(C₅H₅)₂M]⁺ may be directly cyanated by hydrocyanic acid. Dedicated to the memory of Academician A.N. Nesmeyanov, in connection with his centennial.     

Solvent effects on the electron donor acceptor complex properties of ferrocene and tetranitromethane

Summary Spectral investigations in the 350–800 nm range of ferrocene (FcH) and tetranitromethane [C(NO₂)₄] solutions in cyclohexane and carbon tetrachloride at concentration-constant (FcH) and variable (tetranitromethane) were made. The electron donor acceptor (EDA) complex of ferrocene and tetranitromethane and its dissociation to the ferricenium cation (FcH⁺) were studied as a function of the solvent, the initial C(NO₂)₄ concentration and reaction time.     

Application of capillary electrophoresis technique for the enantioseparation of bioactive ferrocene-based compounds versus DFT calculated data

Herein, a series of bioactive ferrocene-modified N-heterocycles with alkyl linkers was prepared in good to quantitative yields starting from easy accessible ferrocene alcohols and heterocycles under acidic or neutral (for imidazole) conditions in racemic forms. The analytical resolution of a number of bioactive racemic ferrocene azoles 1 – 6 (where azole = imidazole, pyrazole, and benzotriazole derivatives) into enantiomers was first carried out by CE using sulfobuthylether-β-CD (captisol) as a chiral selector. The analytical approaches to highly enantiomeric-enriched ferrocene derivatives are based on the formation of their inclusion complexes. The best chiral separation was achieved using zone CE in a quartz capillary. The ACE was used to evaluate the stability constants of captisol complexes with enantiomeric forms of two ferrocene derivatives 1 , FcCHMe-imidazole, and 6 , FcCHMe-benzotriazole. The optimal conditions for the resolution of the studied (R, S)-ferrocene compounds 1 , 2 , and 6 were predicted on the basis of the performed quantum chemical calculations and then implemented by the electrophoretic method. A high correlation between density functional theory calculation results and experimental electrophoresis data were obtained. Successful enantioseparation of racemic mixtures is of great importance for the characterization and further applications of drug candidates in enantiopure forms and in the development of clinical treatment. The advantages of the CE procedure make it possible to have important practical value and significance for determining the purity and enantiomeric excess of other ferrocene-containing compounds.     

Thermal Decomposition Reaction of Ferrocene in the Presence of Oxalic Acid

Thermal decomposition of ferrocene [(C₅H₅)₂Fe] in the presence of oxalic acid [(COOH)₂·2H₂O] samples—prepared by grinding the mixtures of ferrocene and oxalic acid at different weight ratios—is reported in this work. It presents a mathematical analysis of nonisothermal thermogravimetric data using multiheating rates to estimate reaction kinetics as well as thermodynamic parameters. Model‐free (integral isoconversional) methods are employed to analyze thermogravimetric data. The most probable reaction mechanisms for thermal reactions have been identified. Based on the values of the activation energy E_α* and reaction rate A_α for different steps of decomposition, the values of ΔS *, ΔH *, and ΔG * for the formation of activated complex from the precursor are estimated. Besides, this work has proposed reaction pathways indicating the formation of hematite (α‐Fe₂O₃) as the solid end‐product of thermal decomposition of the samples.     

Application of ferrocenylimidazolium salts as catalysts for the transfer hydrogenation of ketones

Ferrocenylimidazolium salts with methylene and phenyl groups bridging the ferrocenyl and alkylimidazolium moieties were synthesized and characterized by spectroscopic and analytical methods. Crystal structures of two new compounds are also reported. Cyclic voltammetry was used to analyze the influence of the two bridging groups or spacers on electrochemical properties of the salts relative to the shifts in the formal electrode or peak potentials (E⁰ or E_1/2) of the ferrocene/ferrocenium redox couple. Results from this study showed that all the salts exhibited higher electrode potentials relative to ferrocene, which is due to the electron‐withdrawing effect of the imidazolium ion on the ferrocenyl moiety. Application of the salts as catalysts in transfer hydrogenation of ketones resulted in high conversion of saturated ketones to corresponding alcohols and turnover numbers as high as 1880. The catalysts were chemoselective towards reduction of the C═C bonds of conjugated 3‐penten‐2‐one and 4‐hexen‐3‐one to yield saturated ketones, while unconjugated 5‐hexen‐2‐one was hydrogenated to an unsaturated alcohol. Copyright © 2012 John Wiley & Sons, Ltd.     

Administration of ferrocene-modified amino acids induces changes in synaptic transmission in the CA1 area of the hippocampus

A series of ferrocene-modified amino acid methyl esters with pyrazole linker was prepared in good to quantitative yields starting from easy accessible ferrocene pyrazole carbaldehyde and amino acids in racemic and enantio enriched forms under reductive amination conditions (NaBH (OAc)₃, reflux, 3 hr). The resulting enantiomers were resolved using analytical HPLC on modified cellulose or amylose as chiral selectors. In vivo electrophysiological experiments were performed in the CA1 field of the hippocampus on 3a Fc-Gly, (L)- 3b Fc-Ala, and (D)- 3b Fc-Ala compounds. An increasing in the amplitudes of responses of local potentials (up to 25%) of the CA1 region in the studied groups was found after intraperitoneal administration of ferrocene compounds 3a and (D)- 3b compared with control rats treated with saline.     

Trihaloacetate-Selective Electrodes Based on Hexyl p-Trifluoroacetylbenzoate

Analytical properties of trihaloacetate-selective film electrodes with membranes containing hexyl p-trifluoroacetylbenxoate as a solvating agent were studied. The use of trichloroacetate-selective electrodes for the determination of trichloroacetic acid and its salts in medical diagnostic kits was shown in examples.     

Ferrocene and Ferricenium Ion as Versatile Photometric Titrants of H2O2 and D-Glucose in the Presence of Peroxidase and Glucose Oxidase. A Ferrocene-Peroxidase Stairway #

Abstract

Hydrogen peroxide can routinely be determined in the presence of ferrocene (FcH) and horseradish peroxidase by monitoring at 617 nm the enzymatically produced ferricenium dye. In contrast, D-glucose can be assayed by following the fading of the ferricenium dye FcH⁺PF₆ ^? in the presence of glucose oxidase. The change in absorbance in both cases corresponds to the amount of analyte. viz. H₂O₂ or D-glucose, in solution. The routine is very simple, invariant to the concentrations of both ferrocenes/ferricenium salt and enzyme and allows numerous “one pot” measuremeats with the detection limit of 10^?4 M for both the analytes. It takes 2–4 and 5–10 min to accomplish one analysis of H₂O₂ and D-glucose in the presence of peroxidase and glucose oxidase, respectively.

     

Organometallic polymers. XXIX. Synthesis and characterization of ferrocene-containing siloxane polymers from bis(dimethylamino)silane–disilanol condensation

A new monomer, 1,1′-bis(dimethylaminodimethylsilyl)ferrocene, was synthesized by two routes and polymerized with three aryl disilanols: dihydroxydiphenylsilane, 1,4-bis(hydroxydimethylsilyl)benzene, and 4,4′-bis(hydroxydimethylsilyl)biphenyl, yielding three different polysiloxanes. Melt polymerizations carried out at 1 torr pressure and 100°C resulted in the highest molecular weight polymers. Intramolecular cyclization competed with intermolecular chain extension in polymerization of the bis(aminosilane) with dihydroxydiphenylsilane, resulting in isolation of a bridged derivative, 1,3,5-trisila-2,4-dioxa-1,1,5,5-tetramethyl-3,3-diphenyl[5]ferrocenophane. Cyclization did not compete significantly during the formation of polymers from this bisaminosilane and the two remaining diols, as evidenced by higher yields and greater molecular weights. These polymers could be cast as tough flexible films, and fibers could be drawn from their melts. TGA and DSC data showed the polymer formed from 1,1′-bis(dimethylaminodimethylsilyl)ferrocene and 1,4-bis(hydroxydimethylsilyl)benzene to be at least as thermally stable as an arylene siloxane polymer which differed from the ferrocenylsiloxane structure only in the replacement of the ferrocene moiety with a p-substituted phenylene linkage. The ferrocene-containing polymers were generally hydrolytically stable under conditions of refluxing THF–H₂O(10 : 1) for 1 hr. The polymer-forming reaction was found to follow second-order kinetics, and the specific rate constants for formation of two of the polymers were measured.