Search

The reaction of α-ferrocenyl(phenyl)methanol with various azoles under the phase transfer catalysis conditions afforded a series of ferrocenyl(alkyl)azoles in high yields. The structure of ferrocenyl(phenylmethyl)-3-trifluoromethyl-5-(2-thienyl)pyrazole was established by X-ray diffraction. The formation of a biradical cation from the intermediately formed ferrocenyl(phenyl)-carbenium ion, FcCH(Ph)+, was detected by ESR spin trap technique. Despite the demonstrated possibility of the formation of biradical cations, no products characteristic of the radical reaction pathway were found, which may serve as an indirect evidence that the reaction follows the SN1-mechanism.

We optimized the process of extraction and purification of betulin from birch bark and modified preparative syntheses of the simplest derivatives of betulin, namely, betulonic acid, betulonic aldehyde, and 3-aminobetulinic acid, as a platform for subsequent modifications.

Cobaltocenium acetylsalicylate was synthesized and characterized for the first time. The concentration dependences observed in its interaction with the double helix of DNA have been studied by circular dichroism. In these spectra, changes in the positions and decrease in the intensities of the curves in the positive and negative regions are observed when adding in increasing concentrations of cobaltocenium acetylsalicylate to calf thymus DNA. The observed changes in the effects of Cotton were interpreted as local changes in the conformation of the DNA double helix caused by the interaction of positively charged metallocenium cations with phosphate DNA fragments.

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.

The interaction between cyclodextrins (β- and γ-CD) and ferrocenyl azoles (i.e., pyrazole ferrocenes (I, III–V) and benzimidazole ferrocenes (VI, VII)), along with 1-ferrocenylethanol (II), each in the form of (R)- and (S)-enantiomers, in forming inclusion complexes is studied for the first time using detailed quantum chemical calculations. Compounds are calculated in terms of the density functional theory (DFT), using the Becke–Lee–Yang–Parr (B3LYP) approach in the 6-31G* basis sets. For the considered CD complexes with enantiomers of I–VII, structures in which a guest partially enters a host cavity from the side of the heterocyclic substituent (pyrazole or benzimidazole) are found to be energetically advantageous. It is shown that for successful resolution of (R,S)-enantiomers on chiral phases containing cyclodextrins, we must consider the interaction between outer hydroxyl groups on the CD cone’s surface, in addition to the correspondence of geometric dimensions. The calculated data correlate well with the data from the chromatographic separation of guest enantiomers on cyclodextrin sorbents.

Circular dichroism spectra of the optically active (R)- and (S)-enantiomers of N,N-(dimethylamino)ethylferrocene (Ugi´s amine) were studied for a free form and for their diastereomeric salts with с l(+)-tartaric acid.

A method for the ferrocene modification of amino acids of natural and synthetic origin has been developed. In the in vivo studies, the hippocampal electrical activity under the action of ferrocenyl(phenylpyrazolyl)glycine (1) was assessed. A meaningful rise (up to 25% compared to the control) in the response amplitudes of the focal potentials of the hippocampal region СА1 after intraperitoneal administration of compound 1 at the dose of 2.0 mg kg–1 was established

Classical synthetic approach to highly enantiomeric-enriched ferrocenes relies on the formation of their conjugates with (R,R)-tartaric acid. Herein, the quantum chemical calculations based on X-ray data as an initial approximation, were carried out for both (R)- and (S)-diastereomers of N,N-(dimethyl-1-ferrocenyl)ethylamine (Ugi’s amine) with (R,R)-tartaric acid. A high correlation between the experimental data and the calculated Gibbs free energies values of solvation was obtained. Based on the advanced DFT calculations, the chemical aspects of the separation of the diastereomeric complexes of (R)- and (S)-FcCH(CH3)N(CH3)2 with (R,R)-tartaric acid were clarified. Quantum chemical calculations made it possible to justify the use of methanol as a solvent in the successful separation of the diastereomeric complexes of the Ugi’s amine. This mathematical approach can be used in practice to separate racemates of other bioactive ferrocene compounds, for example, ferrocenyl alkyl azoles.

Betulonic acid S,S′-bis(carboxymethyl) dithioketal was obtained by condensation of betulonic and thioglycolic acids.

Enantiomeric-enriched ferrocene-modified pyrazoles were synthesized via the reaction of the ferrocene alcohol, (S)-FcCH(OH)CH3 (Fc = ferrocenyl), with various pyrazoles in acidic conditions at room temperature within several minutes. X-ray structural data for racemic (R,S)-1N-(3,5-dimethyl pyrazolyl)ethyl ferrocene (1) and its (S)-enantiomer (S)-1 were determined. A series of racemic pyrazolylalkyl ferrocenes was separated into enantiomers by analytical HPLC on β- and γ-cyclodextrins (CD) chiral stationary phases. The quantum chemical calculations of interaction energies of β-CD were carried out for both (R)- and (S)-enantiomers. A high correlation between experimental HPLC data and calculated interaction energies values was obtained.

We analyzed the research data on antitumor effects of a wide range of ferrocene compounds and discussed possible mechanisms of their bioactivities. Current trends in the study of anticancer effects of ferrocene derivatives were considered. Promising ways in the design of low-toxicity anticancer ferrocene-based drugs of new generation were outlined.

Compounds belonging to three novel groups of oncological drugs (metal polyacrylates, ferrocene derivatives, and polysuccinimide) showed antitumor activity. The most efficient compounds, viz., gold polyacrylate (auracryl), 2-[(1-ferrocenylethyl)sulfanyl]pyrimidine (LS-17), and polysuccinimide, inhibit the growth of murine solid tumors by 70–95% and are recommended for further thorough preclinical studies of their antitumor properties and mechanisms of action.

The results of the authors on the synthesis of ferrocene-containing organic compounds obtained in 1998–2013 are summarized. The review is focused on the ferrocene modifications of purine and pyrimidine bases, thiopyrimidines, natural and synthetic amino acids, azoles (including polyfluoroazoles and mercaptoazoles) and ferrocenyl quinoline synthesis. The special attention is given to the scale synthesis of compounds for biological trials.

The structures, electrochemical properties, enantiomeric separation of ferrocenyl-(alkyl)pyrimidines and ferrocenyl(ethyl)adenine and their effects on the DNA synthesis in tumor cells were studied. Enantiomeric mixtures were separated by HPLC on modified cellulose as the chiral selector. The electrochemical properties of compounds were studied by cyclic voltammetry. All compounds have reversible single-electron redox transition in the region of 0.52–0.60 V, which belongs to ferrocene—ferrocenium with a positive shift compared to ferrocene (0.52 V). The molecular structure of 1-N-(ferrocenylbenzyl)-5-iodocytosine was studied by X-ray diffraction. 1-N-(Ferrocenylethyl)adenine was studied for ability to inhibit the DNA synthesis in the human ovarian cancer cell culture by the 3H-thymidine test.

Ferrocenylalkyl thiopyrimidines (6a–d to 9a–d) were prepared via the reaction of the α-(hydroxy)alkyl ferrocenes, FcCHR(OH) (1a–d; Fc = ferrocenyl; R = H, Me, Et, Ph), with 2-thiopyrimidines (2–5) in acetone at room temperature in the presence of TFA, yielding 50–95%. The resulting enantiomers were resolved using HPLC on modified cellulose as chiral selector. The antitumor activities of S-ferrocenylethyl 2-thiopyrimidine (6b) against two murine solid tumor models, carcinoma 755 (Ca755) and Lewis lung carcinoma (LLC) were evaluated in vivo. The strong antitumor effect of compound 6b on Ca755 and LLC was demonstrated. The index of tumor growth inhibition on Ca755 equaled 95% in comparison with control. Copyright © 2010 John Wiley & Sons, Ltd.

Data on the antitumor activities of ferrocene compounds and the results concerning the mechanisms of their action published between 1995 and 2010 are discussed. The biomedical aspects of the study of ferrocene derivatives are briefly analyzed.

Ferrocenylalkyl nucleobases (1–14) were prepared via the reaction of the α-(hydroxy)alkyl ferrocenes FcCHR(OH) (Fc = ferrocenyl; R = H, Me, Et, Ph) with thymine, cytosine, iodo-cytosine and adenine in DMSO at 100 °C, yields being 50–80%. The antitumor activities of ferrocenylmethyl thymine (1) against solid tumor models, carcinoma 755 (Ca755) and Lewis lung carcinoma (LLC) were studied in vivo. Therapeutic synergism of antitumor activity against LLC was demonstrated in the case of combined application of compound 1 with anticancer drug cyclophosphamide. Copyright © 2009 John Wiley & Sons, Ltd.

The antitumor activity of o-carboxybenzoylferrocene sodium salt (1) was studied in vivo. Interaction between o-carboxybenzoylferrocene (2) and N,N′-carbonyldiimidazole in boiling methylene dichloride leads to 3-(N-imidazolyl)-3-ferrocenylisobenzofuran-1(3H)-one (5). The structure of compound 5 was established by X-ray analysis. Aminolysis of compound 5 in toluene gave rise to ferrocenoylbenzamides (6a–d)–derivatives of dimethylamine, piperidine, pyrrolidine and morpholine. Copyright © 2008 John Wiley & Sons, Ltd.

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.

The electrospray ionization behavior of some ferrocenylalkylazoles CpFeC5H4CH(R)Az (AzH are derivatives of imidazole, pyrazole, triazole and their benzo analogs; R = H, Me, Et, Ph), ferrocenylalkanols CpFeC5H4CH(R)OH (R = H, Me), and mixtures of the latter with azoles was studied. The electrospray ionization mass spectra of these compounds, in addition to the molecular ion [M]+·, the protonated molecule [M + H]+, and ferrocenylalkyl cation [FcCHR]+ peaks, exhibit also intensive peaks for the binuclear ions [(FcCHR)2X]+ (X = Az or O), resulting from ferrocenylalkylation of the initial compounds with the ferrocenylalkyl cations. Electrospray ionization of an equimolar mixture of ferrocenylmethanol FcCH2OH and imidazole gives the protonated ferrocenylmethylimidazole molecule [FcCH2Im + H]+ and the [FcCH2(Im)2 + H]+ dimer, apart from the ions typical of each component, i.e., ferrocenylalkylation of azoles with the ferrocenylalkylcarbinols, known in the chemistry of solutions, takes place under electrospray conditions.

The syntheses, structures, electrochemical properties of the series of ferrocenylalkyl azoles, FcAlkAz, as well as the antitumor activity of ferrocenylmethyl benzimidazole ( 8 ) have been studied. Above mentioned compounds were investigated by the method of cyclic voltametry. All of them exhibited a reversible one-electron oxidation–reduction wave owing to the ferrocene–ferrocenium redox couple with a positive shift (0.50–0.65 V) compared with that of ferrocene (0.42 V). The X-ray determination of molecular structures of 1-(ferrocenylmethyl)imidazole ( 4 ), 1-(ferrocenylbenzyl)imidazole ( 7 ) and 1-(ferrocenylmethyl)bezimidazole ( 8 ) was carried out. Compound 4 with imidazolyl substituent was found to be present in N -protonated form. Antitumor activity of 1-(ferrocenylmethyl)benzimidazole ( 8 ) against some solid tumor models such as adenocarcinoma 755 (Ca755), melanoma B16 (B16) and Lewis lung carcinoma was studied. The antitumor activity of compound 8 was compared with cisplatin effectiveness against some experimental tumor systems.

Ferrocenyl(alkyl)azoles were synthesized in high yields by interaction of α-ferrocenylcarbinoles with azoles in aqueous–organic in the presence of HBF 4 or by interaction of α-ferrocenylcarbinoles with N , N ′-carbonyldiimidazole, N , N ′-thionyldiimidazole, N , N ′-thionyldibenzimidazole in boiling dichloromethane. The resulting enantiomers of ferrocenyl(alkyl)azoles and some carbinoles were separated using HPLC on silica bonded chiral stationary phases based on cyclodextrins and modified cellulose.

The title compounds were synthesized in quantitative yields by interacting α-hydroxyalkyl ferrocenes with polyfluoroalkyl benzimidazoles in an aqueous-organic medium in the presence of HBF4. The resulting diastereomers and enantiomers were resolved using HPLC on silica bonded chiral stationary phases based on chiral cyclodextrins and cyclic antibiotics. The X-ray determination of molecular and crystal structure of 1-ferrocenylmethyl-2-(trifluoromethoxyfluoromethyl)benzimidazole (1) was carried out.

9-(α-Ferrocenylethyl)adenine was prepared by the reaction of adenine with α-hydroxyethylferrocene in a two-phase aqueous-organic medium in the presence of HBF4. The structure of the resulting compound was established by X-ray diffraction analysis.

Electron ionization mass spectra of biologically active ferrocenylalkylazoles CpFeC5H4CH(R)Az (R = H, Me, Et, Pr, or Ph; AzH is pyrazole, imidazole, indazole, benzoimidazole, benzotriazole, adenine, or their derivatives) were studied. The nature of the heterocyclic fragment (its ionization energy) is the main factor determining the reactivity of these compounds under conditions of dissociative electron ionization.

The stereochemistry of two processes, viz., α-ferrocenylalkylation of indazole with optically active S-(+)-1-ferrocenylethanol and the thermal rearrangement of S-(+)-2-N-(ferrocenylethyl)indazole into S-(+)-1-N-(ferrocenylethyl)indazole, was studied. Both reactions proceed stereoselectively.

The reactions of hydroxymethylferrocene, α-hydroxyethylferrocene, and 1,1′-bis(α-hydroxyethyl)ferrocene withN-ferrocenylalkyl-substituted benzotriazoles, hexamethylenetetramine, and azaferrocene in the CH2Cl2 — 48% aqueous HBF4 two-phase system affordedN-mono-,N-1,1′-ferrocenylene-bis-α-alkylated, and 1,3-bis-ferrocenylalkylated tetrafluoroborates of the above-mentioned heterocyclic compounds in high yields. An X-ray structural study of 1,3-bis-(ferrocenylmethyl)benzotriazolium tetrafluoroborate confirmed unambiguously the 1,3-arrangement of the ferrocenylmethyl groups in the heterocycle.

a-Ferrocenylalkylation reactions [1] are used to prepare various ferrocene derivatives exhibiting a wide spectrum of biological activity [2, 3]. With the goal of further search for more efficient compounds of this series, in the present work we effected for the first time a-ferrocenylalkylation of some biologically active compounds [4], such as Cyclophosphan, 5-fluorouracil (as sodium salt), and glycine and phenylalanine ethyl esters, by the action of ferrocenylmethanol (I) in the two-phase system CH2Cl23 48% aqueous HBF4 at room temperature under vigorous stirring. It is known [5] that under these conditions a-ferrocenylcarbocation II is readily generated from alcohol I. Cation II reacts with the above nucleophilic substrates at their most electron-rich centers. As a result, we obtained in high yields ferrocene-containing compounds III3VI (Scheme 1) whose structure was confirmed by the data of elemental analysis, IR and H NMR spectroscopy, and mass spectrometry and by chemical transformations. The IR spectra of compounds III3VI contain absorption bands typical of vibrations of the ferrocenyl fragment [6] and other functional groups (PIO, CIO, NAH). Their H NMR spectra were also consistent with the assumed structures. Compound VI showed in the H NMR spectrum a double set of signals due to the presence of two isomers (N and and N) which we failed to separate by column chromatography on Al2O3 (compound VI turned out to be unstable). According to the H signal intensities, the ratio of the Nand N-isomers is 65 : 35. The mass spectra of III3VI contained low-intense (538%) molecular ion peaks; the most abundant ions were [FcCH2] +

a-Ferrocenylalkylation reactions [1] are used to prepare various ferrocene derivatives exhibiting a wide spectrum of biological activity [2, 3]. With the goal of further search for more efficient compounds of this series, in the present work we effected for the first time a-ferrocenylalkylation of some biologically active compounds [4], such as Cyclophosphan, 5-fluorouracil (as sodium salt), and glycine and phenylalanine ethyl esters, by the action of ferrocenylmethanol (I) in the two-phase system CH2Cl23 48% aqueous HBF4 at room temperature under vigorous stirring. It is known [5] that under these conditions a-ferrocenylcarbocation II is readily generated from alcohol I. Cation II reacts with the above nucleophilic substrates at their most electron-rich centers. As a result, we obtained in high yields ferrocene-containing compounds III3VI (Scheme 1) whose structure was confirmed by the data of elemental analysis, IR and H NMR spectroscopy, and mass spectrometry and by chemical transformations. The IR spectra of compounds III3VI contain absorption bands typical of vibrations of the ferrocenyl fragment [6] and other functional groups (PIO, CIO, NAH). Their H NMR spectra were also consistent with the assumed structures. Compound VI showed in the H NMR spectrum a double set of signals due to the presence of two isomers (N and and N) which we failed to separate by column chromatography on Al2O3 (compound VI turned out to be unstable). According to the H signal intensities, the ratio of the Nand N-isomers is 65 : 35. The mass spectra of III3VI contained low-intense (538%) molecular ion peaks; the most abundant ions were [FcCH2] +

A suitable method for the synthesis of ferrocenyl(alkyl)imidazoles is proposed. The treatment of α-ferrocenylcarbinols with N , N ′-carbonyldiimidazole affords the title compounds, are in more than 80% yields.