Terézia Szabó-Plánka

Biological activity and coordination modes of copper(II) complexes of Schiff base-derived coumarin ligands

The coordination modes of copper(II) complexes of Schiff base-derived coumarin ligands, which had previously shown good anti-Candida activity, were investigated by pH-potentiometric and UV-Vis spectroscopic methods. These studies confirmed the coordination mode of the ligands to be through the N of the imine and deprotonated phenol of the coumarin-derived ligand in solution. In addition, the more active complexes and their corresponding ligands were investigated in the presence of copper(II) in liquid and frozen solution by ESR spectroscopic methods. A series of secondary amine derivatives of the Schiff base ligands, were isolated with good solubility characteristics but showed little anti-Candida activity. However, cytotoxicity studies of the secondary amines, together with the copper complexes and their corresponding ligands, against human colon cancer and human breast cancer cells identified the chemotherapeutic potential of these new ligands.

An electron spin resonance study of coordination modes in the copper(II)-histamine and copper(II)-L-histidine systems in fluid aqueous solution

Abstract Copper(II)–histamine and copper(II)– l -histidine equilibrium systems were studied in fluid aqueous solution by ESR spectroscopy. Eighty-seven spectra taken in a circulating system at various ligand-to-metal concentration ratios and pH were analysed. The experimental curves were decomposed to one to four component spectra which were built up from the hyperfine lines of 63Cu and 65Cu, and a maximum of four non-equivalent 14N nuclei. The isotropic ESR parameters (g-factors, hyperfine coupling constants and relaxation parameters) and the relative concentrations of the different species were optimized. New, pH-potentiometrically non-identified species were also considered in the equilibrium models. In the copper(II)–histamine system the complex [CuLH−2] was added to the species [CuLH]3+, [CuL]2+, [CuLH−1]+, [Cu2L2H−2], [CuL2H]3+ and [CuL2]2+. In the copper(II)– l -histidine system, in addition to the complexes [CuLH]2+, [CuL]+, [CuLH−1], [Cu2L2H−2], [CuL2H2]2+, [CuL2H]+ and [CuL2], the new species [CuLH2]3+ and [CuLH−2]− were found. The relative concentrations obtained from the ESR spectra are in good accordance with the concentrations calculated from the literature pH-potentiometric formation constants. The two ligands in their ‘LH’ states are bound differently: the histamine by the imidazole, and the l -histidine through the amino and the carboxylate groups in equatorial positions (complexes [CuLH], [CuL2H] and [CuL2H2]). For the [CuL], [CuL2H] and [CuL2] complexes of both histamine and l -histidine, the first ‘L’ ligand is coordinated equatorially by the amino and imidazole nitrogens. The second ‘L’ ligand in the [CuL2] complexes is either bound in the former way, or its imidazole group occupies an axial site. The carboxylate group of l -histidine is coordinated to the metal ion in each complex, in either an equatorial or an axial position. The deprotonation of the [CuL] complex takes place from the imidazole ring, which is followed by the proton loss of the equatorial water molecule in the highly alkaline region.

ESR study of copper(II) complexes of α-amino acids. Coordination modes and metal-ligand bonds in frozen aqueous solutions

Abstract Various copper(II) complexes of potentially terdentate α-amino acids and, for comparison, those of ethylenediamine and histamine have been investigated. The ESR spectra at 1 : 1 and 1 : 4 metal-ligand concentration ratios over different pH regions have been recorded in frozen aqueous solutions. The parallel and perpendicular components of the g and A tensors, the nitrogen superhyperfine coupling constants in the different directions, and the numbers of equatorial nitrogen donor atoms have been determined by computer simulation of the spectra. The energies of the d-d electronic transitions have been determined by Gaussian analysis of the visible absorption bands. Molecular orbital coefficients characteristic of the metal-ligand bonds have been derived for an effective D 4h local symmetry. Near the freezing point, the equilibrium for the complexes involving bis(glycinato) coordination is shifted towards the trans isomer. The amino groups of R,S-2,3-diaminopropionic acid and R,S-2,4-diaminobutyric a...

Copper(II)-binding ability of stereoisomeric cis- and trans -2-aminocyclohexanecarboxylic acid-l-phenylalanine dipeptides. A combined CW/pulsed EPR and DFT study

With the aim of an improved understanding of the metal-complexation properties of alicyclic β-amino acid stereoisomers, and their peptides, the complex equilibria and modes of coordination with copper(II) of L-phenylalanine (F) derivatives of cis/trans-2-aminocyclohexanecarboxylic acid (c/tACHC), i.e. the dipeptides F-c/tACHC and c/tACHC-F, were investigated by a combination of CW and pulsed EPR methods. For the interpretation of the experimental data, DFT quantum-chemical calculations were carried out. Simulation of a pH-dependent series of room-temperature CW-EPR spectra revealed the presence of EPR-active complexes ([Cu(aqua)](2+), [CuL](+), [CuLH(-1)], [CuLH(-2)](-), and [CuL(2)H(-1)](-)), and an EPR-inactive species ([Cu(2)L(2)H(-3)](-)) in aqueous solutions for all studied cases. [CuLH](2+) was included in the equilibrium model for the c/tACHC-F-copper(II) systems, and [CuL(2)], together with two coordination isomers of [CuL(2)H(-1)](-), were also identified in the F-tACHC-copper(II) system. Comparison of the complexation properties of the diastereomeric ligand pair F-(1S,2R)-ACHC and F-(1R,2S)-ACHC did not reveal significant differences. Considerably lower formation constants were obtained for the trans than for the cis isomers for both the F-c/tACHC and the c/tACHC-F pairs in the case of [CuLH(-1)] involving tridentate coordination by the amino, the deprotonated peptide, and the carboxylate groups. A detailed structural analysis by pulsed EPR methods and DFT calculations indicated that there was no significant destabilization for the complexes of the trans isomers. The lower stability of their complexes was explained by the limitation that only the conformer with donor groups in equatorial-equatorial ring positions can bind to copper(II), whereas both equatorial-axial conformers of the cis isomers are capable of binding. From a consideration of the proton couplings obtained with X-band (1)H HYSCORE, (2)H exchange experiments, and DFT, the thermodynamically most stable cyclohexane ring conformer was assigned for all four [CuLH(-1)] complexes. For the F-cACHC case, the conformer did not match the most stable conformer of the free ligand.

ESR STUDY OF THE COPPER(II)-GLYCYLGLYCINE EQUILIBRIUM SYSTEM IN FLUID AQUEOUS SOLUTION. COMPUTER ANALYSIS OF OVERLAPPING MULTISPECIES SPECTRA

Various predominant and minor complexes of glycylglycine with the copper(II) ion were studied in fluid aqueous solution by ESR spectroscopy. The computer analysis of a series of overlapping spectra was carried out including at most four independent species. The spectra were built as a hyperfine structure of copper isotopes and a variable number of non‐equivalent nitrogen atoms. The isotropic ESR parameters and relative concentrations of different species were optimized giving a good spectral fit. The variations of the relative concentrations of the complexes are consistent with those calculated from formation constants obtained by pH‐metric and spectrophotometric studies, and the ESR parameters of each species determined from different spectra agree well. For the complex [CuL2H−1]− two kinds of coordination exist. In both isomers one of the glycylglycine ligands is coordinated equatorially through its amino nitrogen, deprotonated peptide nitrogen and carboxylate oxygen atoms. For the major isomer the amino group of the second ligand occupies an axial position, while the fourth equatorial donor atom is the peptide oxygen. For the minor isomer the donor atoms of the second ligand are interchanged. For the 1 : 1 complexes also the above terdentate equatorial coordination of the ligand exists, except for [CuL]+. Some features of the metal–ligand bonds and geometric distortions for the various species are discussed. Copyright

An ESR study of co-ordination modes in copper(II) complexes of l-serine in aqueous solution at ligand excess above pH 7

Abstract Co-ordination modes for the bis complexes of l-serine with copper(II) ion have been studied in fluid aqueous solution by ESR spectroscopy. The computer analysis of a series of overlapping spectra taken in neutral and alkaline solutions was carried out including one to four independent species. For the component spectra a hyperfine splitting by isotopes 63Cu and 65Cu and two equivalent nitrogen atoms were taken into consideration. The isotropic ESR parameters and relative concentrations of different species were optimized. The distribution of copper(II) amongst different species is in accordance with literature formation constants obtained by pH-metric and spectrophotometric studies. For both the [CuL2] and [CuL2H−1]− complexes two kinds of co-ordination exist. The spectra of smaller copper and nitrogen hyperfine coupling constants, which give the major contribution to the experimental curves, are assigned to the cis isomer, while the minor species is the trans isomer of higher hyperfine coupling constants. For the complex [CuL2H−2]2− only one mode of co-ordination exists with cis arrangement of the equatorial N and O donor atoms, respectively. The values of ESR parameters indicate the equatorial binding of deprotonated OH groups of side chains and a geometric distortion of the cis complexes.

An ESR study of the copper(II)-glycyl-l-histidine system in aqueous solution by the simultaneous analysis of multi-component spectra. Formation constants and coordination modes

Abstract A series of multi-component ESR spectra of fluid aqueous solutions containing glycyl- l -histidine and copper(II) at 1:1 and 20:1 concentration ratios, taken in a circulating system at various pH, have been analysed simultaneously. The isotropic ESR parameters (g-factors, hyperfine coupling constants for the 63 Cu and 65 Cu isotopes and maximum four non-equivalent 14 N nuclei, and relaxation parameters) and the formation constants of the various complexes were optimized. In the acidic region, the new species [CuLH 2 ] 3+ , has been shown and the formation of the pH-metrically identified species [CuLH] 2+ , [CuL] + and [CuLH −1 ] has been supported. The coordination in the first three complexes is reminiscent of that in simple dipeptides: it is likely to take place at first by the carboxylate O, then by the amino N and peptide O, and then by the amino N, deprotonated peptide N and carboxylate O atoms in equatorial positions, respectively, while the imidazole ring remains protonated. In the species [CuLH −1 ], the non-protonated imidazole nitrogen displaces the carboxylate oxygen from the equatorial coordination. In the alkaline region of the equimolar solutions the spectra could be described consistently in terms of the formation of four species: three of them, the complex [Cu 2 L 2 H −3 ] − and the two coordination isomers of the complex [CuLH −2 ] − are ESR-active, while the tetramer [Cu 4 L 4 H −8 ] 4− is ESR-inactive. For the complex [CuLH −2 ] − , one of the isomers is the species [CuLH −1 (OH)] − , while the other one has the imidazole ring deprotonated. At ligand excess the region pH 7–10 is dominated by the pH-metrically identified complexes [CuL 2 ] and [CuL 2 H −1 ] − . In these species the first ligand is bound equatorially by the amino, deprotonated peptide and imidazole nitrogen atoms. The second dipeptide is co-ordinated either by the amino nitrogen in equatorial and the peptide oxygen in axial position (4N isomer), or vice versa (3N isomer) in both bis complexes.

Electron spin resonance study of copper(II) complexes of X-glycine and glycyl-X type dipeptides, and related tripeptides. Variation of co-ordination modes with ligand excess and pH in fluid and frozen aqueous solutions

Co-ordination modes for the various copper(II) complexes of glycine(Gly)-containing di- and tri-peptides (HL) with non-co-ordinating side-chains have been investigated. The e.s.r. spectra of predominant species at 1 : 1, 2 : 1, and 50 : 1 ligand : metal concentration ratios in the region pH ≈ 6–13 have been recorded in fluid and frozen aqueous solutions, and evaluated by computer simulation. The energies of the d–d electronic transitions have been determined by Gaussian analysis of the visible absorption spectra. Molecular-orbital coefficients characteristic of metal–ligand bonds for the various 1 : 1 and 1 : 2 complexes have been calculated assuming effective D4h symmetry. At ligand excess in alkaline solution, the temperature strongly affects the chemical equilibria: low temperature promotes the formation of 1 : 2 complexes: [Cu(LH–1)L]– at pH ≈ 9, and [Cu(LH–1)2]2– at pH ≈ 13 in the case of X-Gly type dipeptides. In the predominant isomers of these complexes one of the dipeptide molecules is co-ordinated equatorially through its amino nitrogen, deprotonated peptide nitrogen, and carboxylate oxygen atoms. The amino group of the other dipeptide occupies an axial position, while the fourth equatorial donor atom is either the peptide oxygen (pH ≈ 9) or the deprotonated peptide nitrogen (pH ≈ 13) of the second ligand. In the latter case, axial co-ordination of the second carboxylate group is also likely. Competition can be observed between the σ and π bonds in the equatorial plane on the one hand, and between the σ bonds of different symmetries on the other hand. The influence of the co-ordination modes, the type of ligand, and the temperature on the covalent character of the metal–ligand bonds is discussed.

An ESR study of the copper(II)–glycyl-l-serine and copper(II)–l-seryl-glycine systems by the simultaneous analysis of multi-component isotropic spectra. Formation constants and coordination modes

Abstract The formation constants and the isotropic ESR parameters (g-factors, 63Cu, 65Cu, 14N hyperfine coupling constants and relaxation parameters) of the various species were determined by the simultaneous analysis of a series of spectra, taken in a circulating system at various pH and ligand-to-metal concentration ratio. For both systems the new [CuLH]2+ complex was identified in acidic solutions. With the glycyl- l -serine ligand below pH 11.5 the same complexes and coordination modes are formed than with simple dipeptides. The side-chain donor group is bound only over pH 11.5 in the complex [CuLH−2(OH)]2−, where it is deprotonated and substitutes the carboxylate O in the third equatorial site. For the bis complex [CuLH−1(L)]− an isomeric equilibrium was shown, where the difference between the isomers was based on which of the donor atoms of the ‘L’ ligand, the peptide O or the amino N, occupies the fourth equatorial position, and which one is coordinated axially. The l -seryl-glycine ligand forms the same species as simple dipeptides and glycyl- l -serine up to pH 8. The only difference is that the axial binding of the alcoholic OH group fairly stabilizes the bidentate equatorial coordination of the ‘L’ ligand through the amino N and peptide O atoms in the [CuL]+ complex as well as in the major isomer of the [CuLH−1(L)]− complex. For this system we showed that (1) proton loss and the equatorial coordination of the alcoholic OH group occurs at relatively low pH (over pH 8–9), which results in the [CuL2H−2]2− complex with excess ligand, and also the newly identified species [Cu2L2H−4]2−: (2) this process is in competition with the proton loss of a coordinated water molecule. For both systems, the ESR-inactive species [Cu2L2H−3]− was also shown.

Effect of fluorine position on the coordinating ability of fluorosalicylic acids - An experimental study complemented with computations

The complexation of 3-, 4-, and 6-fluorosalicylic acids (HL) with copper(II) was investigated in aqueous solution by pH-potentiometry combined with UV-visible spectrophotometry, and in 50 v/v % water-methanol mixture by the two-dimensional ESR simulation method. Both methods showed the formation of [CuLH(-1)] and [CuL(2)H(-2)](2-) of high stabilities, and, at low excess of ligand, the ESR-silent mixed hydroxido complex [Cu(2)L(2)H(-3)](-). Further species were also identified by the two-dimensional ESR simulation method: [CuL](+) in the acidic region, the minor dimer [Cu(2)L(2)H(-2)], and the cis and the trans isomers for [CuL(2)H(-2)](2-). The position of the fluorine atom in the aromatic ring had significant effect on the coordination abilities of the ligands, in good correlation with their reported biological activities. It was 3-fluorosalicylic acid, which formed the most stable complexes [CuLH(-1)] and [CuL(2)H(-2)](2-), while the mononuclear complexes with 6-fluorosalicylic acid were found to be the least stable. For the other ligands (including 5-fluorosalicylic acid studied recently), complexes of medium stabilities were formed. For the interpretation of these findings, ab initio and semi-empirical quantum chemical calculations were carried out for the ligand molecules, isolated and surrounded by water molecules, respectively.