Aqueous Solution Equilibria and Spectral Features of Copper Complexes with Tripeptides Containing Glycine or Sarcosine and Leucine or Phenylalanine (original) (raw)
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Copper anti-inflammatory drugs in rheumatoid arthritis. Part 1. Computer aided drug design
Inorganica Chimica Acta, 1988
Based on the premise that low molecular weight copper complexes are important in the reduction of inflammation associated with rheumatoid arthritis, a computer model of blood plasma has been used to evaluate the factors affecting the ability of a ligand to increase this low molecular weight copper pool in vivo. The results suggest that linear quadradentate polyamines, which give rise to a 5, 6, 5 ring system when complexed, are best. Neutral complexes can be achieved using two carboxylate, phenolate or methyl phosphate groups. Experimental All calculations were carried out using the ECCLES program and data base [l]. Additional equilibrium constants were extracted from the literature [2] and, where necessary, adjusted to 37 'C and an ionic strength of 0.15. In certain cases, where equilibrium constants were not available in the literature, they were estimated from analogous model compounds. A complete list of constants is available upon request.
Stability, solution structure and X-ray crystallography of a copper (II) diamide complex
Inorganica Chimica Acta 498 (2019) , 2019
It has been shown that the inflammation associated with rheumatoid arthritis can be reduced using copper complexes. In order to improve the bioavailability of copper and hence efficacy, 3-(2-aminoacetamido)-N-(pyridin-2-ylmethyl)propanamide, H2(5 6 5)NH2, was designed as a potential chelator of copper. Solution equilibrium measurements show that the [Cu(LH-2)] species predominates at physiological pH and blood plasma speciation calculations predict that this ligand is able to mobilise Cu(II) in vivo. A structural study of the Cu(II)/H2(5 6 5)NH2 system was conducted in the solid and solution state using Uv–Vis, CD, 1H NMR and EPR spectroscopy and single crystal X-ray crystallography. The result indicate that the structure of [Cu(H2(5 6 5)NH2)H-2] in the solid and solution state are similar and confirm that, the metal binds to the pyridine nitrogen, the two amide nitrogens and the terminal amino group in a distorted square planar geometry.
Scientific Reports
Copper-based compounds are promising entities for target-specific next-generation anticancer and NsAIDs therapeutics. In lieu of this, benzimidazole scaffold plays an important role, because of their wide variety of potential functionalizations and coordination modes. Herein, we report three copper complexes 1-3 with benzimidazole-derived scaffolds, a biocompatible molecule, and secondary ligands viz, 1-10-phenanthroline and 2,2′-bipyridyl. All the copper complexes have been designed, synthesized and adequately characterized using various spectroscopic techniques. In-vitro, human serum albumin (HSA) binding was also carried out using fluorescence technique and in-silico molecular modeling studies, which exhibited significant binding affinities of the complexes with HSA. Furthermore, copper complexes 1-3 were tested for biological studies, i.e., anticancer as well as NSAIDS. In vitro cytotoxicity results were carried out on cultured MCF-7 cell lines. To get the insight over the mechanism of action, GSH depletion and change in lipid peroxidation were tested and thus confirmed the role of ROS generation, responsible for the cytotoxicity of the complexes 1-3. Moreover, the copper complexes 1-3 were tested for potential to act as NSAIDS on albino rats and mice in animal studies in-vivo. Additionally, we also predicted the mechanism of action of the copper complexes 1-3 using molecular modeling studies with COX-2 inhibitor.
Spectrochimica Acta Part A: Molecular Spectroscopy, 1993
The complex formation between copper(II) and the tetrapeptide glycyl-glycyI-L-histidyI-L-alanine ([H3L] z+) has been studied in aqueous solution at t = 25°C and 1= 0.1 tool dm -3 by potentiometric, visible spectrophotometric and circular dichroism measurements. All the experimental techniques show that the complex [CuLH_z]-is predominant over a wide pH range, while the monodentate [CuLH] 2+ is formed in the acidic region and a further deprotonated [CuLH_3] z-species exists at pH higher than 10. The formation constants of the three above complexes are reported and a structure is proposed on the basis of spectroscopic results. The structure of [CuLH_2]-species very probably involves four nitrogen donors in the plane, excluding coordination by the L-alanine residue, while it seems likely that [CuLH_a] 2-is formed by simple dissociation of the N-1 pyrrole hydrogen.
Journal of Inorganic Biochemistry, 2007
The systematic investigation of the copper(II) complexes of tripeptides Xaa-Xaa-His, Xaa-His-Xaa and His-Xaa-Xaa, where Xaa = Gly or Ala was performed by combined pH-metry, spectrophotometry, CD and in part EPR spectroscopy. The matrix rank analysis of the spectral data revealed the number of the coloured and optically active species as a basis for the solution speciation. A critical evaluation on the speciation and solution structure of the complexes formed is presented on the basis of their d-d band optical activity. The replacement of a Gly residue with the chiral Ala amino acid allowed us to gain decisive information on the solution structure of the complexes by CD spectroscopy. It was shown that the tripeptides with histidine in the third position formed CuH À2 L species with (NH 2 , 2N À , ImN-where Im stands for imidazole) coordination sphere as a major species, and only the macrochelated CuL complexes as minor species around pH 5.0. In copper(II)-Xaa-His-Xaa tripeptide systems the CuH À1 L (NH 2 , N À , ImN) is the most stable species at physiological pH, but the vacant fourth site around copper(II)ions is offered for further deprotonation, most probably resulting in mixed hydroxo species at low (<5 • 10 À4 M) metal ion concentrations, while a tetrameric complex is dominant when the copper concentration exceeds 3 • 10 À3 M. The histamine type coordination mode in CuL and CuL 2 complexes of His-Xaa-Xaa ligands predominates at low pH. The structural consequences drawn from the CD spectra for the mono and bis parent complexes were supported by theoretical calculations. CD spectra strongly suggest the participation of the imidazole nitrogen both in the Cu 2 H À2 L 2 and CuH À2 L complexes.
Spectrochimica Acta Part a Molecular Spectroscopy, 1993
The complex formation between copper(II) and the tetrapeptide glycyl-glycyI-L-histidyI-L-alanine ([H3L] z+) has been studied in aqueous solution at t = 25°C and 1= 0.1 tool dm-3 by potentiometric, visible spectrophotometric and circular dichroism measurements. All the experimental techniques show that the complex [CuLH_z]-is predominant over a wide pH range, while the monodentate [CuLH] 2+ is formed in the acidic region and a further deprotonated [CuLH_3] z-species exists at pH higher than 10. The formation constants of the three above complexes are reported and a structure is proposed on the basis of spectroscopic results. The structure of [CuLH_2]-species very probably involves four nitrogen donors in the plane, excluding coordination by the L-alanine residue, while it seems likely that [CuLH_a] 2-is formed by simple dissociation of the N-1 pyrrole hydrogen.
Polyhedron, 2000
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.
Journal of Inorganic Biochemistry, 2007
An in vitro and in vivo study of some copper chelating anti-inflammatory agents for alleviation of inflammation associated with rheumatoid arthritis (RA) has been conducted. Two copper chelating agents, N 1 -(2-aminoethyl)-N 2 -(pyridin-2-ylmethyl)ethane-1,2-diamine ([555-N]) and N-(2-(2-aminoethylamino)ethyl)picolinamide ([H(555)-N]) have been synthesized as their hydrochloride salt; their protonation constants and formation constants with Cu(II), Zn(II) and Ca(II) determined by glass electrode potentiometry at 298 K and an ionic strength of 0.15 M. Cu(II) formed stable complexes at physiological pH while the in vivo competitors, Zn(II) and Ca(II) formed weak complexes with both chelating agents. Both [555-N] and [H(555)-N] showed better selectivity for Cu(II) than for Zn(II) and Ca(II).
Zenodo (CERN European Organization for Nuclear Research), 2003
In order to obtain new potential antioxidants with molecular mass lower than those of the metal-proteins, a new copper(II) compound with mixed ligands, L-histidine and urea was synthesised. The compounds containing only one of the two mentioned ligands, Cu-urea and Cu-L-histidine was also synthesised as intermediates in the synthesis of the compound with mixed ligands or for comparative purposes. The spectral analysis indicates an axial symmetry of the Cu 11 ions in the compound with mixed ligands. Stability studies, in time and in different Jill-conditions, were carried out by absorption electronic spectroscopy; the results revealed satisfactory stability in time, at the pH of the physiologic serum of the compounds with mixed ligands; the compound is also stable in aqueous solutions at pH 7.2-5.5. The study of compatibility with physiological mediums indicates that the compound displays significant lypophilic character.
Polyhedron, 2001
The formation constants and the isotropic ESR parameters (g-factors, 63 Cu, 65 Cu, 14 N 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 [CuL 2 H − 2 ] 2 − complex with excess ligand, and also the newly identified species [Cu 2 L 2 H − 4 ] 2 − : (2) this process is in competition with the proton loss of a coordinated water molecule. For both systems, the ESR-inactive species [Cu 2 L 2 H − 3 ] − was also shown.