Imidazolate-bridged dicopper(II) and copper(II)–zinc(II) complexes of macrocyclic ligand with methylimidazol pendants: Model study of copper(II)–zinc(II) superoxide dismutase

doi:10.1016/j.jinorgbio.2009.06.003

Journal of Inorganic Biochemistry

Volume 103, Issue 8, August 2009, Pages 1156-1161

https://doi.org/10.1016/j.jinorgbio.2009.06.003 Get rights and content

Abstract

Two new homo- and hetero-dinuclear complexes, [Cu₂L(im)](ClO₄)₃⋅4H₂O (1) and [CuZnL(im)](ClO₄)₃⋅4H₂O (2) (where Im=1H-1midazole and L = 3, 6, 9, 16, 19, 22-hexaaza-6, 19-bis(1H-imidazol-4-ylmethyl)tricycle[22, 2, 2, 2^11,14]triaconta-1, 11, 13, 24, 27, 29-hexaene) were synthesized and characterized as model compounds for the active site of copper(II)–zinc(II) superoxide dismutase (Cu₂Zn₂–SOD). X-ray crystal structure analysis revealed that the metal centers in both complexes exhibit distorted trigonal-bipyramid coordination geometry and the Cu⋯Cu and Cu⋯Zn distances are both 6.02 Å. Magnetic and ESR spectral measurements of 1 showed antiferromagnetic exchange interactions between the imidazolate-bridged Cu(II) ions. The ESR spectrum of 2 displays typical signals of mononuclear Cu(II) complex, demonstrating the formation of heterodinuclear complex 2 rather than a mixture of homodinuclear Cu(II)/Zn(II) complexes. pH-dependent ESR and UV–visible spectral measurements manifest that the imidazolate exists as a bridging ligand from pH 6 to 11 for both complexes. The IC₅₀ values of 1.96 and 1.57 μM [per Cu(II) ion] for 1 and 2 suggest that they are good models for the Cu₂Zn₂–SOD.

Introduction

Superoxide anion $(O_{2}^{-})$ is an unavoidable metabolite of oxygen in living organisms and is considered to cause oxidative damage when its production exceeds the catabolic capacity [1], [2], [3]. Copper(II)–zinc(II) superoxide dismutase (Cu₂Zn₂–SOD), a ubiquitous enzyme existing in aerobic lives, is believed to protect cells against the oxidative damage by catalyzing the dismutation of the $O_{2}^{-}$ to O₂ and H₂O₂ [4], [5]. Many undesirable diseases, e.g. inflammation, neurological disorders and multiple types of cancer are found to be associated with the overproduction of $O_{2}^{-}$ . However, as a human pharmaceutical in treating these diseases, natural SOD showed some drawbacks such as short periods, immunogenic response, weak tissue permeability [6], [7]. This calls for synthesizing small molecular complexes to mimic the structure and functionality of natural SOD.

Ever since the X-ray crystal structure analysis revealed the existence of imidazolate-bridged copper–zinc heterodinuclear structure in the active center of the bovine erythrocyte Cu₂Zn₂–SOD, a number of imidazolate-bridged dinuclear complexes have been synthesized [8], [9], [10], [11], [12]. Comparison between [Cu₂(TMDT)₂(im)]³⁺ (TMDT = 1, 1, 7, 7-tetramethyldiethylenetriamine) and [Cu₂(bpim)]³⁺ (bpim⁻ = 4,5-bis[2-(2-pyridyl)-ethyliminomethyl]imidazolate) revealed that the imidazolate bridge in the former is stable only over a narrow pH range while the one in the latter is quite stable [13], [14]. Taking account of the stabilization of imidazolate bridge, macrocyclic polyamine ligands have been paid particular attention due to their good solubility in water and willingness to girdle the [Cu₂(im)]³⁺ ion. A number of dinuclear complexes with macrocyclic ligands and imidazolate bridge have been reported with high catalytic activity and good stability [9], [10]. Moreover, the flexibility of macrocyclic polyamine ligands facilitates the transformation of the coordination geometry of the metal center and thereby can enhance the catalytic activity towards the dismutation of the $O_{2}^{-}$ . Hence, macrocyclic polyamine ligands are considered to be useful for synthesizing SOD models. However, no macrocyclic polyamine ligands with imidazole pendants were reported to now, whereas in the active center of the Cu₂Zn₂–SOD, the Cu(II) and Zn(II) are coordinated by imidazole groups of histidine residues. Therefore, we designed a new macrocyclic polyamine ligand with two flexible methylimidazole arms, namely 3, 6, 9, 16, 19, 22-hexaaza-6, 19-bis(1H-imidazol-4-ylmethyl)tricycle[22, 2, 2, 2^11,14]triaconta-1, 11, 13, 24, 27, 29-hexaene (L, Scheme 1), and prepared two imidazolate-bridged dinuclear complexes [Cu₂L(im)](ClO₄)₃⋅4H₂O (1) and [CuZnL(im)](ClO₄)₃⋅4H₂O (2). In this paper, X-ray crystal structures, magnetic properties, ESR, electronic spectroscopic studies, and SOD-like activity of the two complexes are reported.

Section snippets

Materials

All reagents and solvents were purchased from commercial sources and used as received without further purification.

Synthesis of the ligand L

The ligand L was obtained from the condensation of N¹-(2-aminoethyl)-N¹-(1H-imidazol-4-ylmethyl)-ethane-1,2-diamine (L1, Scheme 2) and terephthalaldehyde followed by reduction of the Schiff base. L1 was prepared according to the published procedures [15].

Synthesis of [Cu₂L(im)](ClO₄)₃⋅4H₂O (1)

Cu(ClO₄)₂⋅6H₂O (37.0 mg, 0.1 mmol) and imidazole (13.6 mg, 0.2 mmol) were dissolved in 2 mL of water to form light blue solution. The

[Cu₂L(im)](ClO₄)₃⋅4H₂O (1)

The results of crystal structure analysis revealed that complex 1 belongs to monoclinic C2/c space group and is composed of [Cu₂L(im)]³⁺ cation, three ${ClO}_{4}^{-}$ anions and four uncoordinated water molecules and the asymmetric unit of 1 is half-molecule of [Cu₂L(im)](ClO₄)₃⋅4H₂O. The cationic structure of [Cu₂L(im)]³⁺ is shown in Fig. 1. It is clear that each Cu(II) atom is five-coordinated by four nitrogen atoms from the ligand L and one from the bridging imidazolate. According to the method of

Conclusions

In this study, [Cu₂L(im)](ClO₄)₃⋅4H₂O (1) and [CuZnL(im)](ClO₄)₃⋅4H₂O (2) were synthesized by the direct reaction between the ligand and metal salts. X-ray crystal structure revealed that the metal centers in both complexes adopt distorted trigonal bipyramid geometry. UV–Vis and ESR data show that imidazolate exists as a bridging ligand from pH ca. 6–11 for both complexes. The SOD activity evaluation manifests that the two complexes are good models with remarkable catalytic activity towards the

Acknowledgments

This work was financially supported by the National Science Fund for Distinguished Young Scholars (Grant No. 20425101), the National Natural Science Foundation of China (Grant Nos. 20731004 and 20721002) and the National Basic Research Program of China (Grant No. 2007CB925103).

References (30)

P. Jezek et al.
Int. J. Biochem. Cell Biol.
(2005)
V.C. Culotta et al.
Biochim. Biophys. Acta
(2006)
J. Wawryn et al.
Biochim. Biophys. Acta
(2002)
I. Szilágyi et al.
J. Inorg. Biochem.
(2007)
I. Szilagyi et al.
J. Inorg. Biochem.
(2005)
Z.P. Qi et al.
Polyhedron
(2008)
J.Y. Zhou et al.
J. Pharm. Biomed. Anal.
(2006)
Z. Durackova et al.
J. Inorg. Biochem.
(1995)
U. Weser et al.
J. Mol. Catal.
(1981)
R. Cejudo-Marín et al.
Inorg. Chem.
(2004)

P.A. Bryngelson et al.

J. Am. Chem. Soc.

(2004)

J.P. Renault et al.

Inorg. Chem.

(2000)

G.F. Liu et al.

Inorg. Chem.

(2007)

H. Fu et al.

J. Am. Chem. Soc.

(2006)

S.A. Li et al.

Chem. Commun.

(2003)

Cited by (22)

Electronic investigation of the effect of substituents on the SOD mimic activity of copper (II) complexes with 8-hydroxyquinoline-derived ligands
2021, Journal of Inorganic Biochemistry
Density functional theory (DFT) calculations were used to study the superoxide dismutase (SOD) mimic activity of two Cu²⁺ complexes with ligands derived from 8-hydroxyquinoline (8-HQ). Electron-donating and -withdrawing substituent groups were inserted into the structures to verify changes in the reactivity. The theoretical parameters obtained were compared and validated with the experimental data available. The results showed that the reduction process occurs with greater participation of the 8-HQ ligand and the oxidation step occurs with participation of the copper atom in the complexes, where the electron received during the reduction step is used to reduce the Cu²⁺ to Cu⁺. The calculated electronic affinity showed good correlation with the experimental mimetic activity, and the analysis of this property, of total charge and of molecular orbitals indicated an increase in the mimetic activity with the insertion of electron-withdrawing substituent groups in the structures.
Theoretical study of binuclear Cu-M complexes (M = Zn, Cu, Ni) with p-xylylene-bridged-bis(1,4,7-triazacyclononane) ligands: Possible CuZnSOD mimics
2020, Inorganica Chimica Acta
Citation Excerpt :
There is therefore a need to synthesize small molecular complexes to mimic the structure and catalytic activity of SOD [12,13]. A number of Cu(II) complexes have been characterized as models of the CuZnSOD enzyme, including homo- and heterodinuclear Cu(II)-Zn(II) with imidazolate-bridged Cu-im-Zn [10,12,14]. In work by Daier et al., homodinuclear Cu-im-Cu was more active than the Cu-im-Zn complex [10].
DFT calculations were used to study a series of binuclear complexes with the general formula [CuM(pxbtacn-R₂)Cl₄] (pxbtacn = p-xylylene-bridged-bis(1,4,7-triazacyclononane); M = Zn, Cu and Ni; R = -H, -CH₃, -CH(CH₃)₂) as potential mimics of superoxide dismutase. The obtained results indicate that all complexes have similar structures to the experimental structure reported for [Cu₂(pxbtacn)Cl₄] complex. In the reduction process, the loss occurs of one of the Cl- ligands in which the generated Cu(I) show distorted tetrahedral geometry. An analysis of acceptor (oxidized complexes) and donor (reduced complexes) orbitals shows that these orbitals have significant participation from Cu (II) and Cu (I), respectively. This indicates that the reduction process occurs via Cu(II) receiving an electron and the oxidation process occurs with the removal of this electron from Cu(I), according to the process observed in the native enzyme. The Gibbs free energy shows that the catalysis is spontaneous for all of the complexes studied, and the reduction step is the predominant stage of the global process. For the three series studied here, the calculated values of the Gibbs free energy and electronic affinity indicate that complexes with R = -CH₃ and -CH(CH₃)₂ have the greatest ability to reduce, in accordance with the reported experimental mimic activity. Complexes with these substituents should therefore have a higher mimic activity.
Preparation, characterization, and study of the antimicrobial activity of a Hinokitiol-copper(II)/γ-cyclodextrin ternary complex
2019, Journal of Molecular Structure
Citation Excerpt :
Cu2+ and 4 ligands lie in the same plane while the other 2 ligands are located on a straight line that includes the metal ion perpendicular to that plane. Cu in copper (II) acetate maintains a dimeric configuration in a solid state, and Cu (II) is known to be ESR-inactive as a result of antiferromagnetic interaction [30]. Thus, characteristic spectra for copper (II) acetate were not evident in the current study (Fig. 5a).
The aim of the current study was to prepare a ternary complex of hinokitiol (HT), a metal ion (Cu (II)) and γ-cyclodextrin (γCD) via coprecipitation and to assess its physicochemical properties and the effects of complexation on the antimicrobial activity of HT.
Single-crystal X-ray structural analysis, powder X-ray diffraction (PXRD), near-infrared (NIR) absorption spectroscopy, and electron spin resonance (ESR) spectroscopy were performed to assess the complex in a solid state. Agar dilution was used to determine the minimum inhibitory concentration (MIC) of HT-Cu complex and the ternary inclusion complex with respect to Escherichia coli, Bacillus subtilis, Staphylococcus aureus, and Pseudomonas aeruginosa.
A ternary HT-Cu/γCD inclusion complex formed as a result of coprecipitation. Results of an antimicrobial test revealed that the ternary HT-Cu/γCD inclusion complex had increased antimicrobial activity compared to that of HT alone. The level of antibacterial activity of ternary complex had action equivalent to that of an HT/γCD inclusion complex.
The antimicrobial action of HT can presumably be capitalized on by including HT in CD without a metal in certain applications. The current results should provide a basis for use of hinokitiol as a human and environmentally friendly antimicrobial.
Biomimetic Cu, Zn and Cu<inf>2</inf> complexes inserted in mesoporous silica as catalysts for superoxide dismutation
2019, Microporous and Mesoporous Materials
Citation Excerpt :
Therefore, efforts have been focused on the design of low molecular-weight antioxidant catalysts (SOD-mimics) as potential therapeutic agents with better bioavailability than exogenously administered SOD enzymes [9]. A number of heterodinuclear CuZn and homodinuclear Cu2 complexes have been evaluated as CuZn-SOD mimics [10–17]. For these complexes, kcat values are one or two orders of magnitude higher than for O2•− self-disproportionation (kdisp = 5 × 105 M−1 s−1, pH 7) [18].
Three CuZn-superoxide dismutase (SOD) functional mimics, [CuZn(dien)₂(μ-Im)](ClO₄)₃ (1), [Cu₂(dien)₂(μ-Im)](ClO₄)₃ (2) (Im = imidazole, dien = diethylenetriamine), and [CuZn(salpn)Cl₂] (3) (H₂salpn = 1,3-bis(salicylideneamino)propane), were successfully inserted into the nanochannels of SBA-15 type mesoporous silica with retention of the silica mesostructure. X-ray absorption spectroscopic studies indicate that the encapsulated complexes keep unchanged the first-shell environment of Cu(II) and Zn(II) ions. Magnetic measurements suggest that the nanochannels constrain the geometry of the μ-imidazolate-Cu(II)₂ core modifying the relative orientation of the two copper coordination planes. Confinement imposed by the silica nanochannels upon encapsulation of complexes 1 and 2 leads to stable hybrid materials at physiological pH with enhanced SOD activity relative to the free complexes. Unlike the imidazolato-bridged compounds, insertion of 3 in mesoporous silica leads to a less stable hybrid material exhibiting partial release into the aqueous solution and O₂^•− dismutation rate slower than the free complex. The covalent binding of a mononuclear Cu(dien)Im⁺ moiety to the mesoporous silica showed lower SOD activity than encapsulated imidazolato-bridged CuZn and Cu₂ complexes. The results emphasize the positive effect of encapsulation on SOD activity of imidazolato-bridged dinuclear complexes.
Metal Complexes as Receptors
2017, Comprehensive Supramolecular Chemistry II
The role played by metal complexes as receptors of different substrates is discussed. For this purpose, several relevant examples of the work performed by different research groups have been briefly discussed. The metal complexes have been organized attending to the molecular topology of the ligands employed. The article ends with the description of metallocages in which at least one of the metal ions constituting the cage framework binds the guest through coordinative bonds.
Synthesis, characterization and activity of imidazolate-bridged and Schiff-base dinuclear complexes as models of Cu,Zn-SOD. A comparative study
2016, Journal of Inorganic Biochemistry
Citation Excerpt :
Because of the limitations associated with the therapeutic applications of the enzyme, such as solution instability, limited cellular accessibility, immunogenicity, bell-shaped dose response curves, short half-lives, costs of production, and proteolytic digestion, a significant amount of research focuses on SOD mimics with low molecular weight aiming at developing potential therapeutic antioxidant compounds [11,12]. A number of CuII complexes have been characterized as models of the Cu,Zn-SOD enzyme, including CuII complexes obtained with Schiff base ligands [13–17], imidazolate bridged diCuII[18–22] and heterodinuclear CuIIZnII complexes [20,23–27]. Although some of them have proven to be effective in removing superoxide, the key features (type of ligands, nuclearity, redox potential) behind their activity are still elusive.
Two imidazolate-bridged diCu^II and Cu^IIZn^II complexes, [CuZn(dien)₂(μ-Im)](ClO₄)₃·MeOH (1) and [Cu₂(dien)₂(μ-Im)](ClO₄)₃ (2) (Im = imidazole, dien = diethylenetriamine), and two complexes formed with Schiff base ligands, [CuZn(salpn)Cl₂] (3) and [Cu₂(salbutO)ClO₄] (4) (H₂salpn = 1,3-bis(salicylidenamino)propane, H₃salbutO = 1,4-bis(salicylidenamino)butan-2-ol) have been prepared and characterized. The reaction of [Cu(dien)(ImH)](ClO₄)₂ with [Zn(dien)(H₂O)](ClO₄)₂ at pH ≥ 11 yields complex 1; at lower pH, the Cu₃Zn tetranuclear complex [{(dien)Cu(μ-Im)}₃Zn(OH₂)(ClO₄)₂](ClO₄)₃ (1a) forms as the main reaction product. X-ray diffraction of 1a reveals that the complex contains a metal centered windmill-shaped cation having three blades with a central Zn ion and three peripheral capping Cu(dien) moieties bound to the central Zn ion through three imidazolate bridges. The four complexes are able to disproportionate O₂⁻ in aqueous medium at pH 7.8, with relative rates 4 > 1 > 2 ≫ 3. [Cu₂(salbutO)]⁺ (4) is the most easily reducible of the four complexes and exhibits the highest activity among the SOD models reported so far; a fact related to the ligand flexibility to accommodate the copper ion in both Cu^I and Cu^II oxidation states and the lability of the fourth coordination position of copper facilitating stereochemical rearrangements.

View all citing articles on Scopus

View full text

Imidazolate-bridged dicopper(II) and copper(II)–zinc(II) complexes of macrocyclic ligand with methylimidazol pendants: Model study of copper(II)–zinc(II) superoxide dismutase

Abstract

Introduction

Section snippets

Materials

Synthesis of the ligand L

Synthesis of [Cu2L(im)](ClO4)3⋅4H2O (1)

[Cu2L(im)](ClO4)3⋅4H2O (1)

Conclusions

Acknowledgments

Int. J. Biochem. Cell Biol.

Biochim. Biophys. Acta

Biochim. Biophys. Acta

J. Inorg. Biochem.

J. Inorg. Biochem.

Polyhedron

J. Pharm. Biomed. Anal.

J. Inorg. Biochem.

J. Mol. Catal.

Inorg. Chem.

J. Am. Chem. Soc.

Inorg. Chem.

Inorg. Chem.

J. Am. Chem. Soc.

Chem. Commun.

Synthesis of [Cu₂L(im)](ClO₄)₃⋅4H₂O (1)

[Cu₂L(im)](ClO₄)₃⋅4H₂O (1)