Copper(II), Nickel(II) and Zinc(II) Complexes of Peptide Fragments of Tau Protein.

Copper(II), nickel(II) and zinc(II) complexes of various peptide fragments of tau protein were studied by potentiometric and spectroscopic techniques. All peptides contained one histidyl residue and represented the sequences of tau(91-97) (Ac-AQPHTEI-NH2), tau(385-390) (Ac-KTDHGA-NH2) and tau(404-409) (Ac-SPRHLS-NH2). Imidazole-N donors of histidine were the primary metal binding sites for all peptides and all metal ions, but in the case of copper(II) and nickel(II), the deprotonated amide groups were also involved in metal binding by increasing pH. The most stable complexes were formed with copper(II) ions, but the presence of prolyl residues resulted in significant changes in the thermodynamic stability and speciation of the systems. It was also demonstrated that nickel(II) and especially zinc(II) complexes have relatively low thermodynamic stability with these peptides. The copper(II)-catalyzed oxidation of the peptides was also studied. In the presence of H2O2, the fragmentation of peptides was detected in all cases. In the simultaneous presence of H2O2 and ascorbic acid, the fragmentation of the peptide is less preferred, and the formation of 2-oxo-histidine also occurs.

Characterization of Copper(II) and Zinc(II) Complexes of Peptides Mimicking the CuZnSOD Enzyme.

Antimicrobial peptides are short cationic peptides that are present on biological surfaces susceptible to infection, and they play an important role in innate immunity. These peptides, like other compounds with antimicrobial activity, often have significant superoxide dismutase (SOD) activity. One direction of our research is the characterization of peptides modeling the CuZnSOD enzyme and the determination of their biological activity, and these results may contribute to the development of novel antimicrobial peptides. In the framework of this research, we have synthesized 10, 15, and 16-membered model peptides containing the amino acid sequence corresponding to the Cu(II) and Zn(II) binding sites of the CuZnSOD enzyme, namely the Zn(II)-binding HVGD sequence (80-83. fragments), the Cu(II)-binding sequence HVH (fragments 46-48), and the histidine (His63), which links the two metal ions as an imidazolate bridge: Ac-FHVHEGPHFN-NH2 (L1(10)), Ac-FHVHAGPHFNGGHVG-NH2 (L2(15)), and Ac-FHVHEGPHFNGGHVGD-NH2 (L3(16)). pH-potentiometric, UV-Vis-, and CD-spectroscopy studies of the Cu(II), Zn(II), and Cu(II)-Zn(II) mixed complexes of these peptides were performed, and the SOD activity of the complexes was determined. The binding sites preferred by Cu(II) and Zn(II) were identified by means of CD-spectroscopy. From the results obtained for these systems, it can be concluded that in equimolar solution, the -(NGG)HVGD- sequence of the peptides is the preferred binding site for copper(II) ion. However, in the presence of both metal ions, according to the native enzyme, the -HVGD- sequence offers the main binding site for Zn(II), while the majority of Cu(II) binds to the -FHVH- sequence. Based on the SOD activity assays, complexes of the 15- and 16-membered peptide have a significant SOD activity. Although this activity is smaller than that of the native CuZnSOD enzyme, the complexes showed better performance in the degradation of superoxide anion than other SOD mimics. Thus, the incorporation of specific amino acid sequences mimicking the CuZnSOD enzyme increases the efficiency of model systems in the catalytic decomposition of superoxide anion.

Interactions of Copper(II) and Zinc(II) Ions with the Peptide Fragments of Proteins Related to Neurodegenerative Disorders: Similarities and Differences.

Metal binding ability and coordination modes of the copper(II) and zinc(II) complexes of various peptide fragments of prion, amyloid-ß, and tau proteins, are summarized in this review. Imidazole-N donors are the primary metal binding sites of all three proteins, but the difference in the location of these residues and the presence or absence of other coordinating side chains result in significant differences in the complex formation processes. The presence of macrochelates and the possibility of forming multicopper complexes are the most important characteristic of prion fragments. Amyloid-ß can form highly stable complexes with both copper(II) and zinc(II) ions, but the preferred binding sites are different for the two metal ions. Similar observations are obtained for the tau fragments, but the metal ion selectivity of the various fragments is even more pronounced. In addition to the complex formation, copper(II) ions can play an important role in the various oxidative reactions of peptides. Results of the metal ion-catalyzed oxidation of peptide fragments of prion, amyloid-ß, and tau proteins are also summarized. Amino acid side chain oxidation (mostly methionine, histidine and aspartic acid) and protein fragmentations are the most common consequences of this process.

The Role of Side Chains in the Fine-Tuning of the Metal-Binding Ability of Multihistidine Peptides.

The systematic studies of copper(II), nickel(II) and zinc(II) ion complexes of protected multihistidine peptides containing amino acids with different side chains (Ac-SarHAH-NH2, Ac-HADH-NH2, Ac-HDAH-NH2, Ac-HXHYH-NH2 X, Y = A, F, D or K, Ac-HXHAHXH-NH2, X = F or D) have provided information about the metal ion and protein interaction and have made it possible to draw conclusions regarding general trends in the coordination of metal complexes of multihistidine peptides. The stability of the metal complexes significantly depends on the position of the histidines and amino acids, which are present in the neighbourhood of the histidine amino acids as well. The most significant effect was observed on peptides containing aspartic acid or phenylalanine. The redox parameters of complexes, however, depend on the number and position of histidines, and the other side chain donor atoms have practically no effect on the electrochemical properties of imidazole-coordinated species. However, the presence of aspartic acid side chains results in a more distorted geometry of amide-coordinated species and increases the reducibility of these complexes.

Thermodynamics and structural characterization of the nickel(II) and zinc(II) complexes of various peptide fragments of tau protein.

Nickel(II) and zinc(II) complexes of various peptide fragments of tau protein have been investigated by potentiometric, UV-Vis, CD and ESI-MS techniques. The peptides include the native fragment tau(9-16) (Ac-EVMEDHAG-NH2), and the Gln/Lys and Tyr/Ala mutated peptides (Ac-KGGYTMHK-NH2 and Ac-KGGATMHK-NH2) of tau(26-33). Similar to copper(II) the complexes of a chimeric peptide containing both His14 and His32 residues in one molecule (Ac-EDHAGTMHQD-NH2) were also studied. The metal binding ability of the R3 domain was studied by using the native fragment tau(326-333) (Ac-GNIHHKPG-NH2), and its two mutants (Ac-GNIHHKAG-NH2) and (Ac-GNGHHKPG-NH2) and the corresponding 1-histidine mutants (Ac-GNGAHKPG-NH2 and Ac-GNGHAKPG-NH2). The results of this study reveal that the histidyl residues of the N-terminal and R3 regions of tau protein can effectively bind nickel(II) and zinc(II) ions. In the case of nickel(II) and zinc(II) the M-Nim coordinated complexes are the major species in the physiological pH range and their stability is significantly enhanced by the presence of Glu and Asp residues in the neighbourhood of the His14 site. For all studied peptides, nickel(II) ions are able to promote the deprotonation and coordination of amide groups preceding histidine resulting in the exclusive formation of square planar (Nim,3N-) complexes in alkaline solutions. The native fragment of the R3 region and its mutants containing two adjacent histidine moieties also bind only one nickel(II) ion with the His330 residue being the primary metal binding site. Exclusive binding of the independent imidazole side chains (His14 and His32 sites) cannot prevent the hydrolysis of zinc(II) in a slightly basic solution but the adjacent histidines of the R3 domain can promote the formation of amide coordinated zinc(II) complexes.

Ambivalent role of ascorbic acid in the metal-catalyzed oxidation of oligopeptides.

The effect of ascorbic acid on the metal-catalyzed oxidation of a human prion protein model peptide has been studied. The complex formation of the peptide was clarified first. The studied model peptide contains a methionine and a histidine amino acids which are important both as binding sites for metal ions and sensitive parts of the protein for oxidation. pH-potentiometric, UV-Vis and circular dichroism spectroscopic techniques were applied to study the stoichiometry, stability and structure of the copper(II) complexes, while HPLC-MS and MS/MS were used for identifying the products of metal-catalyzed oxidation. 3N and 4N complexes with (Nim,N-,N-,S) and (Nim,N-,N-,N-) coordination modes are formed at pH 7.4, where the oxidation was studied. Singly, doubly and triply oxidized products are formed in which the methionine and/or the histidine side chain is oxidized. The oxidation was carried out with hydrogen peroxide solution by the addition of metal ions, namely copper(II) and iron(III) and/or ascorbic acid.

Metal Binding Ability of Small Peptides Containing Cysteine Residues.

The Cd(II)-, Pb(II)-, Ni(II)- and Zn(II)-complexes of small terminally protected peptides containing CXXX, XXXC, XCCX, CXn C (n=1-3) sequences have been studied with potentiometric, UV/Vis and CD spectroscopic techniques. The cysteine thiolate group is the primary binding site for all studied metal ions, but the presence of a histidyl or aspartyl side chain in the molecule contributes to the stability of the complexes. For two-cysteine containing peptides the (S- ,S- ) coordinated species are formed in the physiological pH range and the stability increases in the Ni(II)

Copper (II) binding properties of an octapeptide fragment from the R3 region of tau protein: A combined potentiometric, spectroscopic and mass spectrometric study.

The copper(II) complexes of a peptide fragment of the R3 domain of tau protein (tau(326-333) Ac-GNIHHKPG-NH2) and its mutants (Ac-GNGHHKPG-NH2, Ac-GNIHHKAG-NH2, Ac-GNGAHKPG-NH2 and Ac-GNGHAKPG-NH2) have been studied by potentiometric and spectroscopic (UV-Vis, CD) methods. ESR spectroscopy and mass spectrometry were also used to prove the coordination mode of the mononuclear complexes and the formation of dinuclear species, respectively. It has been demonstrated that the (326-333) fragment of tau protein is a versatile and effective ligand for copper(II) coordination. The versatility of copper(II) binding is related to the presence of two adjacent histidyl residues in the sequence, which results in the coexistence of mononuclear, bis(ligand) and dinuclear complexes at different metal to ligand ratios. The 1:1 mononuclear complexes are, however, the dominant species with all peptides and the imidazole-N and one to three deprotonated amide nitrogen atoms towards the N-terminal side of the histidyl residue have been suggested as metal binding sites. This binding mode allows the formation of coordination isomers because any of the two histidine moieties can be the primary anchoring site. It is evident from the CD spectroscopic measurements that the isomers are present in almost equal concentration. The copper(II) binding affinity of the native fragment of tau protein is comparable to that of a similar 2-histidine fragment of amyloid-ß mutant, Ac-SGAEGHHQK-NH2 but the comparison with an independent histidyl residue (H32) from the N-terminal region of the protein reveals the predominance of H32 over the histidines in the R3 domain.

Recent Multi-target Approaches on the Development of Anti- Alzheimer's Agents Integrating Metal Chelation Activity.

Alzheimer´s disease (AD) is the most common and severe age-dependent neurodegenerative disorder worldwide. Notwithstanding the large amount of research dedicated to both the elucidation of this pathology and the development of an effective drug, the multifaceted nature and complexity of the disease are certainly a rationale for the absence of cure so far. Currently available drugs are used, mainly to compensate the decline of the neurotransmitter acetylcholine by acetylcholinesterase (AChE) inhibition, though they only provide temporary symptomatic benefits and cannot stop AD progression. Although the multiple factors that contribute to trigger AD onset and progression are not yet fully understood, several pathological features and underneath pathways have been recognized to contribute to its pathology, such as metal dyshomeostasis, protein misfolding, oxidative stress and neurotransmitter deficiencies, some of them being interconnected. Thus, there is widespread recent interest in the development of multitarget-directed ligands (MTDLs) for simultaneous interaction with several pathological targets of AD. In this review, a selection of the most recent reports (2016-up to present) on metal chelators of MTDLs with multifunctionalities is presented. These compounds enable the hitting of several AD targets or pathways, such as modulation of specific biometal ions (e.g., Cu, Fe, Zn) and of protein misfolding (ß-amyloid and tau protein), anti-oxidant activity and AChE inhibition. The properties found for these hybrids are discussed in comparison with the original reference compounds, some MTDLs being outlined as leading compounds for pursuing future studies in view of efficient potential applications in AD therapy.

A comparative study on the nickel binding ability of peptides containing separate cysteinyl residues.

Nickel(ii) complexes of peptides CSSACS-NH2, ACSSACS-NH2, SSCSSACS-NH2 and GACAAH-NH2 have been studied by potentiometric and various spectroscopic (UV-vis, CD, NMR, and ESI-MS) techniques. All peptides have high nickel(ii) binding ability in the form of square planar complexes and the stability order of the peptides is: CSSACS-NH2 > ACSSACS-NH2 > SSCSSACS-NH2 ∼ GACAAH-NH2. The different metal binding affinities of these peptides are related to the differences in the speciation and in the binding modes of the major species. An almost exclusive formation of bis(ligand) complexes via an (NH2,S-) 5-membered chelate from the amino terminus is characteristic of CSSACS-NH2. The (NH2,N-,S-) tridentate chelate is the major coordination mode of ACSSACS-NH2 but the distant cysteine can also contribute to metal binding. The higher nickel(ii) binding ability of AC[combining low line]SSAC[combining low line]S-NH2 relative to the peptides containing an N-terminal XY-Cys motif may have important biological consequences. For example, the occurrence of the (NH2,N-,S-,S-) donor set is a common feature of both the ACSSACS-NH2 ligand and the nickel(ii) binding loop of the NiSOD enzyme (HC[combining low line]DLPC[combining low line]G…..,). In the case of SSCSSACS-NH2 and GACAAH-NH2 the amino terminus of one peptide can completely saturate the coordination sphere of the nickel(ii) ion via the formation of the (NH2,N-,N-,S-) binding mode. This rules out the formation of bis(ligand) complexes and any contribution of the distant cysteine or histidine to nickel(ii) binding in the 1 : 1 complexes. On the other hand the distant cysteine of SSCSSACS-NH2 and histidine of GACAAH-NH2 can behave as independent metal binding sites for the formation of dinuclear complexes in the presence of excess metal ions.

The ability of the NiSOD binding loop to chelate zinc(ii): the role of the terminal amino group in the enzymatic functions.

Equilibrium and detailed spectroscopic characterization of zinc(ii) complexes with NiSOD binding loop and their related model fragments are reported in the whole investigated pH-range. The zinc(ii) complexes of L1 (HCDLPCGVY-NH2), L2 (Ac-HCDLPCGVY-NH2) and L3 (HCDLACGVY-NH2) and the nickel(ii) and zinc(ii) complexes of L4 (HCDLPCG-NH2) were studied by pH-potentiometric and several spectroscopic methods. The results indicated that the macrochelate coordinated zinc(ii) complexes are dominant in a whole pH-range and the side chain donors of the peptides are involved in the metal binding. Therefore, the deprotonation and coordination of the peptide backbone occur only in a strongly alkaline solution. The acetylation of the peptide amino terminus (L2) significantly enhances the zinc(ii) binding ability compared to the corresponding nickel(ii) complexes. L2 complexes of zinc(ii) are 2 or 3 orders of magnitude more stable than the corresponding nickel(ii) complexes. This effect clearly shows the crucial role of the terminal amino group in the nickel binding for the NiSOD enzyme.

Stabilization of the Nickel Binding Loop in NiSOD and Related Model Complexes: Thermodynamic and Structural Features.

Detailed equilibrium and spectroscopic characterization of the complex formation processes of the nickel binding loop in NiSOD and its related fragments is reported in the slightly acidic-alkaline pH range. The N-terminally free and protected nonapeptides HCDLPCGVY-NH2 (NiSODM1), HCDLACGVY-NH2 (NiSODM3), and Ac-HCDLPCGVY-NH2 (NiSODM2) and the N-terminally shortened analogues HCDL-NH2 and HCA-NH2 were synthesized, and their nickel(II) complexes were studied by potentiometric and several spectroscopic techniques. EPR spectroscopy was also used to assign the coordinating donor sites after the in situ oxidation of nickel(II) complexes. The terminal amino groups are the primary metal binding sites for nickel(II) ion in NiSODM1 and NiSODM3, resulting in the high nickel(II) binding affinity of this peptide via the formation of a square-planar, (NH2,N-,S-,S-) or (NH2,NImN-,S-) coordinated species in a wide pH range. The latter coordination sphere prevents the formation of the active structure of NiSOD under physiological pH, reflecting the crucial role of proline in nickel(II) binding. In situ oxidation of the Ni(II) complexes yielded Ni(III) transient species in the case of nonapeptides. The square-pyramidal coordination environment with axial imidazole ligation provides the active structure of the oxidized form of NiSOD in the case of N-terminally free peptides. Consequently, these ligands are promising candidates for modeling NiSOD. The acylation of the amino terminus significantly reduces the nickel(II) binding affinity of the nonapeptide, while the oxidation results in coordination isomers.

Copper(II) Coordination Abilities of the Tau Protein's N-Terminus Peptide Fragments: A Combined Potentiometric, Spectroscopic and Mass Spectrometric Study.

Copper(II) complexes of the N-terminal peptide fragments of tau protein have been studied by potentiometric and various spectroscopic techniques (UV-vis, CD, ESR and ESI-MS). The octapeptide Tau(9-16) (Ac-EVMEDHAG-NH2 ) contains the H14 residue of the native protein, while Tau(26-33) (Ac-QGGYTMHQ-NH2 ) and its mutants Tau(Q26K-Q33K) (Ac-KGGYTMHK-NH2 ) and Tau(Q26K-Y29A-Q33K) (Ac-KGGATMHK-NH2 ) include the H32 residue. To compare the binding ability of H14 and H32 in a single molecule the decapeptide Ac-EDHAGTMHQD-NH2 (Tau(12-16)(30-34)) has also been synthesized and studied. The histidyl residue is the primary metal binding site for metal ions in all the peptide models studied. In the case of Tau(9-16) the side chain carboxylate functions enhance the stability of the M-Nim coordinated complexes compared to Tau(26-33) (logK(Cu-Nim )=5.04 and 3.78, respectively). Deprotonation and metal ion coordination of amide groups occur around the physiological pH range for copper(II). The formation of the imidazole- and amide-coordinated species changes the metal ion preference and the complexes formed with the peptides containing the H32 residue predominate over those of H14 at physiological pH values (90 %-10 %) and in alkaline samples (96 %-4 %).

Coordination, redox properties and SOD activity of Cu(II) complexes of multihistidine peptides.

The results of electrochemical and SOD activity measurements of such copper(II) complexes of terminally protected multihistidine peptides that may mimic the active site of CuZnSOD enzyme are submitted and completed with solution equilibrium studies of some copper(II)-ligand systems. The equilibrium data confirm that the thermodynamic stabilities increase with the increasing number of histidyl residues in the amino acid sequence, the stability order, however, can be finely tuned by the number and quality of amino acids between histidine residues. Based on the cyclic voltammetric studies we concluded that the formal reduction potential values of imidazole nitrogen coordinated complexes decrease with the increasing number of imidazole donor atoms in the coordination sphere. However, the redox parameters of [CuH-1L]+ and [CuH-2L] complexes containing amide nitrogen coordination can be determined as well. All formal potential values of [CuL]2+, [CuH-1L]+ and [CuH-2L] complexes fall in the middle potential range of SOD activity. Finally, after the detailed analysis of species distribution curves based upon the equilibrium data SOD activity of copper(II) containing systems at two pH (pH=6.8 and 7.4) were determined. The imidazole coordinated [CuL]2+ complexes of the multihistidine peptide containing the HXH sequence exhibit the most significant activity, but the presence of amide nitrogen coordinated species with slightly distorted geometry could considerably contribute to the SOD activity.

The influence of penicillamine/cysteine mutation on the metal complexes of peptides.

N-Terminally free but C-terminally amidated peptides Pen-SSACS-NH2 and CSSA-Pen-S-NH2 containing l-penicillamine (Pen) in sequence have been synthesized and their nickel(ii), zinc(ii) and cadmium(ii) complexes were studied by potentiometric and spectroscopic measurements. This study is the first example of the synthesis and metal complexes of peptides containing penicillamine in a peptide sequence constructed from natural amino acids. The data were compared to those of the two cysteine counterparts, CSSACS-NH2. It was found that the replacement of l-cysteine with l-penicillamine has a significant impact on the complex formation processes with nickel(ii) ions. The major differences include the suppression of polynuclear complex formation, the enhanced metal binding affinity of the amino terminus and the increased tendency for the formation of amide bonded species. The tridentate (NH2,S-,S-) coordination was characteristic of the zinc(ii) and cadmium(ii) complexes in the case of all three peptides containing two thiolate functions.

Copper(II) interaction with the Human Prion 103-112 fragment - Coordination and oxidation.

The prion protein (PrP) is a membrane-anchored cell surface glycoprotein containing 231 amino acids. It has been associated with a group of neurodegenerative disorders. Copper(II) interaction with the Human Prion 103-112 fragment and its mutants has been studied with various techniques. The studied human prion fragment contains both histidine and methionine residues, while methionine residues are systematically replaced or displaced in the studied mutants. pH-potentiometric, UV-Vis and circular dicroism spectroscopic techniques were applied to study the stoichiometry, stability and structure of the copper(II) complexes, while HPLC-MS and MS/MS were used for identifying the products of copper(II) catalyzed oxidation. The complex formation reactions of the studied ligands are rather similar; only 1:1 complexes are formed, where the imidazole nitrogen of the histidine residue is the main binding site beside the amide nitrogens of the peptide chain. The only difference is, that in the peptides which contain methionine in position 109, in addition to the (Nim,N-,N-) coordination mode, a weak interaction of thioether sulfur atoms can be supposed. The mutant peptide which does not contain methionine did not undergo oxidation, only the fragmentation of the peptide chain was perceived. However, in the case of methionine containing peptides, the peptide chain was not cleaved; but the oxidation of methionine to methionine sulfoxide occurred.

Experimental and theoretical studies of copper complexes with isomeric dipeptides as novel candidates against breast cancer.

In the search for new cytotoxic drugs, two copper complexes with isomeric dipeptides (Ala-Phe and Phe-Ala) were developed in order to determine the influence of their different structures in the modulation of the chemical, biochemical and biological properties. Spectroscopic, voltammetric and equilibrium studies were performed providing information about the chemical properties. The superoxide dismutase (SOD) activity was studied and showed differences of IC50 for both Cu-Ala-Phe (IC50=4.5) and Cu-Phe-Ala (IC50=45). The computational results permitted to explain this behavior proposing that it is feasible that the O2- anion is attracted straight to the positive zone in Cu-Ala-Phe whereas for Cu-Phe-Ala this phenomenon would happen to a smaller extent. Confirming our previous studies, both complexes interacted with DNA. Molecular docking studies showed that the position of the phenyl ring modulates the complex-DNA affinity and in Cu-Ala-Phe the docked conformation allows the copper ion to face the DNA basis, giving rise to a more stable complex-DNA adduct than for Cu-Phe-Ala. In spite of the fact that Atomic Force Microscopy showed plasmid compactation and aggregation for both complexes, the image showed softer changes in the case of Cu-Ala-Phe in comparison with those produced by Cu-Phe-Ala. In order to evaluate the effect of Cu-Ala-Phe and Cu-Phe-Ala complexes against tumor cells, we have employed three aggressive metastatic breast adenocarcinoma cellular models, derived from human (MDA-MB-231 and MCF-7) and mouse (4T1) spontaneous tumors. These experiments showed that both Cu-dipeptide complexes have a similar cytotoxic effect against breast cancer cells, and lower toxicity against BJ non-tumor cells in comparison to Cisplatin.

Potentiometric and spectroscopic studies on the copper(II) complexes of rat amylin fragments. The anchoring ability of specific non-coordinating side chains.

Copper(ii) complexes of peptides modelling the sequence of the 17-22 residues of rat amylin have been studied by potentiometric, UV-Vis, CD and ESR spectroscopic methods. The peptides were synthesized in N-terminally free forms, NH2-VRSSNN-NH2, NH2-VRSSAA-NH2, NH2-VRAANN-NH2, NH2-VRSS-NH2, NH2-SSNN-NH2, NH2-SSNA-NH2 and NH2-AANN-NH2, providing a possibility for the comparison of the metal binding abilities of the amino terminus and the -SSNN- domain. The amino terminus was the primary ligating site in all cases and the formation of only mononuclear complexes was obtained for the tetrapeptides. The thermodynamic stability of the (NH2, N(-), N(-)) coordinated complexes was, however, enhanced by the asparaginyl moiety in the case of NH2-SSNN-NH2, NH2-SSNA-NH2 and NH2-AANN-NH2. Among the hexapeptides the formation of dinuclear complexes was characteristic for NH2-VRSSNN-NH2 demonstrating the anchoring ability of the -SSNN- (SerSerAsnAsn) domain. The complexes of the heptapeptide NH2-GGHSSNN-NH2 were also studied and the data supported the above mentioned anchoring ability of the -SSNN- site.

Formation of new non-oxido vanadium(IV) species in aqueous solution and in the solid state by tridentate (O, N, O) ligands and rationalization of their EPR behavior.

The systems formed by the V(IV)O(2+) ion with tridentate ligands provided with the (O, N(imine), O) donor set were described. The ligands studied were 2,2'-dihydroxyazobenzene (Hdhab), α-(2-hydroxy-5-methylphenylimino)-o-cresol (Hhmpic), calmagite (H2calm), anthracene chrome red A (H3anth), calcon (H2calc), and calconcarboxylic acid (H3calc(C)). They can bind vanadium with the two deprotonated phenol groups and the imine nitrogen to give (5,6)-membered chelate rings. The systems were studied with EPR, UV-vis and IR spectroscopy, pH-potentiometry, and DFT methods. The ligands form unusual non-oxido V(IV) compounds both in aqueous solution and in the solid state. [V(anthH(-1))2](4-) and [V(calmH(-1))2](2-) (formed in water at the physiological pH) and [V(dhabH(-1))2] and [V(hmpicH(-1))2] (formed in the solid state in MeOH) are hexa-coordinated with geometry intermediate between the octahedron and the trigonal prism and an unsymmetric facial arrangement of the two ligand molecules. DFT calculations were used to predict the structure and (51)V hyperfine coupling tensor A of the non-oxido species. The EPR behavior of 13 non-oxido V(IV) species was put into relationship with the relevant geometrical parameters and was rationalized in terms of the spin density on the d(xy) orbital. Depending on the geometric isomer formed (meridional or facial), d(z)(2) mixes with the d(xy) orbital, and this effect causes the lowering of the highest (51)V A value.

V(IV)O versus V(IV) complex formation by tridentate (O, N(arom), O) ligands: prediction of geometry, EPR 51V hyperfine coupling constants, and UV-Vis spectra.

Systems formed using the V(IV)O(2+) ion with tridentate ligands containing a (O, N(arom), O) donor set were described. Examined ligands were 3,5-bis(2-hydroxyphenyl)-1-phenyl-1H-1,2,4-triazole (H2hyph(Ph)), 4-[3,5-bis(2-hydroxyphenyl)-1H-1,2,4-triazol-1-yl]benzoic acid (H3hyph(C)), 4-[3,5-bis(2-hydroxyphenyl)-1H-1,2,4-triazol-1-yl]benzenesulfonic acid (H3hyph(S)), and 2,6-bis(2-hydroxyphenyl)pyridine (H2bhpp), with H3hyph(C) being an orally active iron chelator that is commercially available under the name Exjade (Novartis) for treatment of chronic iron overload arising from blood transfusions. The systems were studied using EPR, UV-Vis, and IR spectroscopies, pH potentiometry, and DFT methods. The ligands bind vanadium with the two terminal deprotonated phenol groups and the central aromatic nitrogen to give six-membered chelate rings. In aqueous solution the main species were the mono- and bis-chelated V(IV)O complexes, whereas in the solid state neutral non-oxido V(IV) compounds were formed. [V(hyph(Ph))2] and [V(bhpp)2] are hexacoordinated, with a geometry close to the octahedral and a meridional arrangement of the ligands. DFT calculations allow distinguishing V(IV)O and V(IV) species and predicting their structure, the (51)V hyperfine coupling constant tensor A, and the electronic absorption spectra. Finally, EPR spectra of several non-oxido V(IV) species were compared using relevant geometrical parameters to demonstrate that in the case of tridentate ligands the (51)V hyperfine coupling constant is related to the geometric isomerism (meridional or facial) rather than the twist angle Φ, which measures the distortion of the hexacoordinated structure toward a trigonal prism.