Publications by authors named "Nóra V May"

21 Publications

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Copper Coordination Chemistry of Sulfur Pendant Cyclen Derivatives: An Attempt to Hinder the Reductive-Induced Demetalation in Cu Radiopharmaceuticals.

Inorg Chem 2021 Jul 19. Epub 2021 Jul 19.

Department of Chemical Sciences, University of Padova, via Marzolo 1, 35131 Padova, Italy.

The Cu complexes formed by a series of cyclen derivatives bearing sulfur pendant arms, 1,4,7,10-tetrakis[2-(methylsulfanyl)ethyl]-1,4,7,10-tetraazacyclododecane (DO4S), 1,4,7-tris[2-(methylsulfanyl)ethyl]-1,4,7,10-tetraazacyclododecane (DO3S), 1,4,7-tris[2-(methylsulfanyl)ethyl]-10-acetamido-1,4,7,10-tetraazacyclododecane (DO3SAm), and 1,7-bis[2-(methylsulfanyl)ethyl]-4,10-diacetic acid-1,4,7,10-tetraazacyclododecane (DO2A2S), were studied in aqueous solution at 25 °C from thermodynamic and structural points of view to evaluate their potential as chelators for copper radioisotopes. UV-vis spectrophotometric out-of-cell titrations under strongly acidic conditions, direct in-cell UV-vis titrations, potentiometric measurements at pH >4, and spectrophotometric Ag-Cu competition experiments were performed to evaluate the stoichiometry and stability constants of the Cu complexes. A highly stable 1:1 metal-to-ligand complex (CuL) was found in solution at all pH values for all chelators, and for DO2A2S, protonated species were also detected under acidic conditions. The structures of the Cu complexes in aqueous solution were investigated by UV-vis and electron paramagnetic resonance (EPR), and the results were supported by relativistic density functional theory (DFT) calculations. Isomers were detected that differed from their coordination modes. Crystals of [Cu(DO4S)(NO)]·NO and [Cu(DO2A2S)] suitable for X-ray diffraction were obtained. Cyclic voltammetry (CV) experiments highlighted the remarkable stability of the copper complexes with reference to dissociation upon reduction from Cu to Cu on the CV time scale. The Cu complexes were generated in situ by electrolysis and examined by NMR spectroscopy. DFT calculations gave further structural insights. These results demonstrate that the investigated sulfur-containing chelators are promising candidates for application in copper-based radiopharmaceuticals. In this connection, the high stability of both Cu and Cu complexes can represent a key parameter for avoiding demetalation after bioinduced reduction to Cu, often observed for other well-known chelators that can stabilize only Cu.
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http://dx.doi.org/10.1021/acs.inorgchem.1c01550DOI Listing
July 2021

Copper(II) Complexes of Sulfonated Salan Ligands: Thermodynamic and Spectroscopic Features and Applications for Catalysis of the Henry Reaction.

Inorg Chem 2021 Jul 12. Epub 2021 Jul 12.

Department of Inorganic and Analytical Chemistry, University of Debrecen, Debrecen H-4032, Hungary.

Copper(II) complexes formed with sulfonated salan ligands (HSS) have been synthesized, and their coordination chemistry has been characterized using pH-potentiometry and spectroscopic methods [UV-vis, electron paramagnetic resonance (EPR), and electron-electron double resonance (ELDOR)-detected NMR (EDNMR)] in aqueous solution. Several bridging moieties between the two salicylamine functions were introduced, e.g., ethyl (), propyl (), butyl (), cyclohexyl (-, -), and diphenyl (). All of the investigated ligands feature excellent copper(II) binding ability via the formation of a (O,N,N,O) chelate system. The results indicated that the cyclohexyl moiety significantly enhances the stability of the copper(II) complexes. EPR studies revealed that the arrangement of the coordinated donor atoms is more symmetrical around the copper(II) center and similar for , , , and , respectively, and a higher rhombicity of the tensor was detected for . The copper(II) complexes of the sulfosalan ligands were isolated in solid form also and showed moderate catalytic activity in the Henry (nitroaldol) reaction of aldehydes and nitromethane. The best yield for nitroaldol production was obtained for copper(II) complexes of and , although their metal binding ability is moderate compared to that of the cyclohexyl counterparts. However, these complexes possess larger spin density on the nitrogen nuclei than that for the other cases, which alters their catalytic activity.
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http://dx.doi.org/10.1021/acs.inorgchem.1c01264DOI Listing
July 2021

Binding Models of Copper(II) Thiosemicarbazone Complexes with Human Serum Albumin: A Speciation Study.

Molecules 2021 May 5;26(9). Epub 2021 May 5.

Department of Inorganic and Analytical Chemistry, Interdisciplinary Excellence Centre, University of Szeged, Dóm tér 7, H-6720 Szeged, Hungary.

Copper(II) complexes of thiosemicarbazones (TSCs) often exhibit anticancer properties, and their pharmacokinetic behavior can be affected by their interaction with blood transport proteins. Interaction of copper(II) complexes of an {N,N,S} donor α--pyridyl TSC (Triapine) and an {O,N,S} donor 2-hydroxybenzaldehyde TSC (STSC) with human serum albumin (HSA) was investigated by UV-visible and electron paramagnetic resonance spectroscopy at physiological pH. Asp-Ala-His-Lys and the monodentate N-methylimidazole were also applied as binding models. Conditional formation constants were determined for the ternary copper(II)-TSC complexes formed with HSA, DAHK, and N-methylimidazole based on the spectral changes of both charge transfer and d-d bands. The neutral N-methylimidazole displays a similar binding affinity to both TSC complexes. The partially negatively charged tetrapeptide binds stronger to the positively charged Triapine complex in comparison to the neutral STSC complex, while the opposite trend was observed for HSA, which demonstrates the limitations of the use of simple ligands to model the protein binding. The studied TSC complexes are able to bind to HSA in a fast process, and the conditional constants suggest that their binding strength is only weak-to-moderate.
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http://dx.doi.org/10.3390/molecules26092711DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8125041PMC
May 2021

Half-sandwich organometallic Ru and Rh complexes of (N,N) donor compounds: effect of ligand methylation on solution speciation and anticancer activity.

Dalton Trans 2021 Jun;50(23):8218-8231

Department of Inorganic and Analytical Chemistry, Interdisciplinary Excellence Centre, University of Szeged, Dóm tér 7, H-6720 Szeged, Hungary. and MTA-SZTE Lendület Functional Metal Complexes Research Group, University of Szeged, Dóm tér 7, H-6720 Szeged, Hungary.

A series of half-sandwich polypyridyl complexes was synthesized and compared focusing on structural, cytotoxic and aqueous solution behaviour. The formula of the synthesized complexes is [M(arene)(N,N)Cl]Cl, where M: Ru or Rh, arene: p-cymene, toluene or C5Me5-, (N,N): 2,2'-bipyridine (bpy), 4,4'-dimethyl-2,2'-bipyridine (dmb), 1,10-phenanthroline (phen) or 2,9-dimethyl-1,10-phenanthroline (neo). The structures of five half-sandwich complexes were determined by X-ray crystallography. It was found that introducing methyl groups next to the coordinating nitrogen atoms of the bidentate ligand causes steric congestion around the metal centre which changes the angle between ligand planes. The ligands and the Rh complexes showed significant cytotoxicity in A2780 and MES-SA cancer cell lines (IC50 = 0.1-56 μM) and in the cisplatin-resistant A2780cis cells. Paradoxically, phen and dmb as well as their half-sandwich Rh complexes showed increased toxicity against multidrug resistant MES-SA/Dx5 cells. In contrast, coordination to Ru caused loss of toxicity. Solution equilibrium constants showed that the studied metal complexes have high stability, and no dissociation was found for Ru and Rh complexes even at micromolar concentrations in a wide pH range. However, in the case of Ru complexes a slow and irreversible decomposition, namely arene loss, was also observed, which was more pronounced in light exposure in aqueous solution. In the case of neo, the methyl groups next to the nitrogen atoms significantly decrease the stability of complexes. For Rh complexes, the order of the stability constants corrected with ligand basicity (log K*): 9.78 (phen) > 9.01 (dmb) > 8.89 (bpy) > 3.93 (neo). The coordinated neo resulted in an enormous decrease in the chloride ion affinity of Ru compounds. Based on the results, a universal model was introduced for the prediction of chloride ion capability of half-sandwich Rh and Ru complexes. It combines the effects of the bidentate ligand and the M(arene) part using only two terms, performing multilinear regression procedure.
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http://dx.doi.org/10.1039/d1dt00808kDOI Listing
June 2021

Complex formation of an estrone-salicylaldehyde semicarbazone hybrid with copper(II) and gallium(III): Solution equilibria and biological activity.

J Inorg Biochem 2021 Jul 24;220:111468. Epub 2021 Apr 24.

Department of Inorganic and Analytical Chemistry, Interdisciplinary Excellence Centre, University of Szeged, Dóm tér 7, H-6720 Szeged, Hungary; MTA-SZTE Lendület Functional Metal Complexes Research Group, University of Szeged, Dóm tér 7, H-6720 Szeged, Hungary.

The solution chemical properties such as proton dissociation, complex formation with copper(II) and gallium(III) ions in addition to antibacterial and antitumor activity of a novel tridentate salicyaldehyde semicarbazone-estrone hybrid (estrone-SC) and a related bicyclic compound (thn-SC) were investigated. The crystal structure of complex [Cu(thn-SCH)Cl] was studied by single crystal X-ray diffraction method. Estrone-SC and thn-SC form mono-ligand complexes with Cu(II) characterized by relatively high stability, however, they are much less stable than their thiosemicarbazone analogues. The neutral Cu(II) complexes with (O,N,O)(HO) coordination mode predominate at physiological pH. Estrone-SC and thn-SC are more efficient Ga(III) binders in comparison with thiosemicarbazones, although the complexes also suffer dissociation at pH 7.4. The Cu(II) complex of estrone-SC displayed significant cytotoxicity in A549, SW480 and CH1/PA cancer cells, and moderate apoptosis induction and ROS formation. The semicarbazone compounds did not exhibit antibacterial effect; unlike the related Cu(II)-thiosemicarbazone complexes represented by the fairly low MIC values (3-50 μM) obtained on the Gram-positive Staphylococcus aureus and Enterococcus faecalis bacteria.
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http://dx.doi.org/10.1016/j.jinorgbio.2021.111468DOI Listing
July 2021

Synthesis of dihydrotestosterone derivatives modified in the A-ring with (hetero)arylidene, pyrazolo[1,5-a]pyrimidine and triazolo[1,5-a]pyrimidine moieties and their targeting of the androgen receptor in prostate cancer.

J Steroid Biochem Mol Biol 2021 Jul 29;211:105904. Epub 2021 Apr 29.

Department of Organic Chemistry, University of Szeged, Dóm tér 8, Szeged, H-6720, Hungary. Electronic address:

One of the main directions of steroid research is the preparation of modified derivatives in which, in addition to changes in physicochemical properties, receptor binding is significantly altered, thus a bioactivity different from that of the parent compound predominates. In the frame of this work, 2-arylidene derivatives were first synthesized by regioselective modification of the A-ring of natural sex hormone, 5α-dihydrotestosterone (DHT). After Claisen-Schmidt condensations of DHT with (hetero)aromatic aldehydes in alkaline EtOH, heterocyclizations of the α,β-enones were performed with 3-amino-1,2,4-triazole, 3-aminopyrazole and 3-amino-5-methylpyrazole in the presence of t-BuOK in DMF to afford 7'-epimeric mixtures of A-ring-fused azolo-dihydropyrimidines, respectively. Depending on the electronic demand of the substituents of the arylidene moiety, spontaneous or 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ)-induced oxidation of the heteroring led to triazolo[1,5-a]pyrimidines and pyrazolo[1,5-a]pyrimidines in good yields, while, using the Jones reagent as a strong oxidant, 17-oxidation also occurred. The crystal structures of an arylidene and a triazolopyrimidine product have been determined by single crystal X-ray diffraction and both were found to crystallize in the monoclinic crystal system at P2 space group. Most derivatives were found to diminish the transcriptional activity of androgen receptor (AR) in reporter cell line. The candidate compound (17β-hydroxy-2-(4-chloro)benzylidene-5α-androstan-3-one, 2f) showed to suppress androgen-mediated AR transactivation in a dose-dependent manner. We confirmed the cellular interaction of 2f with AR, described the binding in AR-binding cavity by the flexible docking and showed the ability of the compound to suppress the expression of AR-regulated genes in two prostate cancer cell lines.
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http://dx.doi.org/10.1016/j.jsbmb.2021.105904DOI Listing
July 2021

Catalytic antioxidant nanocomposites based on sequential adsorption of redox active metal complexes and polyelectrolytes on nanoclay particles.

Dalton Trans 2021 Feb;50(7):2426-2435

MTA-SZTE Lendület Biocolloids Research Group, Interdisciplinary Research Center, Department of Physical Chemistry and Materials Science, University of Szeged, H-6720 Szeged, Hungary.

An antioxidant nanocomposite was prepared by successive adsorption of redox active metal complexes (copper(ii)-bipyridyl and iron(iii)-citrate) and polyelectrolytes (poly(styrene sulfonate) and poly(diallyldimethyl ammonium)) on layered double hydroxide nanoclay. The experimental conditions were optimized in each preparation step and thus, the final composite formed highly stable colloids, i.e., excellent resistance against salt-induced aggregation was achieved. Due to the synergistic effect of the metal complexes, the developed composite showed remarkable activity in the dismutation of superoxide radicals, close to the one determined for the native superoxide dismutase enzyme. The obtained composite is highly selective for superoxide radical dismutation, while its activity in other antioxidant tests was close to negligible. Structural characterization of the composite revealed that the excellent superoxide radical scavenging ability originated from the advantageous coordination geometry around the copper(ii) center formed upon immobilization. The structure formed around the metal centers led to optimal redox features and consequently, to an improved superoxide dismutase-like activity. The catalytic antioxidant composite is a promising candidate to reduce oxidative stress in industrial manufacturing processes, where natural enzymes quickly lose their activity due to the harsh environmental conditions.
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http://dx.doi.org/10.1039/d0dt04186fDOI Listing
February 2021

Complex formation and cytotoxicity of Triapine derivatives: a comparative solution study on the effect of the chalcogen atom and NH-methylation.

Dalton Trans 2020 Dec;49(46):16887-16902

Department of Inorganic and Analytical Chemistry, Interdisciplinary Excellence Centre, University of Szeged, Dóm tér 7, H-6720 Szeged, Hungary.

α-N-Heterocyclic thiosemicarbazones are an important class of investigational anticancer drugs. The most prominent representative is 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (Triapine), which has shown promising results in clinical trials and is currently evaluated in phase III. In this study, we investigated the influence of a chalcogen atom exchange from S (Triapine) to O (O-Triapine) and Se (Se-Triapine) and the methylation of the hydrazonic NH moiety (Me-Triapine) on their complexation with Fe(ii), Fe(iii) and Cu(ii) ions and their cytotoxicity. The main aim of this study was to characterize and compare the most feasible chemical forms in solution, their stability and redox properties, as well as to reveal the relationships of the solution speciation and kinetic data with cytotoxic activity. The complex equilibria and redox properties of the complexes were characterized by the combined use of pH-potentiometry, UV-visible spectrophotometry, electron paramagnetic resonance spectroscopy, and cyclic voltammetry. These revealed that Se-Triapine forms Cu(ii) complexes with higher, and O-Triapine with lower stability as compared with Triapine. Me-Triapine, which is not able to coordinate via the typical (N,N,S-) donor set, nevertheless coordinates to Cu(ii) with unexpected high stability. The Cu(ii) complexes of Se-Triapine and Me-Triapine can be relatively slowly reduced by glutathione at pH 7.4 (but not by ascorbate), similarly to Cu(ii)-Triapine. In contrast, the Cu(ii)-O-Triapine complex can be reduced by both reducing agents in rapid redox reactions. Se-Triapine and Triapine form high stability complexes with both Fe(ii) and Fe(iii) ions, while O-Triapine has a much stronger preference towards Fe(iii) and Me-Triapine towards Fe(ii). This difference in the iron preference of the ligands seems to have a strong impact on their cytotoxic effects, which was measured in a human uterine sarcoma cell line (MES-SA) and its multidrug-resistant subline (MES-SA/Dx5). The Cu(ii) complexes of these calcogensemicarbazones are moderately toxic, and the highest level of ROS generation was found for the Cu(ii) complex of O-Triapine, which is the most reducible.
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http://dx.doi.org/10.1039/d0dt03465gDOI Listing
December 2020

High Enzyme Activity of a Binuclear Nickel Complex Formed with the Binding Loops of the NiSOD Enzyme*.

Chemistry 2020 Dec 9;26(70):16767-16773. Epub 2020 Nov 9.

Department of Inorganic and Analytical Chemistry, University of Debrecen, 4032, Debrecen, Hungary.

Detailed equilibrium, spectroscopic and superoxide dismutase (SOD) activity studies are reported on a nickel complex formed with a new metallopeptide bearing two nickel binding loops of NiSOD. The metallopeptide exhibits unique nickel binding ability and the binuclear complex is a major species with 2×(NH ,N ,S ,S ) donor set even in an equimolar solution of the metal ion and the ligand. Nickel(III) species were generated by oxidizing the Ni complexes with KO and the coordination modes were identified by EPR spectroscopy. The binuclear complex formed with the binding motifs exhibits superior SOD activity, in this respect it is an excellent model of the native NiSOD enzyme. A detailed kinetic model is postulated that incorporates spontaneous decomposition of the superoxide ion, the dismutation cycle and fast redox degradation of the binuclear complex. The latter process leads to the elimination of the SOD activity. A unique feature of this system is that the Ni form of the catalyst rapidly accumulates in the dismutation cycle and simultaneously the Ni form becomes a minor species.
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http://dx.doi.org/10.1002/chem.202002706DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756883PMC
December 2020

The Role of the Cysteine Fragments of the Nickel Binding Loop in the Activity of the Ni(II)-Containing SOD Enzyme.

Inorg Chem 2020 Apr 24;59(7):4772-4780. Epub 2020 Mar 24.

Department of Inorganic and Analytical Chemistry, University of Debrecen, H-4032 Debrecen, Hungary.

Detailed equilibrium, spectroscopic, and SOD activity studies are reported on nickel(II) complexes formed with the -terminally free HHDLPCGVY-NH () and HCDLPHGVY-NH () peptides mimicking the nickel binding loop in NiSOD. In these model peptides, cysteine was incorporated in different positions in order to gain better insight into the role of the cysteine residues in NiSOD. The results are compared with those obtained with the wild-type fragment of NiSOD. The complex formation equilibria of nickel(II) with the two peptides exhibit different features. In the case of , the ligand field of the (NH,N,N,S) donor set is not strong enough to cause spin pairing and an octahedral paramagnetic complex is formed under physiological conditions. In contrast, forms a square-planar diamagnetic complex with (NH,N,S,N) donors which exhibits remarkable SOD activity. Our results unambiguously prove that the presence of cysteine in the secondary position of the peptide chain is crucial to establish the square-planar geometry in the reduced form of NiSOD, while the distant cysteine affects the redox properties of the Ni(II)/Ni(III) couple. Compared to the model systems, the Ni(II) complex with the wild-type fragment of NiSOD exhibits superior SOD activity. This confirms that both cysteinyl residues are essential in the efficient degradation of superoxide ion. The enzyme mimetic complexes are also capable of assisting the decomposition of superoxide ion; however, they show considerably smaller catalytic activity due to the absence of one of the cysteine residues.
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http://dx.doi.org/10.1021/acs.inorgchem.0c00057DOI Listing
April 2020

Donepezil-based hybrids as multifunctional anti-Alzheimer's disease chelating agents: Effect of positional isomerization.

J Inorg Biochem 2020 05 16;206:111039. Epub 2020 Feb 16.

Centro de Química Estrutural and Departamento de Engenharia Química, Instituto Superior Técnico, Universidade de Lisboa, Av, Rovisco Pais 1, 1049-001 Lisboa, Portugal. Electronic address:

The intricate and multifactorial nature of Alzheimer's disease (AD) requires the development of compounds able to hit different pathophysiological targets, such as cholinergic dysfunction, deposits of amyloid beta (Aβ) peptide and metal dyshomeostasis. In order to continue the search for new anti-AD drugs, a design strategy was once more followed based on repositioning donepezil (DNP) drug, by ortho-attaching a benzylpiperidine mimetic of DNP moiety to a hydroxyphenyl-benzimidazole (BIM) chelating unit (compound 1). Herein, compound 1 and a positional isomer 2 are compared in terms of their potential multiple properties: both present good acetylcholinesterase (AChE) inhibition (low μmolar range) and are moderate/good inhibitors of Aβ self- and Cu-mediated aggregation, the inhibition process being mainly due to ligand intercalation between the β-sheets of the fibrils; compound 1 has a higher chelating capacity towards Cu and Zn (pCu = 14.3, pZn = 6.4, pH 7.4, C/C = 10, C = 10 M) than 2 (pCu = 10.7, pZn = 6.3), attributed to its ability to establish a tridentate (N,O,O) coordination to the metal ion. Both compounds are eligible as drug candidates for oral administration but compound 1 shows improved neuroprotective role by completely preventing Aβ-induced cell toxicity.
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http://dx.doi.org/10.1016/j.jinorgbio.2020.111039DOI Listing
May 2020

Solution equilibrium, structural and cytotoxicity studies on Ru(η-p-cymene) and copper complexes of pyrazolyl thiosemicarbazones.

J Inorg Biochem 2020 01 22;202:110883. Epub 2019 Oct 22.

Department of Inorganic and Analytical Chemistry, Interdisciplinary Excellence Centre, University of Szeged, Dóm tér 7, H-6720 Szeged, Hungary. Electronic address:

Solution chemical properties of two bidentate pyrazolyl thiosemicarbazones 2-((3-methyl-1-phenyl-1H-pyrazol-4-yl)methylene)hydrazinecarbothioamide (Me-pyrTSC), 2-((1,3-diphenyl-1H-pyrazol-4-yl)methylene)hydrazinecarbothioamide (Ph-pyrTSC), stability of their Cu(II) and Ru(η-p-cymene) complexes were characterized in aqueous solution (with 30% DMSO) by the combined use of UV-visible spectrophotometry, H NMR spectroscopy and electrospray ionization mass spectrometry in addition to their solid phase isolation. The solid phase structures of Me-pyrTSC∙HO, [Ru(η-p-cymene)(Me-pyrTSC)Cl]Cl and [Cu(Ph-pyrTSCH)] were determined by single crystal X-ray diffraction. High stability mononuclear Ru(η-p-cymene) complexes with (N,S) coordination mode are formed in the acidic pH range, and increasing the pH the predominating dinuclear [(Ru(η-p-cymene))(L)] complex with μ-bridging sulphur donor atoms is formed (where L is the deprotonated thiosemicarbazone). [CuL] and [CuL] complexes show much higher stability compared to that of complexes of the reference compound benzaldehyde thiosemicarbazone. [CuL] complexes predominate at neutral pH. Me-pyrTSC and Ph-pyrTSC exhibited moderate cytotoxicity against human colonic adenocarcinoma cell lines (IC = 33-76 μM), while their complexation with Ru(η-p-cymene) (IC = 11-24 μM) and especially Cu(II) (IC = 3-6 μM) resulted in higher cytotoxicity. Cu(II) complexes of the tested thiosemicarbazones were also cytotoxic in three breast cancer and in a hepatocellular carcinoma cell line. No reactive oxygen species production was detected and the relatively high catalase activity of SUM159 breast cancer cells was decreased upon addition of the ligands and the complexes. In the latter cell line the tested compounds interfered with the glutathione synthesis as they decreased the concentration of this cellular reductant.
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http://dx.doi.org/10.1016/j.jinorgbio.2019.110883DOI Listing
January 2020

Copper(II) complexes of coumarin-derived Schiff base ligands: Pro- or antioxidant activity in MCF-7 cells?

J Inorg Biochem 2019 08 5;197:110702. Epub 2019 May 5.

Centre of Applied Science and Health, TU Dublin - Tallaght Campus, Tallaght D24 FKT9, Ireland. Electronic address:

A series of copper(II) complexes of Schiff base-derived ligands (1-7) were studied for their pro- and antioxidant behaviour in the MCF-7 human breast cancer cell line. The coordination modes of two of the copper(II) complexes were investigated by pH-potentiometry, EPR and UV-Vis spectroscopic methods. The solution studies indicated that monomeric species are present in the Cu(II) - L1 system at neutral pH, whereas dinuclear species were observed in the case of the Cu(II) - L7 system. This difference in speciation was reflected in their relative cytotoxicities with the copper(II) complex of L1, showing significant cytotoxicity against MCF-7 cells whilst the complex of L7 was inactive. In fact, only three of the seven complexes studied in this series were cytotoxic to MCF-7 cells but this cytotoxicity did not correlate with their ability to bind to DNA, cleave DNA or act as a pro-oxidant. In contrast to previous copper(II) complexes studied by our group, the compounds studied here do not appear to lead to intracellular reactive oxygen species generation at any significant level. In a yeast-based assay, all of the copper complexes had the ability to protect Saccharomyces cerevisiae against menadione-induced oxidative stress but not hydrogen peroxide-induced stress, indicating a lack of catalase activity. Given that the adaptive mechanisms induced by hypoxia in cancer cells have selective effects, with a fine-tuned protection against damage and stress of many kinds, particularly against oxidative stress, chemotherapeutic compounds which are not pro-oxidants may offer a therapeutic advantage.
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http://dx.doi.org/10.1016/j.jinorgbio.2019.110702DOI Listing
August 2019

Comparative solution and structural studies of half-sandwich rhodium and ruthenium complexes bearing curcumin and acetylacetone.

J Inorg Biochem 2019 06 28;195:91-100. Epub 2019 Feb 28.

Department of Inorganic and Analytical Chemistry, Interdisciplinary Excellence Centre, University of Szeged, Dóm tér 7, H-6720 Szeged, Hungary. Electronic address:

Half-sandwich organometallic complexes of curcumin are extensively investigated as anticancer compounds. Speciation studies were performed to explore the solution stability of curcumin complexes formed with [Rh(η-CMe)(HO)]. Acetylacetone (Hacac), as the simplest β-diketone ligand bearing (O,O) donor set, was involved for comparison and its Ru(η‑p‑cymene), Ru(η‑toluene) complexes were also studied. H NMR, UV-visible and pH-potentiometric titrations revealed a clear trend of stability constants of the acac complexes: Ru(η‑p‑cymene) > Ru(η‑toluene) > Rh(η-CMe). Despite this order, the highest extent of complex formation is seen for the Rh(η-CMe) complexes at pH 7.4. Formation constant of [Rh(η-CMe)(Hcurcumin)(HO)] reveals similar solution stability to that of the acac complex. Additionally, structures of two complexes were determined by X-ray crystallography. The in vitro cytotoxicity of curcumin was not improved by the complexation with these organometallic cations.
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http://dx.doi.org/10.1016/j.jinorgbio.2019.02.015DOI Listing
June 2019

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

Inorg Chem 2019 Jan 8;58(2):1414-1424. Epub 2019 Jan 8.

MTA-DE Redox and Homogeneous Catalytic Reaction Mechanisms Research Group , University of Debrecen , H-4032 Debrecen , Hungary.

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-NH (NiSODM), HCDLACGVY-NH (NiSODM), and Ac-HCDLPCGVY-NH (NiSODM) and the N-terminally shortened analogues HCDL-NH and HCA-NH 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 NiSODM and NiSODM, resulting in the high nickel(II) binding affinity of this peptide via the formation of a square-planar, (NH,N,S,S) or (NH,NN,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.
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http://dx.doi.org/10.1021/acs.inorgchem.8b02952DOI Listing
January 2019

New Water-Soluble Copper(II) Complexes with Morpholine-Thiosemicarbazone Hybrids: Insights into the Anticancer and Antibacterial Mode of Action.

J Med Chem 2019 01 18;62(2):512-530. Epub 2018 Dec 18.

Institute of Inorganic Chemistry , University of Vienna , Währinger Strasse 42 , A-1090 Vienna , Austria.

Six morpholine-(iso)thiosemicarbazone hybrids HL-HL and their Cu(II) complexes with good-to-moderate solubility and stability in water were synthesized and characterized. Cu(II) complexes [Cu(L)Cl] (1-6) formed weak dimeric associates in the solid state, which did not remain intact in solution as evidenced by ESI-MS. The lead proligands and Cu(II) complexes displayed higher antiproliferative activity in cancer cells than triapine. In addition, complexes 2-5 were found to specifically inhibit the growth of Gram-positive bacteria Staphylococcus aureus with MIC values at 2-5 μg/mL. Insights into the processes controlling intracellular accumulation and mechanism of action were investigated for 2 and 5, including the role of ribonucleotide reductase (RNR) inhibition, endoplasmic reticulum stress induction, and regulation of other cancer signaling pathways. Their ability to moderately inhibit R2 RNR protein in the presence of dithiothreitol is likely related to Fe chelating properties of the proligands liberated upon reduction.
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http://dx.doi.org/10.1021/acs.jmedchem.8b01031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6348444PMC
January 2019

Impact of copper and iron binding properties on the anticancer activity of 8-hydroxyquinoline derived Mannich bases.

Dalton Trans 2018 Dec;47(47):17032-17045

Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar Tudósok körútja 2, H-1117 Budapest, Hungary.

The anticancer activity of 8-hydroxyquinolines relies on complex formation with redox active copper and iron ions. Here we employ UV-visible spectrophotometry and EPR spectroscopy to compare proton dissociation and complex formation processes of the reference compound 8-hydroxyquinoline (Q-1) and three related Mannich bases to reveal possible correlations with biological activity. The studied derivatives harbor a CH2-N moiety at position 7 linked to morpholine (Q-2), piperidine (Q-3), and chlorine and fluorobenzylamino (Q-4) substituents. Solid phase structures of Q-3, Q-4·HCl·H2O, [(Cu(HQ-2)2)2]·(CH3OH)2·Cl4·(H2O)2, [Cu(Q-3)2]·Cl2 and [Cu(HQ-4)2(CH3OH)]·ZnCl4·CH3OH were characterized by single-crystal X-ray diffraction analysis. In addition, the redox properties of the copper and iron complexes were studied by cyclic voltammetry, and the direct reaction with physiologically relevant reductants (glutathione and ascorbic acid) was monitored. In vitro cytotoxicity studies conducted with the human uterine sarcoma MES-SA/Dx5 cell line reveal the significant cytotoxicity of Q-2, Q-3, and Q-4 in the sub- to low micromolar range (IC50 values 0.2-3.3 μM). Correlation analysis of the anticancer activity and the metal binding properties of the compound series indicates that, at physiological pH, weaker copper(ii) and iron(iii) binding results in elevated toxicity (e.g.Q4: pCu = 13.0, pFe = 6.8, IC50 = 0.2 μM vs.Q1: pCu = 15.1, pFe = 13.0 IC50 = 2.5 μM). Although the studied 8-hydroxyquinolines preferentially bind copper(ii) over iron(iii), the cyclic voltammetry data revealed that the more cytotoxic ligands preferentially stabilize the lower oxidation state of the metal ions. A linear relationship between the pKa (OH) and IC50 values of the studied 8-hydroxyquinolines was found. In summary, we identify Q-4 as a potent and selective anticancer candidate with significant toxicity in drug resistant cells.
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http://dx.doi.org/10.1039/c8dt03088jDOI Listing
December 2018

Comparative solution equilibrium and structural studies of half-sandwich ruthenium(II)(η-toluene) complexes of picolinate derivatives.

J Inorg Biochem 2018 04 6;181:74-85. Epub 2018 Jan 6.

Department of Inorganic and Analytical Chemistry, University of Szeged, Dóm tér 7, H-6720 Szeged, Hungary. Electronic address:

Five Ru(II)(η-toluene) complexes formed with 2-picolinic acid and its various derivatives have been synthesized and characterized. X-ray structures of four complexes are also reported. Complex formation processes of [Ru(II)(η-toluene)(HO)] organometallic cation with the metal-free ligands were studied in aqueous solution in the presence of chloride ions by the combined use of H NMR spectroscopy, UV-visible spectrophotometry and pH-potentiometry. Solution stability, chloride ion affinity and lipophilicity of the complexes were characterized together with in vitro cytotoxic and antiproliferative activity in cancer cell lines being sensitive and resistant to classic chemotherapy and in normal cells as well. Formation of mono complexes such as [Ru(η-toluene)(L)(Z)] (L: completely deprotonated ligand; Z = HO/Cl) with high stability and [Ru(η-toluene)(L)(OH)] was found in solution. The pK values (8.3-8.7) reflect the formation of low amount of mixed hydroxido species at pH 7.4 at 0.2 M KCl ionic strength. The complexes are fairly hydrophilic and show moderate chloride ion affinity and fast chloride-water exchange processes. The studied complexes exhibit no cytotoxic activity in human cancer cells (IC > 100 μM), only complexes formed with 2-picolinic acid (1) and its 3-methyl derivative (2) represented a moderate antiproliferative effect (IC = 84.8 (1), 79.2 μM (2)) on a multidrug resistant colon adenocarcinoma cell line revealing considerable multidrug resistant selectivity. Complexes 1 and 2 bind to human serum albumin covalently and relatively slowly with moderate strength at multiple binding sites without ligand cleavage.
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http://dx.doi.org/10.1016/j.jinorgbio.2017.12.017DOI Listing
April 2018

Tailoring the local environment around metal ions: a solution chemical and structural study of some multidentate tripodal ligands.

Dalton Trans 2017 Jul;46(26):8626-8642

Department of Inorganic and Analytical Chemistry, University of Szeged, Dóm tér 7, H-6720 Szeged, Hungary. and MTA-SZTE Bioinorganic Chemistry Research Group, Dóm tér 7, H-6720 Szeged, Hungary.

Manganese(ii), copper(ii) and zinc(ii) complexes of four polydentate tripodal ligands (tachpyr (N,N',N''-tris(2-pyridylmethyl)-cis,cis-1,3,5-triaminocyclohexane), trenpyr (tris[2-(2-pyridylmethyl)aminoethyl]amine, tach3pyr (N,N',N''-tris(3-pyridylmethyl)-cis,cis-1,3,5-triaminocyclohexane) and tren3pyr (tris[2-(2-pyridylmethyl)aminoethyl]amine)) were characterized in both solution and solid states. A combined evaluation of potentiometric, UV-VIS, NMR and EPR data allowed the conclusion of both thermodynamic and structural information about the complexes formed in solution. The four tailored polydentate tripodal ligands studied here exhibit a high thermodynamic stability, and a variety of coordination environments/geometries for the studied transition metal ions. Our data indicate that tachpyr is a more efficient zinc(ii) chelator and a similar copper(ii) chelator compared to trenpyr. Considering the higher number of N-donors and conformational flexibility of trenpyr, as well as the energy demanding switch to the triaxial conformation required for metal ion binding of tachpyr, the above observation is surprising and is very likely due to the encapsulating effect of the more rigid tachpyr skeleton. This relative binding preference of tachpyr for zinc(ii) may be related to the observation that zinc(ii) is one of the principal metals targeted by tachpyr in cells. In contrast, trenpyr is a considerably more efficient manganese(ii) chelator, since it acts as a heptadentate ligand in the aqueous Mn(trenpyr) complex. The crystal structures of copper(ii) and zinc(ii) complexes of tachpyr indicated important differences in the ligand conformation, induced by the position of counter ions, as compared to earlier reports. The closely related new ligands, tach3pyr and tren3pyr, have been designed to form oligonuclear complexes. Indeed, we obtained a three dimensional polymer with a copper(ii)/tren3pyr ratio of 11/6. Within this metal-organic framework, three distinctly different copper geometries can be identified: square pyramidal, trigonal bipyramidal and tetrahedral. Two square pyramidal and four trigonal bipyramidal copper centres create a hexanuclear subunit with a large inside cavity. These moieties are linked by tetrahedral copper(ii) centres, constructing the three-dimensional polymer structure. The formation of such polynuclear complexes was not detected in solution. Both tach3pyr and tren3pyr form only mononuclear complexes with square pyramidal and trigonal bipyramidal geometries, respectively.
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http://dx.doi.org/10.1039/c7dt00104eDOI Listing
July 2017

Exploring the boundaries of direct detection and characterization of labile isomers - a case study of copper(ii)-dipeptide systems.

Dalton Trans 2017 Jun;46(25):8157-8166

Department of Inorganic and Analytical Chemistry, University of Szeged, Dóm tér 7, H-6720 Szeged, Hungary.

The investigation of the linkage isomers of biologically essential and kinetically labile metal complexes in aqueous solutions poses a challenge, as these microspecies cannot be separately studied. Therefore, derivatives are commonly used to initially determine the stability or spectral characteristics of at least one of the isomers. Here we directly detect the isomers, describe the metal ion coordination sphere, speciation and thermodynamic parameters by a synergistic application of temperature dependent EPR and CD spectroscopic measurements in copper(ii)-dipeptide systems including His-Gly and His-Ala ligands. The ΔH = (-23 ± 4) kJ mol value of the standard enthalpy change corresponding to the peptide-type to histamine-type isomerisation equilibrium of the [CuL] complex was corroborated by several techniques. The preferential coordination of the side-chains was observed at lower temperatures, whereas, metal-binding of the backbone atoms became favourable upon increasing temperature. This study exemplifies the necessity of using temperature dependent multiple methodologies for a reliable description of similar systems for upstream applications.
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http://dx.doi.org/10.1039/c7dt00884hDOI Listing
June 2017

Comparative solution equilibrium studies of antitumor ruthenium(η-p-cymene) and rhodium(η-CMe) complexes of 8-hydroxyquinolines.

Dalton Trans 2017 Mar;46(13):4382-4396

Department of Inorganic and Analytical Chemistry, University of Szeged, Dóm tér 7, H-6720 Szeged, Hungary.

Complex formation processes of [Ru(η-p-cymene)(HO)] and [Rh(η-CMe)(HO)] organometallic cations with 8-hydroxyquinoline (HQ) ligands were studied in aqueous solution by the combined use of H NMR spectroscopy, UV-visible spectrophotometry and pH-potentiometry. Solution stability, chloride ion affinity and lipophilicity of the complexes were characterized together with the in vitro cytotoxicity against a pair of cancer cell lines, responsive and resistant to classic chemotherapy. The solid phase structure of the [Rh(η-CMe)(8-quinolinolato)(Cl)] complex was characterized by single-crystal X-ray diffraction analysis. In addition to the unsubstituted HQ its 7-(1-piperidinylmethyl) (PHQ) and 5-sulfonate (HQS) derivatives were involved. PHQ has a significant preference for targeting multidrug resistant cancer cell lines, while HQS served as a water soluble model compound. The equilibrium studies revealed the formation of mono[M(L)(HO)] complexes with prominently high solution stability, which predominate at physiological pH even in the micromolar concentration range, and the formation of mixed hydroxido [M(L)(OH)] complexes was characterized by relatively high pK values (8.5-10.3). In comparison to the Rh(η-CMe) species the complexation process with Ru(η-p-cymene) is much slower, and both the pK values and the HO/Cl co-ligand exchange constants are lower by 1-1.5 orders of magnitude. The stability order obtained for these organometallic complexes is as follows: HQS > HQ > PHQ. The cytotoxicity of the ligands and their Ru(η-p-cymene) and Rh(η-CMe) complexes was investigated against MES-SA (human uterine sarcoma) cell line and its multidrug resistant counterpart (MES-SA/Dx5). HQ and its complexes show similar cytotoxicity in both cell lines. In contrast, PHQ and its Rh(η-CMe) complex are more potent against MES-SA/Dx5 cells, while this selectivity could not be observed for the Ru(η-p-cymene) complex.
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http://dx.doi.org/10.1039/c7dt00439gDOI Listing
March 2017
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