Publications by authors named "Éva A Enyedy"

71 Publications

Triapine Analogues and Their Copper(II) Complexes: Synthesis, Characterization, Solution Speciation, Redox Activity, Cytotoxicity, and mR2 RNR Inhibition.

Inorg Chem 2021 Jul 19. Epub 2021 Jul 19.

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

Three new thiosemicarbazones (TSCs) - as triapine analogues bearing a redox-active phenolic moiety at the terminal nitrogen atom were prepared. Reactions of - with CuCl·2HO in anoxic methanol afforded three copper(II) complexes, namely, (), [ (), and (), in good yields. Solution speciation studies revealed that the metal-free ligands are stable as - at pH 7.4, while being air-sensitive in the basic pH range. In dimethyl sulfoxide they exist as a mixture of and isomers. A mechanism of the isomerization with an inversion at the nitrogen atom of the Schiff base imine bond is proposed. The monocationic complexes are the most abundant species in aqueous solutions at pH 7.4. Electrochemical and spectroelectrochemical studies of , , and confirmed their redox activity in both the cathodic and the anodic region of potentials. The one-electron reduction was identified as metal-centered by electron paramagnetic resonance spectroelectrochemistry. An electrochemical oxidation pointed out the ligand-centered oxidation, while chemical oxidations of and as well as and afforded several two-electron and four-electron oxidation products, which were isolated and comprehensively characterized. Complexes and showed an antiproliferative activity in Colo205 and Colo320 cancer cell lines with half-maximal inhibitory concentration values in the low micromolar concentration range, while with the most closely related ligand to triapine displayed the best selectivity for cancer cells versus normal fibroblast cells (MRC-5). and in the presence of 1,4-dithiothreitol are as potent inhibitors of mR2 ribonucleotide reductase as triapine.
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http://dx.doi.org/10.1021/acs.inorgchem.1c01275DOI Listing
July 2021

Comparison of Solution Chemical Properties and Biological Activity of Ruthenium Complexes of Selected -Diketone, 8-Hydroxyquinoline and Pyrithione Ligands.

Pharmaceuticals (Basel) 2021 May 27;14(6). Epub 2021 May 27.

MTA-SZTE Lendület Functional Metal Complexes Research Group, University of Szeged, Dóm Tér 7, H-6720 Szeged, Hungary.

In this work, the various biological activities of eight organoruthenium(II) complexes were evaluated to reveal correlations with their stability and reactivity in aqueous media. Complexes with general formula [Ru(η--cymene)(X,Y)(Z)] were prepared, where (X,Y) represents either an ,-ligand (-diketone), ,-ligand (8-hydroxyquinoline) or ,-pyrithione-type ligands (pyrithione = 1-hydroxypyridine-2(1)-thione) with Cl or 1,3,5-triaza-7-phosphaadamantane (PTA) as a co-ligand (Z). The tested complexes inhibit the chlamydial growth on HeLa cells, and one of the complexes inhibits the growth of the human herpes simplex virus-2. The chlorido complexes with ,- and ,-ligands displayed strong antibacterial activity on Gram-positive strains including the resistant (MRSA) and were cytotoxic in adenocarcinoma cell lines. Effect of the structural variation on the biological properties and solution stability was clearly revealed. The decreased bioactivity of the -diketone complexes can be related to their lower stability in solution. In contrast, the ,-pyrithione-type complexes are highly stable in solution and the complexation prevents the oxidation of the ,-ligands. Comparing the binding of PTA and the chlorido co-ligands, it can be concluded that PTA is generally more strongly coordinated to ruthenium, which at the same time decreased the reactivity of complexes with human serum albumin or 1-methylimidazole as well as diminished their bioactivity.
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http://dx.doi.org/10.3390/ph14060518DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8226722PMC
May 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

Multifunctional Pt(iv) prodrug candidates featuring the carboplatin core and deferoxamine.

Dalton Trans 2021 Jun 25;50(23):8167-8178. Epub 2021 May 25.

Institute of Inorganic Chemistry, University of Vienna, Waehringer Str. 42, 1090 Vienna, Austria.

The synergistic combination of the anticancer drug carboplatin and the iron chelator deferoxamine (DFO) served as a foundation for the development of novel multifunctional prodrugs. Hence, five platinum(iv) complexes, featuring the equatorial coordination sphere of carboplatin, and one or two DFO units incorporated at axial positions, were synthesized and characterized using ESI-HRMS, multinuclear (H, C, N, Pt) NMR spectroscopy and elemental analysis. Analytical studies demonstrated that the chelating properties of the DFO moiety were not compromised after coupling to the platinum(iv) core. The cytotoxic activity of the compounds was evaluated in monolayer (2D) and spheroid (3D) cancer cell models, derived from ovarian teratocarcinoma (CH1/PA-1), colon carcinoma (SW480) and non-small cell lung cancer (A549). The platinum(iv)-DFO prodrugs demonstrated moderate in vitro cytotoxicity (a consequence of their slow activation kinetics) but with less pronounced differences between intrinsically chemoresistant and chemosensitive cell lines as well as between 2D and 3D models than the clinically used platinum(ii) drug carboplatin.
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http://dx.doi.org/10.1039/d1dt00214gDOI 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

Deposition of pentamidine analogues in the human body - spectroscopic and computational approaches.

Eur J Pharm Sci 2021 Jun 2;161:105779. Epub 2021 Mar 2.

Department of Organic Chemistry, Faculty of Pharmacy, Medical University of Warsaw, Banacha 1, 02-097 Warsaw, Poland. Electronic address:

Bis-benzamidines are a diverse group of compounds with high potential in pharmacotherapy, and among them, pentamidine is a drug of great therapeutic significance in Pneumocystis jiroveci pneumonia (PJP) prophylaxis and therapy. Pharmacokinetic properties of these cationic species such as transport, acid/base equilibria, and interactions with potential target molecules are still of interest, especially for recently designed compounds. To broaden our knowledge drug-likeness, human serum albumin binding, and acidity constants (K) were experimentally and theoretically examined for five pentamidine analogues 1 - 5 with -NH-CO-chain-CO-NH-bridges of increasing length and O, N, and S atoms in the chain. The studied analogues display very marked activity against Pneumocystis carinii without cytotoxicity that inspired us to perform an in silico analysis of their mode of action based on the hypothesis that the small DNA groove of rich in adenine-thymine pairs is their molecular target. These studies allowed us to classify them as very promising lead molecules.
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http://dx.doi.org/10.1016/j.ejps.2021.105779DOI Listing
June 2021

Relation of Metal-Binding Property and Selective Toxicity of 8-Hydroxyquinoline Derived Mannich Bases Targeting Multidrug Resistant Cancer Cells.

Cancers (Basel) 2021 Jan 5;13(1). Epub 2021 Jan 5.

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

Resistance to chemotherapeutic agents is a major obstacle in cancer treatment. A recently proposed strategy is to target the collateral sensitivity of multidrug resistant (MDR) cancer. Paradoxically, the toxicity of certain metal chelating agents is increased, rather than decreased, by the function of P-glycoprotein (Pgp), which is known to confer resistance by effluxing chemotherapeutic compounds from cancer cells. We have recently characterized and compared the solution's chemical properties including ligand protonation and the metal binding properties of a set of structurally related 8-hydroxyquinoline derived Mannich bases. Here we characterize the impact of the solution stability and redox activity of their iron(III) and copper(II) complexes on MDR-selective toxicity. Our results show that the MDR-selective anticancer activity of the studied 8-hydroxyquinoline derived Mannich bases is associated with the iron deprivation of MDR cells and the preferential formation of redox-active copper(II) complexes, which undergo intracellular redox-cycling to induce oxidative stress.
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http://dx.doi.org/10.3390/cancers13010154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7796460PMC
January 2021

Improving the Stability of EGFR Inhibitor Cobalt(III) Prodrugs.

Inorg Chem 2020 Dec 21;59(23):17794-17810. Epub 2020 Nov 21.

Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Waehringer Straße 42, 1090 Vienna, Austria.

Although tyrosine kinase inhibitors (TKIs) have revolutionized cancer therapy in the past two decades, severe drawbacks such as strong adverse effects and drug resistance limit their clinical application. Prodrugs represent a valuable approach to overcoming these disadvantages by administration of an inactive drug with tumor-specific activation. We have recently shown that hypoxic prodrug activation is a promising strategy for a cobalt(III) complex bearing a TKI of the epidermal growth factor receptor (EGFR). The aim of this study was the optimization of the physicochemical properties and enhancement of the stability of this compound class. Therefore, we synthesized a series of novel derivatives to investigate the influence of the electron-donating properties of methyl substituents at the metal-chelating moiety of the EGFR inhibitor and/or the ancillary acetylacetonate (acac) ligand. To understand the effect of the different methylations on the redox properties, the newly synthesized complexes were analyzed by cyclic voltammetry and their behavior was studied in the presence of natural low-molecular weight reducing agents. Furthermore, it was proven that reduction to cobalt(II) resulted in a lower stability of the complexes and subsequent release of the coordinated TKI ligand. Moreover, the stability of the cobalt(III) prodrugs was investigated in blood serum as well as in cell culture by diverse cell and molecular biological methods. These analyses revealed that the complexes bearing the methylated acac ligand are characterized by distinctly enhanced stability. Finally, the cytotoxic activity of all new compounds was tested in cell culture under normoxic and various hypoxic conditions, and their prodrug nature could be correlated convincingly with the stability data. In summary, the performed chemical modifications resulted in new cobalt(III) prodrugs with strongly improved stabilities together with retained hypoxia-activatable properties.
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http://dx.doi.org/10.1021/acs.inorgchem.0c03083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7724630PMC
December 2020

Cancer Cell Resistance Against the Clinically Investigated Thiosemicarbazone COTI-2 Is Based on Formation of Intracellular Copper Complex Glutathione Adducts and ABCC1-Mediated Efflux.

J Med Chem 2020 11 15;63(22):13719-13732. Epub 2020 Nov 15.

Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Waehringer Strasse 42, Vienna 1090, Austria.

COTI-2 is a novel anticancer thiosemicarbazone in phase I clinical trial. However, the effects of metal complexation (a main characteristic of thiosemicarbazones) and acquired resistance mechanisms are widely unknown. Therefore, in this study, the copper and iron complexes of COTI-2 were synthesized and evaluated for their anticancer activity and impact on drug resistance in comparison to metal-free thiosemicarbazones. Investigations using Triapine-resistant SW480/Tria and newly established COTI-2-resistant SW480/Coti cells revealed distinct structure-activity relationships. SW480/Coti cells were found to overexpress ABCC1, and COTI-2 being a substrate for this efflux pump. This was unexpected, as ABCC1 has strong selectivity for glutathione adducts. The recognition by ABCC1 could be explained by the reduction kinetics of a ternary Cu-COTI-2 complex with glutathione. Thus, only thiosemicarbazones forming stable, nonreducible copper(II)-glutathione adducts are recognized and, in turn, effluxed by ABCC1. This reveals a crucial connection between copper complex chemistry, glutathione interaction, and the resistance profile of clinically relevant thiosemicarbazones.
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http://dx.doi.org/10.1021/acs.jmedchem.0c01277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7706001PMC
November 2020

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

Triapine Derivatives Act as Copper Delivery Vehicles to Induce Deadly Metal Overload in Cancer Cells.

Biomolecules 2020 09 19;10(9). Epub 2020 Sep 19.

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

Thiosemicarbazones continue to attract the interest of researchers as potential anticancer drugs. For example, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone, or triapine, is the most well-known representative of this class of compounds that has entered multiple phase I and II clinical trials. Two new triapine derivatives and were prepared by condensation reactions of 2-pyridinamidrazone and S-methylisothiosemicarbazidium chloride with 3--(-butyloxycarbonyl) amino-pyridine-2-carboxaldehyde, followed by a Boc-deprotection procedure. Subsequent reaction of and with CuCl·2HO in 1:1 molar ratio in methanol produced the complexes () and (). The reaction of with Fe(NO)∙9HO in 2:1 molar ratio in the presence of triethylamine afforded the complex (), in which the isothiosemicarbazone acts as a tridentate monoanionic ligand. The crystal structures of , and metal complexes and were determined by single crystal X-ray diffraction. The UV-Vis and EPR spectroelectrochemical measurements revealed that complexes and underwent irreversible reduction of Cu(II) with subsequent ligand release, while showed an almost reversible electrochemical reduction in dimethyl sulfoxide (DMSO). Aqueous solution behaviour of and as well as of and its complex , was monitored as well. Complexes - were tested against ovarian carcinoma cells, as well as noncancerous embryonic kidney cells, in comparison to respective free ligands, triapine and cisplatin. While the free ligands and were devoid of antiproliferative activity, their respective metal complexes showed remarkable antiproliferative activity in a micromolar concentration range. The activity was not related to the inhibition of ribonucleotide reductase (RNR) R2 protein, but rather to cancer cell homeostasis disturbance-leading to the disruption of cancer cell signalling.
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http://dx.doi.org/10.3390/biom10091336DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564244PMC
September 2020

Insight into the Anticancer Activity of Copper(II) 5-Methylenetrimethylammonium-Thiosemicarbazonates and Their Interaction with Organic Cation Transporters.

Biomolecules 2020 08 20;10(9). Epub 2020 Aug 20.

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

A series of four water-soluble salicylaldehyde thiosemicarbazones with a positively charged trimethylammonium moiety ([HL]Cl, R = H, Me, Et, Ph) and four copper(II) complexes [Cu(HL)Cl]Cl (-) were synthesised with the aim to study (i) their antiproliferative activity in cancer cells and, (ii) for the first time for thiosemicarbazones, the interaction with membrane transport proteins, specifically organic cation transporters OCT1-3. The compounds were comprehensively characterised by analytical, spectroscopic and X-ray diffraction methods. The highest cytotoxic effect was observed in the neuroblastoma cell line SH-5YSY after 24 h exposure and follows the rank order: > > > > >>[HL]Cl. The copper(II) complexes showed marked interaction with OCT1-3, comparable to that of well-known OCT inhibitors (decynium 22, prazosin and corticosterone) in the cell-based radiotracer uptake assays. The work paves the way for the development of more potent and selective anticancer drugs and/or OCT inhibitors.
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http://dx.doi.org/10.3390/biom10091213DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7565988PMC
August 2020

An 8-hydroxyquinoline-proline hybrid with multidrug resistance reversal activity and the solution chemistry of its half-sandwich organometallic Ru and Rh complexes.

Dalton Trans 2020 Jun 5;49(23):7977-7992. Epub 2020 Jun 5.

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

Herein the design and synthesis of a new 8-hydroxyquinoline derivative, (S)-5-chloro-7-((proline-1-yl)methyl)8-hydroxyquinoline (HQCl-Pro), with good water solubility and multidrug resistance reversal activity are reported. In this work the proton dissociation processes of HQCl-Pro and its complex formation with [Rh(η-CMe)(HO)], [Ru(η-p-cymene)(HO)] and [Ru(η-toluene)(HO)] were investigated by the combined use of pH-potentiometry, UV-visible spectrometry and H NMR spectroscopy. Our results revealed the prominent solution stability of the complexes in all cases. The lipophilicity of the complexes increased with the chloride ion concentration, and the complexes showed moderate log D values (-0.8 to +0.4) at pH 7.4 at all tested Cl concentrations. The formation of mixed hydroxido complexes from the aqua complexes was characterized by relatively high pK values (8.45-9.62 in chloride-free medium). Complexation processes are much slower with the Ru(η-arene) triaqua cations than with [Rh(η-CMe)(HO)]. Both the pK values and HO/Cl exchange constants of the Ru-complexes are lower by 0.5-1.0 orders of magnitude than those of the Rh analogue. Arene loss (p-cymene and toluene) and oxidation were found in the case of Ru-complexes when an excess of HQCl-Pro and aromatic (N,N) bidentate ligands was added. The cytotoxicity and antiproliferative effect of HQCl-Pro and its complexes were assayed in vitro. In contrast to the structurally familiar 8-hydroxyquinoline, HQCl-Pro and its Rh(η-CMe) complex were somewhat more effective against drug resistant Colo 320 adenocarcinoma human cells compared to the drug sensitive Colo 205 cells. The Ru- and Rh-complexes showed a similar metal uptake level after 4 h, while a longer incubation time resulted in higher cellular Rh concentration.
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http://dx.doi.org/10.1039/d0dt01256dDOI Listing
June 2020

Synthesis and characterisation of Co(iii) complexes of N-formyl hydroxylamines and antibacterial activity of a Co(iii) peptide deformylase inhibitor complex.

Dalton Trans 2020 Jun;49(21):6980-6988

Department of Chemistry, Royal College of Surgeons in Ireland, 123 St. Stephens Green, Dublin 2, Ireland. and SSPC, Synthesis and Solid State Pharmaceutical Centre, Ireland.

The X-ray crystal structure and pKa values of GSK322, a well-known and effective peptide deformylase inhibitor and antibacterial drug candidate, are reported. The first examples of Co(iii) complexes of N-formyl hydroxylamines are reported. Reaction of N-hydroxy-N-phenylformamide (HFA) with [Co(tren)Cl2]Cl and [Co(tpa)Cl2]Cl (where tren = tris(2-aminoethyl)amine, tpa = tris(2-pyridylmethyl)amine) with one equivalent of NaOH in H2O afforded [Co(tren)(HFA-1H)](PF6)1.5Cl0.5 (1) and [Co(tpa)(HFA-1H)]Cl2 (2), respectively. X-ray crystal structures of both complexes revealed that the N-formyl hydroxylamine group acts as a bidentate ligand, coordinating the Co(iii) centres via the carbonyl oxygen and deprotonated hydroxy group (O,O'), a coordination mode typically observed for closely related mono-deprotonated hydroxamic acids. Reaction of the N-formyl hydroxylamine-based GSK322 with [Co(tpa)Cl2]Cl afforded the corresponding Co(iii) chaperone complex of the peptide deformylase inhibitor, [Co(tpa)(GSK322-1H)](PF6)2. GSK322 and [Co(tpa)(GSK322-1H)](PF6)2 exhibited better Gram-positive activity than Gram-negative, where low MICs (1.56-6.25 μM) were determined for S. aureus strains, independent of their antibiotic susceptibility.
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http://dx.doi.org/10.1039/d0dt01123aDOI Listing
June 2020

High Copper Complex Stability and Slow Reduction Kinetics as Key Parameters for Improved Activity, Paraptosis Induction, and Impact on Drug-Resistant Cells of Anticancer Thiosemicarbazones.

Antioxid Redox Signal 2020 08 9;33(6):395-414. Epub 2020 Jun 9.

Institute of Cancer Research, Medical University of Vienna, Vienna, Austria.

Due to their significant biological activity, thiosemicarbazones (TSCs) are promising candidates for anticancer therapy. In part, the efficacy of TSCs is linked to their ability to chelate essential metal ions such as copper and iron. Triapine, the best-studied anticancer TSC, has been tested clinically with promising results in hematological diseases. During the past few years, a novel subclass of TSCs with improved anticancer activity was found to induce paraptosis, a recently characterized form of cell death. The aim of this study was to identify structural and chemical properties associated with anticancer activity and paraptosis induction of TSCs. When testing a panel of structurally related TSCs, compounds with nanomolar anticancer activity and paraptosis-inducing properties showed higher copper(II) complex solution stability and a slower reduction rate, which resulted in reduced redox activity. In contrast, TSCs with lower anticancer activity induced higher levels of superoxide that rapidly stimulated superoxide dismutase expression in treated cells, effectively protecting the cells from drug-induced redox stress. Consequently, we hypothesize that in the case of close Triapine derivatives, intracellular reduction leads to rapid dissociation of intracellularly formed copper complexes. In contrast, TSCs characterized by highly stable, slowly reducible copper(II) complexes are able to reach new intracellular targets such as the endoplasmic reticulum-resident protein disulfide isomerase. The additional modes of actions observed with highly active TSC derivatives are based on intracellular formation of stable copper complexes, offering a new approach to combat (drug-resistant) cancer cells.
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http://dx.doi.org/10.1089/ars.2019.7854DOI Listing
August 2020

A Maltol-Containing Ruthenium Polypyridyl Complex as a Potential Anticancer Agent.

Chemistry 2020 Apr 26;26(22):4997-5009. Epub 2020 Mar 26.

Chimie ParisTech, PSL University, CNRS, Institute of Chemistry for Life and Health Sciences, Laboratory for Inorganic Chemical Biology, 75005, Paris, France.

Cancer is one of the main causes of death worldwide. Chemotherapy, despite its severe side effects, is to date one of the leading strategies against cancer. Metal-based drugs present several potential advantages when compared to organic compounds and they have gained trust from the scientific community after the approval on the market of the drug cisplatin. Recently, we reported the ruthenium complex ([Ru(DIP) (sq)](PF ) (where DIP is 4,7-diphenyl-1,10-phenantroline and sq is semiquinonate) with a remarkable potential as chemotherapeutic agent against cancer, both in vitro and in vivo. In this work, we analyse a structurally similar compound, namely [Ru(DIP) (mal)](PF ), carrying the flavour-enhancing agent approved by the FDA, maltol (mal). To possess an FDA approved ligand is crucial for a complex, whose mechanism of action might include ligand exchange. Herein, we describe the synthesis and characterisation of [Ru(DIP) (mal)](PF ), its stability in solutions and under conditions that resemble the physiological ones, and its in-depth biological investigation. Cytotoxicity tests on different cell lines in 2D model and on HeLa MultiCellular Tumour Spheroids (MCTS) demonstrated that our compound has higher activity than cisplatin, inspiring further tests. [Ru(DIP) (mal)](PF ) was efficiently internalised by HeLa cells through a passive transport mechanism and severely affected the mitochondrial metabolism.
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http://dx.doi.org/10.1002/chem.201904877DOI Listing
April 2020

Synthesis, characterization and albumin binding capabilities of quinizarin containing ternary cobalt(III) complexes.

J Inorg Biochem 2020 03 17;204:110963. Epub 2019 Dec 17.

Department of Inorganic and Analytical Chemistry, University of Debrecen, Egyetem tér 1, H-4032 Debrecen, Hungary. Electronic address:

Four Co(III) ternary complexes with the composition of [(Co(4 N))(quin)](ClO) or [(Co(4 N))(quinS)](ClO), where 4 N = tris(2-aminoethyl)amine (tren) or tris(2-pyridylmethyl)amine (tpa), quinH = quinizarin (1,4-dihydroxy-9,10-anthraquinone), quinSH = quinizarin-2-sulfonic acid (1,4-dihydroxy-9,10-anthraquinone-2-sulfonic acid), were synthesized, characterized and their human serum albumin (HSA) binding capabilities were also tested. The complexes can be considered as likely chaperons of quinizarins which are structural models for anthracycline-based anticancer drugs like doxorubicin. All the Co(III) complexes are dinuclear and were isolated as mixture of isomers. Comparison of the cyclic voltammograms of the free ligands and the appropriate Co(III) complexes revealed that the new signals belonging to reversible processes in the range -400-0 mV (vs. Ag/AgCl) for the complexes can be attributed to the reversible reduction of the Co(III) centre. These potentials are in the range of typical (O,O) chelated Co(III) ternary complexes bearing 4 N donor ligands and follow the order being more positive for the tpa containing complexes. Presence of the sulfonate group in the quinizarin results in slightly more negative reduction potential of the Co(III) complexes. HSA binding capabilities of the quinH and quinSH ligands as well as the appropriate complexes showed that quinSH has higher affinity to the protein than quinH while none of the complexes seem to bind to HSA.
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http://dx.doi.org/10.1016/j.jinorgbio.2019.110963DOI Listing
March 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

Binding mechanisms of half-sandwich Rh(III) and Ru(II) arene complexes on human serum albumin: a comparative study.

J Biol Inorg Chem 2019 08 12;24(5):703-719. Epub 2019 Jul 12.

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

Various half-sandwich ruthenium(II) arene complexes and rhodium(III) arene complexes have been intensively investigated due to their prominent anticancer activity. The interaction of the organometallic complexes of Ru(η-p-cymene) and Rh(η-CMe) with human serum albumin (HSA) was studied in detail by a combination of various methods such as ultrafiltration, capillary electrophoresis, H NMR spectroscopy, fluorometry and UV-visible spectrophotometry in the presence of 100 mM chloride ions. Binding characteristics of the organometallic ions and their complexes with deferiprone, 2-picolinic acid, maltol, 6-methyl-2-picolinic acid and 2-quinaldic acid were evaluated. Kinetic aspects and reversibility of the albumin binding are also discussed. The effect of low-molecular-mass blood components on the protein binding was studied in addition to the interaction of organorhodium complexes with cell culture medium components. The organometallic ions were found to bind to HSA to a high extent via a coordination bond. Release of the bound metal ions was kinetically hindered and could not be induced by the denaturation of the protein. Binding of the Ru(η-p-cymene) triaqua cation was much slower (ca. 24 h) compared to the rhodium congener (few min), while their complexes interacted with the protein relatively fast (1-2 h). The studied complexes were bound to HSA coordinatively. The highly stable and kinetically inert 2-picolinate Ru(η-p-cymene) complex bound in an associative manner preserving its original entity, while lower stability complexes decomposed partly or completely upon binding to HSA. Fast, non-specific and high-affinity binding of the complexes on HSA highlights their coordinative interaction with various types of proteins possibly decreasing effective drug concentration.
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http://dx.doi.org/10.1007/s00775-019-01683-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6682546PMC
August 2019

Novel latonduine derived proligands and their copper(ii) complexes show cytotoxicity in the nanomolar range in human colon adenocarcinoma cells and in vitro cancer selectivity.

Dalton Trans 2019 Jul;48(28):10464-10478

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

Four Schiff bases derived from 7-hydrazin-yl-5,8-dihydroindolo[2,3-d][2]benzazepin-(6H)-one and its bromo-substituted analogue (HL1-HL4) and four copper(ii) complexes 1-4 have been synthesised and fully characterised by standard spectroscopic methods (1H and 13C NMR, UV-vis), ESI mass spectrometry, single crystal X-ray diffraction and spectroelectrochemistry. In addition, two previously reported complexes with paullone ligands 5 and 6 were prepared and studied for comparison reasons. The CuII ion in 1-4 is five-coordinate and adopts a square-pyramidal or slightly distorted square-pyramidal coordination geometry. The ligands HL1-4 act as tridentate, the other two coordination places are occupied by two chlorido co-ligands. The organic ligands in 2 and 3 are bound tighter to copper(ii) when compared to related paullone ligands in 5 and 6. The new compounds show very strong cytotoxic activity against human colon adenocarcinoma doxorubicin-sensitive Colo 205 and multidrug resistant Colo 320 cancer cell lines with IC50 values in the low micromolar to nanomolar concentration range.
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http://dx.doi.org/10.1039/c9dt01238aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6635014PMC
July 2019

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

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

Evaluation of blood-brain barrier penetration and examination of binding to human serum albumin of 7-O-arylpiperazinylcoumarins as potential antipsychotic agents.

Bioorg Chem 2019 03 22;84:211-225. Epub 2018 Nov 22.

Department of Organic Chemistry, Faculty of Pharmacy, Medical University of Warsaw, Banacha 1, 02-097 Warsaw, Poland. Electronic address:

The delivery of drugs to the brain is complicated by the multiple factors including low blood-brain barrier (BBB) passive permeability, active BBB efflux systems, and plasma protein binding. Thus, a detailed understanding of the transport of the new potent substances through the membranes is vitally important and their physico-chemical characteristics should be analyzed at first. This work presents an evaluation of drug likeness of eight 7-O-arylpiperazinylcoumarin derivatives with high affinity towards serotoninergic receptors 5-HT and 5-HT with particular analysis of the requirements for the CNS chemotherapeutics. The binding constants to human serum albumin (HSA) were determined at physiological pH using fluorescence spectroscopy, and then their mode of action was explained by analysis of theoretical HSA complexes. Dynamic simulation of systems allowed for reliable evaluation of the interaction strength. The analyzed coumarins were able to pass BBB, and they present good drug likeness properties. They showed high affinities to HSA (log K = 5.3-6.0 which corresponds to -8.12 to -7.15 kcalmol of Gibbs free energy). The changes of the emission intensity upon binding to HSA were scrutinized showing the different mode of action for 4-phenylpiperazinylcoumarins. The values of computed Gibbs free energy and determined on the basis of experimentally obtained binding constants log K coincide suggesting a good quality of the theoretical model. Overall the 8-acetyl-7-O-arylpiperazinyl-4-methylcoumarin derivatives represent valuable lead compounds to be further tested in various preclinical assays as a possible chemotherapeutics against CNS diseases. Studied coumarins can be metabolized by cytochrome P450 to aldehydes and hydroxy derivatives. The existence of other binding sites inside HSA than Sudlow's site 1 was postulated. The longer aliphatic linker between coumarin and piperazine moieties favored binding to HSA in other than Sudlow site 1 pocket.
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http://dx.doi.org/10.1016/j.bioorg.2018.11.034DOI Listing
March 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

Synthesis and biological evaluation of biotin-conjugated anticancer thiosemicarbazones and their iron(III) and copper(II) complexes.

J Inorg Biochem 2019 01 19;190:85-97. Epub 2018 Oct 19.

Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Waehringer Str. 42, A-1090 Vienna, Austria; Research Cluster "Translational Cancer Therapy Research", Vienna, Austria.

Triapine, the most prominent anticancer drug candidate from the substance class of thiosemicarbazones, was investigated in >30 clinical phase I and II studies. However, the results were rather disappointing against solid tumors, which can be explained (at least partially) due to inefficient delivery to the tumor site. Hence, we synthesized the first biotin-functionalized thiosemicarbazone derivatives in order to increase tumor specificity and accumulation. Additionally, for Triapine and one biotin conjugate the iron(III) and copper(II) complexes were prepared. Subsequently, the novel compounds were biologically evaluated on a cell line panel with different biotin uptake. The metal-free biotin-conjugated ligands showed comparable activity to the reference compound Triapine. However, astonishingly, the metal complexes of the biotinylated derivative showed strikingly decreased anticancer activity. To further analyze possible differences between the metal complexes, detailed physico- and electrochemical experiments were performed. However, neither lipophilicity or complex solution stability, nor the reduction potential or behavior in the presence of biologically relevant reducing agents showed strong variations between the biotinylated and non-biotinylated derivatives (only some differences in the reduction kinetics were observed). Nonetheless, the metal-free biotin-conjugate of Triapine revealed distinct activity in a colon cancer mouse model upon oral application comparable to Triapine. Therefore, this type of biotin-conjugated thiosemicarbazone is of interest for further synthetic strategies and biological studies.
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http://dx.doi.org/10.1016/j.jinorgbio.2018.10.006DOI Listing
January 2019

NO Releasing and Anticancer Properties of Octahedral Ruthenium-Nitrosyl Complexes with Equatorial 1 H-Indazole Ligands.

Inorg Chem 2018 Sep 14;57(17):10702-10717. Epub 2018 Aug 14.

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

With the aim of enhancing the biological activity of ruthenium-nitrosyl complexes, new compounds with four equatorially bound indazole ligands, namely, trans-[RuCl(Hind)(NO)]Cl·HO ([3]Cl·HO) and trans-[RuOH(Hind)(NO)]Cl·HO ([4]Cl·HO), have been prepared from trans-[Ru(NO)(Hind)] ([2]). When the pH-dependent solution behavior of [3]Cl·HO and [4]Cl·HO was studied, two new complexes with two deprotonated indazole ligands were isolated, namely [RuCl(ind)(Hind)(NO)] ([5]) and [RuOH(ind)(Hind)(NO)] ([6]). All prepared compounds were comprehensively characterized by spectroscopic (IR, UV-vis, H NMR) techniques. Compound [2], as well as [3]Cl·2(CH)CO, [4]Cl·2(CH)CO, and [5]·0.8CHCl, the latter three obtained by recrystallization of the first isolated compounds (hydrates or anhydrous species) from acetone and dichloromethane, respectively, were studied by X-ray diffraction methods. The photoinduced release of NO in [3]Cl and [4]Cl was investigated by cyclic voltammetry and resulting paramagnetic NO species were detected by EPR spectroscopy. The quantum yields of NO release were calculated and found to be low (3-6%), which could be explained by NO dissociation and recombination dynamics, assessed by femtosecond pump-probe spectroscopy. The geometry and electronic parameters of Ru species formed upon NO release were identified by DFT calculations. The complexes [3]Cl and [4]Cl showed considerable antiproliferative activity in human cancer cell lines with IC values in low micromolar or submicromolar concentration range and are suitable for further development as potential anticancer drugs. p53-dependence of Ru-NO complexes [3]Cl and [4]Cl was studied and p53-independent mode of action was confirmed. The effects of NO release on the cytotoxicity of the complexes with or without light irradiation were investigated using NO scavenger carboxy-PTIO.
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http://dx.doi.org/10.1021/acs.inorgchem.8b01341DOI Listing
September 2018

Comparative studies on the human serum albumin binding of the clinically approved EGFR inhibitors gefitinib, erlotinib, afatinib, osimertinib and the investigational inhibitor KP2187.

J Pharm Biomed Anal 2018 May 11;154:321-331. Epub 2018 Mar 11.

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

Binding interactions between human serum albumin (HSA) and four approved epidermal growth factor receptor (EGFR) inhibitors gefitinib (GEF), erlotinib (ERL), afatinib (AFA), osimertinib (OSI), as well as the experimental drug KP2187, were investigated by means of spectrofluorometric and molecular modelling methods. Steady-state and time resolved spectrofluorometric techniques were carried out, including direct quenching of protein fluorescence and site marker displacement measurements. Proton dissociation processes and solvent dependent fluorescence properties were investigated as well. The EGFR inhibitors were predominantly presented in their single protonated form (HL) at physiological pH except ERL, which is charge-neutral. Significant solvent dependent fluorescence properties were found for GEF, ERL and KP2187, namely their emission spectra show strong dependence on the polarity and the hydrogen bonding ability of the solvents. The inhibitors proved to be bound at site I of HSA (in subdomain IIA) in a weak-to-moderate fashion (logK' 3.9-4.9) using spectrofluorometry. OSI (logK' 4.3) and KP2187 can additionally bind in site II (in subdomain IIIA), while GEF, ERL and AFA clearly show no interaction here. Docking methods qualitatively confirmed binding site preferences of compounds GEF and KP2187, and indicated that they probably bind to HSA in their neutral forms. Binding constants calculated on the basis of the various experimental data indicate a weak-to-moderate binding on HSA, only OSI exhibits somewhat higher affinity towards this protein. However, model calculations performed at physiological blood concentrations of HSA resulted in high (ca. 90%) bound fractions for the inhibitors, highlighting the importance of plasma protein binding.
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http://dx.doi.org/10.1016/j.jpba.2018.03.011DOI Listing
May 2018

Speciation of Metal Complexes of Medicinal Interest: Relationship between Solution Equilibria and Pharmaceutical Properties.

Curr Med Chem 2019 ;26(4):580-606

Department of Inorganic and Analytical Chemistry, University of Szeged, Dom ter 7, H-6720 Szeged, Hungary.

Biospeciation of essential and toxic metal ions, metal complexes with biological or medicinal activity are discussed in the paper in order to emphasize the importance of the distribution of metal ions in biological milieu. The exact knowledge of the chemical species present in the different organs/compartments/fluids/cells may provide essential information about the pharmacokinetic properties and the biological effect of the metal ion or the drug candidate metal complex. The transport of essential and toxic metal ions in the blood serum is discussed first, which is followed by the description of biodistribution of several important metal complexes with medicinal interest such as (i) anticancer, (ii) insulin-enhancing and (iii) MRI contrast agents in biological fluids.
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http://dx.doi.org/10.2174/0929867325666180307113435DOI Listing
November 2019
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