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Article ; Online: Evaluation of In Vitro Distribution and Plasma Protein Binding of Selected Antiviral Drugs (Favipiravir, Molnupiravir and Imatinib) against SARS-CoV-2

Orsolya Dömötör / Éva A. Enyedy

International Journal of Molecular Sciences, Vol 24, Iss 2849, p

2023 Volume 2849

Abstract: There are a number of uncertainties regarding plasma protein binding and blood distribution of the active drugs favipiravir (FAVI), molnupiravir (MOLNU) and imatinib (IMA), which were recently proposed as therapeutics for the treatment of COVID-19 ... ...

Abstract	There are a number of uncertainties regarding plasma protein binding and blood distribution of the active drugs favipiravir (FAVI), molnupiravir (MOLNU) and imatinib (IMA), which were recently proposed as therapeutics for the treatment of COVID-19 disease. Therefore, proton dissociation processes, solubility, lipophilicity, and serum protein binding of these three substances were investigated in detail. The drugs display various degrees of lipophilicity at gastric (pH 2.0) and blood pH (pH 7.4). The determined p K a values explain well the changes in lipophilic character of the respective compounds. The serum protein binding was studied by membrane ultrafiltration, frontal analysis capillary electrophoresis, steady-state fluorometry, and fluorescence anisotropy techniques. The studies revealed that the ester bond in MOLNU is hydrolyzed by protein constituents of blood serum. Molnupiravir and its hydrolyzed form do not bind considerably to blood proteins. Likewise, FAVI does not bind to human serum albumin (HSA) and α1-acid glycoprotein (AGP) and shows relatively weak binding to the protein fraction of whole blood serum. Imatinib binds to AGP with high affinity (log K ′ = 5.8–6.0), while its binding to HSA is much weaker (log K ′ ≤ 4.0). The computed constants were used to model the distribution of IMA in blood plasma under physiological and ‘acute-phase’ conditions as well.
Keywords	tyrosine kinase inhibitor ; COVID-19 ; proton dissociation ; lipophilicity ; plasma protein binding ; binding constants ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	500
Language	English
Publishing date	2023-02-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Binding Models of Copper(II) Thiosemicarbazone Complexes with Human Serum Albumin

Nóra V. May / Attila Jancsó / Éva A. Enyedy

Molecules, Vol 26, Iss 2711, p

A Speciation Study

2021 Volume 2711

Abstract: 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- N - ... ...

Abstract	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- N -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.
Keywords	peptide model ; albumin binding ; EPR spectroscopy ; ternary complexes ; Organic chemistry ; QD241-441
Subject code	540
Language	English
Publishing date	2021-05-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Solution Equilibrium Studies on Salicylidene Aminoguanidine Schiff Base Metal Complexes

Orsolya Dömötör / Nóra V. May / G. Tamás Gál / Gabriella Spengler / Aliona Dobrova / Vladimir B. Arion / Éva A. Enyedy

Molecules, Vol 27, Iss 2044, p

Impact of the Hybridization with L-Proline on Stability, Redox Activity and Cytotoxicity

2022 Volume 2044

Abstract: The proton dissociation processes of two tridentate salicylidene aminoguanidine Schiff bases (SISC, Pro-SISC-Me), the solution stability and electrochemical properties of their Cu(II), Fe(II) and Fe(III) complexes were characterized using pH- ... ...

Abstract	The proton dissociation processes of two tridentate salicylidene aminoguanidine Schiff bases (SISC, Pro-SISC-Me), the solution stability and electrochemical properties of their Cu(II), Fe(II) and Fe(III) complexes were characterized using pH-potentiometry, cyclic voltammetry and UV-visible, 1 H NMR and electron paramagnetic resonance spectroscopic methods. The structure of the proline derivative (Pro-SISC-Me) was determined by X-ray crystallography. The conjugation of L-proline to the simplest salicylidene aminoguanidine Schiff base (SISC) increased the water solubility due to its zwitterionic structure in a wide pH range. The formation of mono complexes with both ligands was found in the case of Cu(II) and Fe(II), while bis complexes were also formed with Fe(III). In the complexes these tridentate ligands coordinate via the phenolato O, azomethine N and the amidine N, except the complex [Fe(III)L 2 ] + of Pro-SISC-Me in which the (O,N) donor atoms of the proline moiety are coordinated beside the phenolato O, confirmed by single crystal X-ray crystallographic analysis. This binding mode yielded a stronger Fe(III) preference for Pro-SISC-Me over Fe(II) in comparison to SISC. This finding is also reflected in the lower redox potential value of the iron-Pro-SISC-Me complexes. The ligands alone were not cytotoxic against human colon cancer cell lines, while complexation of SISC with Cu(II) resulted in moderate activity, unlike the case of its more hydrophilic counterpart.
Keywords	stability constants ; aminoguanidine ; EPR spectroscopy ; anticancer ; thiosemicarbazone ; Organic chemistry ; QD241-441
Subject code	500 ; 540
Language	English
Publishing date	2022-03-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: 8-Hydroxyquinoline-Amino Acid Hybrids and Their Half-Sandwich Rh and Ru Complexes

Tamás Pivarcsik / Orsolya Dömötör / János P. Mészáros / Nóra V. May / Gabriella Spengler / Oszkár Csuvik / István Szatmári / Éva A. Enyedy

International Journal of Molecular Sciences, Vol 22, Iss 11281, p

Synthesis, Anticancer Activities, Solution Chemistry and Interaction with Biomolecules

2021 Volume 11281

Abstract: Solution chemical properties of two novel 8-hydroxyquinoline-D-proline and homo-proline hybrids were investigated along with their complex formation with [Rh(η 5 -C 5 Me 5 )(H 2 O) 3 ] 2+ and [Ru(η 6 - p -cymene)(H 2 O) 3 ] 2+ ions by pH-potentiometry, ... ...

Abstract	Solution chemical properties of two novel 8-hydroxyquinoline-D-proline and homo-proline hybrids were investigated along with their complex formation with [Rh(η 5 -C 5 Me 5 )(H 2 O) 3 ] 2+ and [Ru(η 6 - p -cymene)(H 2 O) 3 ] 2+ ions by pH-potentiometry, UV-visible spectrophotometry and 1 H NMR spectroscopy. Due to the zwitterionic structure of the ligands, they possess excellent water solubility as well as their complexes. The complexes exhibit high solution stability in a wide pH range; no significant dissociation occurs at physiological pH. The hybrids and their Rh(η 5 -C 5 Me 5 ) complexes displayed enhanced cytotoxicity in human colon adenocarcinoma cell lines and exhibited multidrug resistance selectivity. In addition, the Rh(η 5 -C 5 Me 5 ) complexes showed increased selectivity to the chemosensitive cancer cells over the normal cells; meanwhile, the Ru(η 6 - p -cymene) complexes were inactive, most likely due to arene loss. Interaction of the complexes with human serum albumin (HSA) and calf-thymus DNA (ct-DNA) was investigated by capillary electrophoresis, fluorometry and circular dichroism. The complexes are able to bind strongly to HSA and ct-DNA, but DNA cleavage was not observed. Changing the five-membered proline ring to the six-membered homoproline resulted in increased lipophilicity and cytotoxicity of the Rh(η 5 -C 5 Me 5 ) complexes while changing the configuration (L vs. D) rather has an impact on HSA or ct-DNA binding.
Keywords	multidrug resistance ; solution speciation ; cytotoxicity ; organometallic ; DNA binding ; albumin binding ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	333
Language	English
Publishing date	2021-10-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Comparison of Solution Chemical Properties and Biological Activity of Ruthenium Complexes of Selected β -Diketone, 8-Hydroxyquinoline and Pyrithione Ligands

Tamás Pivarcsik / Gábor Tóth / Nikoletta Szemerédi / Anita Bogdanov / Gabriella Spengler / Jakob Kljun / Jerneja Kladnik / Iztok Turel / Éva A. Enyedy

Pharmaceuticals, Vol 14, Iss 518, p

2021 Volume 518

Abstract: 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 6 - p -cymene)(X,Y)(Z)] were prepared, ...

Abstract	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 6 - p -cymene)(X,Y)(Z)] were prepared, where (X,Y) represents either an O , O -ligand ( β -diketone), N , O -ligand (8-hydroxyquinoline) or O , S -pyrithione-type ligands (pyrithione = 1-hydroxypyridine-2(1 H )-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 N , O - and O , S -ligands displayed strong antibacterial activity on Gram-positive strains including the resistant S. aureus (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 β -diketone complexes can be related to their lower stability in solution. In contrast, the O , S -pyrithione-type complexes are highly stable in solution and the complexation prevents the oxidation of the O , S -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.
Keywords	MTT assay ; UV-vis ; solution stability ; MRSA ; albumin binding ; ligand effect ; Medicine ; R ; Pharmacy and materia medica ; RS1-441
Subject code	540
Language	English
Publishing date	2021-05-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Metal Complexes of a 5-Nitro-8-Hydroxyquinoline-Proline Hybrid with Enhanced Water Solubility Targeting Multidrug Resistant Cancer Cells

Tamás Pivarcsik / Vivien Pósa / Hilda Kovács / Nóra V. May / Gabriella Spengler / Szonja P. Pósa / Szilárd Tóth / Zeinab Nezafat Yazdi / Csilla Özvegy-Laczka / Imre Ugrai / István Szatmári / Gergely Szakács / Éva A. Enyedy

International Journal of Molecular Sciences, Vol 24, Iss 1, p

2022 Volume 593

Abstract: Multidrug resistance (MDR) in cancer is one of the major obstacles of chemotherapy. We have recently identified a series of 8-hydroxyquinoline Mannich base derivatives with MDR-selective toxicity, however with limited solubility. In this work, a novel 5- ... ...

Abstract	Multidrug resistance (MDR) in cancer is one of the major obstacles of chemotherapy. We have recently identified a series of 8-hydroxyquinoline Mannich base derivatives with MDR-selective toxicity, however with limited solubility. In this work, a novel 5-nitro-8-hydroxyquinoline-proline hybrid and its Rh(η 5 -C 5 Me 5 ) and Ru(η 6 - p -cymene) complexes with excellent aqueous solubility were developed, characterized, and tested against sensitive and MDR cells. Complex formation of the ligand with essential metal ions was also investigated using UV-visible, circular dichroism, 1 H NMR (Zn(II)), and electron paramagnetic resonance (Cu(II)) spectroscopic methods. Formation of mono and bis complexes was found in all cases with versatile coordination modes, while tris complexes were also formed with Fe(II) and Fe(III) ions, revealing the metal binding affinity of the ligand at pH 7.4: Cu(II) > Zn(II) > Fe(II) > Fe(III). The ligand and its Rh(III) complex displayed enhanced cytotoxicity against the resistant MES-SA/Dx5 and Colo320 human cancer cell lines compared to their chemosensitive counterparts. Both organometallic complexes possess high stability in solution, however the Ru(II) complex has lower chloride ion affinity and slower ligand exchange processes, along with the readiness to lose the arene ring that is likely connected to its inactivity.
Keywords	speciation ; solution structure ; organometallic complexes ; cytotoxicity ; multidrug resistance ; 8-hydroxyquinoline ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	540
Language	English
Publishing date	2022-12-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Estradiol-Based Salicylaldehyde (Thio)Semicarbazones and Their Copper Complexes with Anticancer, Antibacterial and Antioxidant Activities

Tatsiana V. Petrasheuskaya / Ferenc Kovács / Nóra Igaz / Andrea Rónavári / Bálint Hajdu / Laura Bereczki / Nóra V. May / Gabriella Spengler / Béla Gyurcsik / Mónika Kiricsi / Éva Frank / Éva A. Enyedy

Molecules, Vol 28, Iss 1, p

2022 Volume 54

Abstract: A series of novel estradiol-based salicylaldehyde (thio)semicarbazones ((T)SCs) bearing (O,N,S) and (O,N,O) donor sets and their Cu(II) complexes were developed and characterized in detail by 1 H and ¹³C nuclear magnetic resonance spectroscopy, UV– ... ...

Abstract	A series of novel estradiol-based salicylaldehyde (thio)semicarbazones ((T)SCs) bearing (O,N,S) and (O,N,O) donor sets and their Cu(II) complexes were developed and characterized in detail by 1 H and ¹³C nuclear magnetic resonance spectroscopy, UV–visible and electron paramagnetic resonance spectroscopy, electrospray ionization mass spectrometry and elemental analysis. The structure of the Cu(II)-estradiol-semicarbazone complex was revealed by X-ray crystallography. Proton dissociation constants of the ligands and stability constants of the metal complexes were determined in 30% ( v/v ) DMSO/H 2 O. Estradiol-(T)SCs form mono-ligand complexes with Cu(II) ions and exhibit high stability with the exception of estradiol-SC. The Cu(II) complexes of estradiol-TSC and its N,N -dimethyl derivative displayed the highest cytotoxicity among the tested compounds in MCF-7, MCF-7 KCR, DU-145, and A549 cancer cells. The complexes do not damage DNA according to both in vitro cell-free and cellular assays. All the Cu(II)-TSC complexes revealed significant activity against the Gram-positive Staphylococcus aureus bacteria strain. Estradiol-TSCs showed efficient antioxidant activity, which was decreased by complexation with Cu(II) ions. The exchange of estrone moiety to estradiol did not result in significant changes to physico-chemical and biological properties.
Keywords	estradiol hybrids ; (thio)semicarbazones ; cytotoxicity ; solution equilibrium ; EPR spectroscopy ; X-ray crystal structure ; Organic chemistry ; QD241-441
Subject code	540 ; 500
Language	English
Publishing date	2022-12-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Microwave-Assisted Synthesis, Proton Dissociation Processes, and Anticancer Evaluation of Novel D-Ring-Fused Steroidal 5-Amino-1-Arylpyrazoles

Gergő Mótyán / Ádám Baji / Małgorzata Anna Marć / Mohana Krishna Gopisetty / Dóra I. Adamecz / Mónika Kiricsi / Éva A. Enyedy / Éva Frank

Applied Sciences, Vol 10, Iss 1, p

2019 Volume 229

Abstract: Taking into account the pharmacological relevance of heterocycle-fused natural steroids, the objective of the current study was to develop a multistep reaction sequence for the efficient synthesis of novel D-ring-condensed 5-amino-1-arylpyrazoles from ... ...

Abstract	Taking into account the pharmacological relevance of heterocycle-fused natural steroids, the objective of the current study was to develop a multistep reaction sequence for the efficient synthesis of novel D-ring-condensed 5-amino-1-arylpyrazoles from dehydroepiandrosterone (DHEA). A condensation reaction of 16-formyl-DHEA with hydroxylamine afforded the corresponding oxime, which was demonstrated to be stable in one of its cyclic isoxazoline forms due to possible ring-chain tautomerism. The subsequent base-induced dehydration to a diastereomeric β-ketonitrile, followed by microwave-assisted heterocyclization with different arylhydrazines led to the desired pyrazoles. The generally good yields of the products depended slightly on the electronic character of the substituent present on the aromatic ring of the reagent. The proton dissociation processes of the DHEA-derived heterocycles were investigated in aqueous solution by UV-visible spectrophotometric titrations to reveal their actual chemical forms at physiological pH. The determined pK a values attributed to the pyrazole NH + moiety were low (1.8−4.0) and varied by the different substituents of the benzene ring. The antiproliferative effects of the structurally similar compounds were screened in vitro on human cancer cells (namely on HeLa, U2Os, MCF-7, PC-3, and A549), along with a noncancerous cell line (MRC-5). The IC 50 values of the most active derivative were determined on all cell lines.
Keywords	steroid ; heterocycles ; aminopyrazole ; microwave ; organic synthesis ; proton dissociation ; anticancer activity ; Technology ; T ; Engineering (General). Civil engineering (General) ; TA1-2040 ; Biology (General) ; QH301-705.5 ; Physics ; QC1-999 ; Chemistry ; QD1-999
Subject code	540
Language	English
Publishing date	2019-12-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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