Wydział Medyczny / Faculty of Medicine

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https://hdl.handle.net/20.500.12153/25
* Instytut Nauk Biologicznych * Instytut Nauk o Zdrowiu * Instytut Nauk Medycznych * Centrum Badań Eksperymentalnych

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Browsing Wydział Medyczny / Faculty of Medicine by Author "Demchuk, Oleg M."

Now showing 1 - 19 of 19
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    A clean and simple method for deprotection of phosphines from borane complexes
    (Walter de Gruyter, 2017) Demchuk, Oleg M.; Jasiński, Radomir; Strzelecka, Dorota; Dziuba, Kamil; Kula, Karolina; Chrzanowski, Jacek; Krasowska, Dorota
    Simple, efficient, clean, and stereospecific protocols of protection of phosphorus atom with borane and deprotection from the borane complexes of the tertiary phosphines in mild conditions are reported. The proposed protection/deprotection reactions tolerate a range of functional groups and lead to pure products with excellent yield with no need for application of chromatographic or crystallisation purification procedures. For the first time mechanisms of the reactions of phosphine protection and deprotection have been studied based on experimental kinetic data as well as quantumchemical calculations, which allows designing reaction conditions suitable for a given substrate.
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    A General Phenomenon of Spontaneous Amplification of Optical Purity under Achiral Chromatographic Conditions
    (MDPI, 2019) Demchuk, Oleg M.; Pietrusiewicz, Kazimierz Michał; Borkowski, Mariusz; Strzelecka, Dorota; Kielar, Katarzyna; Kicińska, Wioleta; Karevych, Sergei; Jasiński, Radomir
    This work explores the behavior of chiral compound mixtures enriched in one of the enantiomers whilst a typical chromatography on the achiral stationary phase is employed. The influence of several factors, such as the eluent composition, ratio of the compound to the stationary phase, and the initial enatiomeric purity of the compound used on the distribution of the enantiomers in the collected chromatographic fraction, was studied. The obtained results indicate that the phenomenon of Self Disproportionation of Enantiomer (SDE) occurred in all cases, and some of the collected fractions got higher optical purities than the initial one. Thus, achiral column chromatography could be applied in some cases as the simplest approach for chiral purification. Based on the experimental results and DFT calculations, an alternative concept explaining the SDE phenomenon was proposed. Due to its generality and simplicity, SDE may also be responsible for the formation of the first chiral non-racemic compounds on the early Earth.
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    A Quantum-Chemical DFT Approach to Elucidation of the Chirality Transfer Mechanism of the Enantioselective Suzuki–Miyaura Cross-Coupling Reaction
    (Hindawi, 2017) Demchuk, Oleg M.; Jasiński, Radomir; Babyuk, Dmytro
    The DFT calculations of the simplified model of the asymmetric Suzuki–Miyaura coupling reaction were performed at the M062x/LANL2DZ theory level at first. It was found that enantioselective reactions mediated by the palladium complexes of chiral C,P-ligands follow a four-stage mechanism similar to that proposed previously as one of the most credible mechanisms. It should be underlined that the presence of substituents in the substrates and the chiral ligand at ortho positions determines the energies of possible diastereoisomeric transition states and intermediates in initial reaction steps. This suggests that, in practice, a sharp selection of theoretically possible paths of chirality transfer from the catalyst to the product should have a place and, therefore, the absolute configuration of the formed atropisomeric product is defined and can be predicted.
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    A representative of arylcyanomethylenequinone oximes effectively inhibits growth and formation of hyphae in Candida albicans and influences the activity of protein kinases in vitro
    (Elsevier, 2018) Masłyk, Maciej; Janeczko, Monika; Demchuk, Oleg M.; Boguszewska-Czubara, Anna; Golczyk, Hieronim; Sierosławska, Anna; Rymuszka, Anna; Martyna, Aleksandra; Kubiński, Konrad
    In this study, we applied various assays to reveal new activities of phenylcyanomethylenequinone oxime-4-(hydroxyimino) cyclohexa-2,5-dien-1-ylidene](phenyl)ethanenitrile (4-AN) for potential anti-microbial applications. These assays demonstrated (a) the antimicrobial effect on bacterial and fungal cultures, (b) the effect on the in vitro activity of the kinase CK2, (c) toxicity towards human erythrocytes, the Caco-2 cancer cell line, and embryonic development of Zebrafish. We demonstrated the activity of 4-AN against selected bacteria and Candida spp. The MIC ranging from 4 µg/ml to 125 µg/ml proved effective in inhibition of formation of hyphae and cell aggregation in Candida, which was demonstrated at the cytological level. Noteworthy, 4-AN was found to inhibit the CK2 kinase with moderate potency. Moreover, at low concentrations, it did not exert any evident toxic effects on human erythrocytes, Caco-2 cells, or Zebrafish embryos. 4-AN can be a potential candidate as a novel drug against Candida infections.
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    A straightforward, environmentally benefcial synthesis of spiro[diindeno[1,2‑b:2′,1′‑e]py ridine‑11,3′‑indoline]‑2′,10,12‑tri ones mediated by a nano‑ordered reusable catalyst
    (Nature Research, 2021) Demchuk, Oleg M.; Fathi, Mahsa; Naimi-Jamal, M. Reza; Dekamin, Mohammad G.; Panahi, Leila
    A library of new spiro[diindeno[1,2-b:2′,1′-e]pyridine-11,3′-indoline]-2′,10,12-trione derivatives has been prepared in an efficient, one-pot pseudo four-component method mediated by a reusable heterogeneous nano-ordered mesoporous SO3H functionalized-silica (MCM-41-SO3H) catalyst. Excellent yields, short reaction times, as well as convenient non-chromatographic purification of the products and environmental benefits such as green and metal-free conditions constitute the main advantages of the developed synthetic methodology. The obtained fused indole-indenone dyes would be of interest to pharmaceutical and medicinal chemistry. Furthermore, due to their sensitivity to pH changes, they could be used as novel pH indicators.
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    Antifungal Agent 4-AN Changes the Genome-Wide Expression Profile, Downregulates Virulence-Associated Genes and Induces Necrosis in Candida albicans Cells
    (MDPI, 2020) Martyna, Aleksandra; Masłyk, Maciej; Janeczko, Monika; Kochanowicz, Elżbieta; Gielniewski, Bartłomiej; Świercz, Aleksandra; Demchuk, Oleg M.; Kubiński, Konrad
    In the light of the increasing occurrence of antifungal resistance, there is an urgent need to search for new therapeutic strategies to overcome this phenomenon. One of the applied approaches is the synthesis of small-molecule compounds showing antifungal properties. Here we present a continuation of the research on the recently discovered anti-Candida albicans agent 4-AN. Using next generation sequencing and transcriptional analysis, we revealed that the treatment of C. albicans with 4-AN can change the expression profile of a large number of genes. The highest upregulation was observed in the case of genes involved in cell stress, while the highest downregulation was shown for genes coding sugar transporters. Real-time PCR analysis revealed 4-AN mediated reduction of the relative expression of genes engaged in fungal virulence (ALS1, ALS3, BCR1, CPH1, ECE1, EFG1, HWP1, HYR1 and SAP1). The determination of the fractional inhibitory concentration index (FICI) showed that the combination of 4-AN with amphotericin B is synergistic. Finally, flow cytometry analysis revealed that the compound induces mainly necrosis in C. albicans cells.
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    Cholinesterase inhibitors isolated from bilberry fruit
    (Elsevier, 2014) Demchuk, Oleg M.; Borowiec, Kamila; Szwajgier, Dominik; Targoński, Zdzisław; Cybulska, Justyna; Czernecki, Tomasz; Malik, Agnieszka
    Cholinesterases (ChEs) are key enzymes in the pathogenesis of Alzheimer's disease (AD). A growing body of evidence suggests that plants deliver compounds able to inhibit ChEs (e.g., huperzine A, galanthamine, and physostigmine), thus playing a beneficial therapeutic role in the treatment of AD. Screening for cholinesterase inhibitors (ChEIs) in selected fruits and vegetables showed that extract prepared from bilberry fruit effectively inhibited the activity of acetyl- and butyrylcholinesterase. The purification of ChEIs from bilberry fruit followed by HPLC-UV, FT-IR, NMR, and LC–MS demonstrated that the studied compounds were derivatives of chlorogenic and benzoic acids. These results confirm that bilberry fruit may serve as a useful source of ChEIs, leading to the attenuation of memory deficit caused by AD.
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    Efficient Oxidative Resolution of 1-Phenylphosphol-2-Ene and Diels–Alder Synthesis of Enantiopure Bicyclic and Tricyclic P-Stereogenic C-P Heterocycles
    (MDPI, 2020) Demchuk, Oleg M.; Pietrusiewicz, Kazimierz Michał; Koprowski, Marek; Drzazga, Zbigniew; Parcheta, Renata; Łastawiecka, Elżbieta; Justyniak, Iwona
    1-Phenylphosphol-2-ene 1-oxide is effectively resolved by L-menthyl bromoacetate to afford both SP and RP enantiomers of 1-phenylphosphol-2-ene 1-oxide on a multigram scale. The resolved 1-phenylphosphol-2-ene oxide has been found to undergo face-selective and endo-selective cycloadditions with a series of acyclic and cyclic dienes to produce enantiopure P-stereogenic C-P heterocycles of hexahydrophosphindole and hexahydrobenzophosphindole as well as phospha[5.2.1.02,6]decene and phospha[5.2.2.02,6]undecene structures. Conversions of these cycloadducts to the fully saturated heterocyclic systems as well as to their P (III), P = S, P = Se and P-BH3 derivatives have been demonstrated to occur with retention of configuration and preservation of configurational homogeneity at P. A perplexing case of stereomutation at P during reduction of a tricyclic β-hydroxy phosphine oxide by PhSiH3 at 80 °C has been recorded.
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    Green in water sonochemical synthesis of tetrazolopyrimidine derivatives by a novel core-shell magnetic nanostructure catalyst
    (Elsevier, 2018) Demchuk, Oleg M.; Maleki, Ali; Rahimi, Jamal; Wilczewska, Agnieszka Z.; Jasiński, Radomir
    A green approach for the one-pot four-component sonochemical synthesis of 5-methyl-7-aryl-4,7-dihydrotetrazolo[1,5-a]pyrimidine-6-carboxylic esters from the reaction of 2-cyano-guanidine, sodium azide, various aromatic aldehydes and methyl or ethyl acetoacetate in the presence of a catalytic amount of Fe2O3@SiO2-(CH2)3NHC(O)(CH2)2PPh2 as a new hybrid organic–inorganic core–shell nanomagnetic catalyst is described. This is the first design, preparation, characterization and application of the present nanomaterial and also the first ultrasound irradiated synthesis of the biologically and pharmaceutically important heterocyclic compounds in water as a green solvent. This novel sonocatalysis/nanocatalysis protocol offers several advantages such as high yields, short reaction times, environmentally-friendly reaction media, easily isolation of the products, simple preparation, full characterization and recoverability of the nanocatalyst by an external magnet and reusing several times without significant loss of activity.
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    Metathetic approach to new NORPHOS-related bisphosphanes: facile synthesis and application in asymmetric hydrogenation
    (Walter de Gruyter, 2021) Demchuk, Oleg M.; Szwaczko, Katarzyna; Mirosław, Barbara; Wójciuk, Grzegorz; Mazur, Liliana; Pietrusiewicz, Kazimierz Michał
    A highly efficient synthesis of new chiral bisphosphanes derived from the renowned NORPHOS ligand is presented. The synthesis involves ring-opening metathesis of NORPHOS dioxide with an external olefin, followed by saturation of the new double bonds and adjustment of the oxidation level of phosphorus centers oxidation level. The synthesized bisphosphanes retain the configuration and enantiomeric purity of the starting NORPHOS. Their utility as ligands in asymmetric catalysis is exemplified using an open-NORPHOS ligand in some benchmark Rh-catalyzed hydrogenations of enamides where excellent chemical yields and enantiomeric purities of the products have been secured. The proposed protocol demonstrated the possibility of a straightforward synthesis of new chiral catalysts to be utilized in the asymmetric synthesis of pharmaceutically important compounds, such as amino acid derivatives.
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    New Insights into the Mechanism of Reduction of Tertiary Phosphine Oxides by Means of Phenylsilane
    (Wiley-Blackwell, 2015) Demchuk, Oleg M.; Jasiński, Radomir; Pietrusiewicz, Kazimierz Michał
    The mechanism of the reduction of phosphine oxides by PhSiH3 was established on the basis of kinetic measurements and Density Functional Theory (DFT) calculations. In particular, it has been proved that the model reaction between tri-n-butylphosphine oxide and phenylsilane occurs via a nonpolar mechanism. The data presented herein allow prediction and verification of the applicability of the new reduction reagents and conditions for industrially attractive processes.
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    New Perspectives for Fisetin
    (Frontiers Media, 2019) Demchuk, Oleg M.; Grynkiewicz, Grzegorz
    Fisetin is a flavonol that shares distinct antioxidant properties with a plethora of other plant polyphenols. Additionally, it exhibits a specific biological activity of considerable interest as regards the protection of functional macromolecules against stress which results in the sustenance of normal cells cytoprotection. Moreover, it shows potential as an anti-inflammatory, chemopreventive, chemotherapeutic and recently also senotherapeutic agent. In view of its prospective applications in healthcare and likely demand for fisetin, methods for its preparation and their suitability for pharmaceutical use are discussed herein.
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    New Rigid Polycyclic Bis(phosphane) for Asymmetric Catalysis
    (MDPI, 2019) Demchuk, Oleg M.; Pietrusiewicz, Kazimierz Michał; Szwaczko, Katarzyna; Mirosław, Barbara; Dybała, Izabela; Jasiński, Radomir
    A simple, highly efficient synthesis of a series of novel chiral non-racemic rigid tetracyclic phosphorus ligands, applicable in important chemical asymmetric transformations, was performed. In a tandem cross-coupling/C-H bond activation reaction, a well-recognised and readily available ligand (R,R)-NORPHOS was used as the starting material. The palladium complexes of new ligands were obtained and characterised on the example of a crystalline dichloropalladium complex of [(1R,2R,9S,10S,11R,12R)-4-phenyltetracyclo[8.2.1.02,9.03,8]trideca-3,5,7-triene-11,12-diyl]bis(diphenylphosphane). A notably high activity and stereoselectivity of the palladium catalysts based on the new ligands were confirmed in a model asymmetric allylic substitution reaction. Herein, we discuss the geometry of the palladium complexes formed and its impact on the efficiency of the catalysts. A comparison of their geometric features with other bis(phosphane) ligand complexes found in the Cambridge Structural Database and built density functional theory (DFT) commutated models is also presented and rationalised.
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    New Supramolecular Drug Carriers: The Study of Organogel Conjugated Gold Nanoparticles
    (MDPI, 2021) Demchuk, Oleg M.; Kowalczuk, Joanna; Łapiński, Andrzej; Stolarczyk, Elżbieta; Kubiński, Konrad; Janeczko, Monika; Martyna, Aleksandra; Masłyk, Maciej; Turczyniak-Surdacka, Sylwia
    An aqueous solution of sodium citrate stabilized gold nanoparticles (AuNP) in the presence of N-lauroyl-L-alanine (C12ALA) forms a stable gel. The structure of the gel and the distribution profile of AuNP in it were analyzed. Will nanoparticles separated from each other with sodium citrate behave in the same way in solution and trapped in the gel matrix? Will the spatial limitation of solvent molecules aggregate nanoparticles and destroy their homogeneity? These questions are very important from the point of view of the use of gold nanoparticles, trapped in the gel structure, as carriers of drugs in the slow-release process. The lack of homogeneity of this distribution will have a major impact on the rate of release of the appropriate amount of therapeutic drug from the matrix. In this work, we attempt to answer these questions. The performed biological assays revealed that both C12ALA and C12ALA-AuNP show an excellent level of biological neutrality. They might be used as a transporting medium for a drug delivery without affecting the drug’s activity.
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    Novel functionalized β-nitrostyrenes: Promising candidates for new antibacterial drugs
    (Elsevier, 2019) Demchuk, Oleg M.; Boguszewska-Czubara, Anna; Kula, Karolina; Wnorowski, Artur; Biernasiuk, Anna; Popiołek, Łukasz; Miodowski, Dawid; Jasiński, Radomir
    The process of searching for new antibacterial agents is more and more challenging due to the increasing drug resistance, which has become a major concern in the field of infection management. Our study presents a synthesis and characterization by IR, UV, 1H NMR and 13C NMR spectra of a homogenous series of 1-EWG functionalized 2-aryl-1-nitroethenes which could prove good candidates for the replacement of traditional antibacterial drugs In vitro screening against a panel of the reference strains of bacteria and fungi and their cytotoxicity towards cultured human HepG2 and HaCaT cells was performed. Antimicrobial results indicated that four of the synthesized compounds exhibited a significant antimicrobial activity against all tested reference bacteria and fungi belonging to yeasts with a specific and strong activity towards B. subtilis ATCC 6633. Two of these compounds had no detectable cytotoxicity towards the cultured human cell lines, making them promising candidates for new antibacterial drugs.
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    Rational design of novel ligands for environmentally benign cross-coupling reactions
    (Walter de Gruyter, 2011) Demchuk, Oleg M.; Kielar, Katarzyna; Pietrusiewicz, Kazimierz Michał
    Transition-metal (TM) complexes of new phosphines, readily prepared by a straight forward three-step modular synthesis, were successfully employed in difficult crosscoupling reactions conducted under mild conditions (water, “open-flask”, low temperature) that aspire to meet green chemistry criteria. High yielding catalyzed by bismuth or rhodium complexes oxidative arylation of naphthoquinone gave the key 2-arylnaphthoquinone intermediates for facile bismuth triflate-catalyzed Michael addition of secondary phosphine oxides. Subsequent O-methylation and reductions of the resulting products gave access to the target air-stable phosphine ligands in good overall yields (up to 60 %).
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    Regio- and stereoselectivity of polar [2+3] cycloaddition reactions between (Z)-C-(3,4,5-trimethoxyphenyl)-N-methylnitrone and selected (E)-2-substituted nitroethenes
    (Versita, 2014) Demchuk, Oleg M.; Jasiński, Radomir; Ziółkowska, Magda; Maziarka, Agata
    [2+3] Cycloaddition reactions of the highly reactive (Z)-C-(3,4,5-trimethoxyphenyl)-N-methylnitrone with (E)-2-R-nitroethenes proceed under mild conditions and yield mixtures of stereoisomeric 2-methyl-3-(3,4,5-trimethoxyphenyl)-4-nitro-5-R-isoxazolidines. The effect of regiospecificity of the cycloadditions may be accounted for by the theory of electrophilicity indexes. Stereoselectivity, however, is determined by a compilation of steric and secondary orbital effects.
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    Regiospecific formation of the nitromethyl-substituted 3-phenyl-4,5-dihydroisoxazole via [3 + 2] cycloaddition
    (Springer Nature, 2018) Demchuk, Oleg M.; Mirosław, Barbara; Babyuk, Dmytro; Łapczuk-Krygier, Agnieszka; Kącka-Zych, Agnieszka; Jasiński, Radomir
    5-(Nitromethyl)-3-phenyl-4,5-dihydroisoxazole was obtained as a product of a high-yielding [3 + 2] cycloaddition reaction of in situ-generated benzonitrile N-oxide and 3-nitroprop-1-ene. For the first time, the regiochemistry of this reaction was unambiguously proven by X-ray structural analysis. The quantum-chemical calculation performed at the M06-2X/6-31G(d) (PCM) theoretical level affords a basis for explaining the course of reaction as well as the nature of transition states. Next, further DFT calculations together with spectral data shed light on structural aspects of the product.
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    The Anti-Candida albicans Agent 4-AN Inhibits Multiple Protein Kinases
    (MDPI, 2019) Masłyk, Maciej; Janeczko, Monika; Martyna, Aleksandra; Czernik, Sławomir; Tokarska-Rodak, Małgorzata; Chwedczuk, Marta; Foll-Josselin, Béatrice; Ruchaud, Sandrine; Bach, Stéphane; Demchuk, Oleg M.; Kubiński, Konrad
    Small molecules containing quinone and/or oxime moieties have been found as promising anti-fungal agents. One of them is 4-AN, a recently reported potent anti-Candida compound, which inhibits the formation of hyphae, decreases the level of cellular phosphoproteome, and finally shows no toxicity towards human erythrocytes and zebrafish embryos. Here, further research on 4-AN is presented. The results revealed that the compound: (i) Kills Candida clinical isolates, including these with developed antibiotic resistance, (ii) affects mature biofilm, and (iii) moderately disrupts membrane permeability. Atomic force microscopy studies revealed a slight influence of 4-AN on the cell surface architecture. 4-AN was also shown to inhibit multiple various protein kinases, a characteristic shared by most of the ATP-competitive inhibitors. The presented compound can be used in novel strategies in the fight against candidiasis, and reversible protein phosphorylation should be taken into consideration as a target in designing these strategies.