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  1. Article ; Online: Novel 3,9-Disubstituted Acridines with Strong Inhibition Activity against Topoisomerase I

    Kristína Krochtová / Annamária Halečková / Ladislav Janovec / Michaela Blizniaková / Katarína Kušnírová / Mária Kožurková

    Molecules, Vol 28, Iss 1308, p

    Synthesis, Biological Evaluation and Molecular Docking Study

    2023  Volume 1308

    Abstract: A series of novel 3,9-disubstituted acridines were synthesized and their biological potential was investigated. The synthetic plan consists of eight reaction steps, which produce the final products, derivatives 17a – 17j , in a moderate yield. The ... ...

    Abstract A series of novel 3,9-disubstituted acridines were synthesized and their biological potential was investigated. The synthetic plan consists of eight reaction steps, which produce the final products, derivatives 17a – 17j , in a moderate yield. The principles of cheminformatics and computational chemistry were applied in order to study the relationship between the physicochemical properties of the 3,9-disubstituted acridines and their biological activity at a cellular and molecular level. The selected 3,9-disubstituted acridine derivatives were studied in the presence of DNA using spectroscopic (UV-Vis, circular dichroism, and thermal denaturation) and electrophoretic (nuclease activity, relaxation and unwinding assays for topoisomerase I and decatenation assay for topoisomerase IIα) methods. Binding constants (2.81–9.03 × 10 4 M −1 ) were calculated for the derivatives from the results of the absorption titration spectra. The derivatives were found to have caused the inhibition of both topoisomerase I and topoisomerase IIα. Molecular docking simulations suggested a different way in which the acridines 17a – 17j can interact with topoisomerase I versus topoisomerase IIα. A strong correlation between the lipophilicity of the derivatives and their ability to stabilize the intercalation complex was identified for all of the studied agents. Acridines 17a – 17j were also subjected to in vitro screening conducted by the Developmental Therapeutic Program of the National Cancer Institute (NCI) against a panel of 60 cancer cell lines. The strongest biological activity was displayed by aniline acridine 17a (MCF7–GI 50 18.6 nM) and N , N -dimethylaniline acridine 17b (SR–GI 50 38.0 nM). The relationship between the cytostatic activity of the most active substances (derivatives 17a , 17b , and 17e – 17h ) and their values of K B , Log P , Δ S °, and δ was also investigated. Due to the fact that a significant correlation was only found in the case of charge density, δ, it is possible to assume that the cytostatic effect might ...
    Keywords antiproliferation ; acridines ; cheminformatics ; computational chemistry ; nucleic acids ; structure–activity relationships ; Organic chemistry ; QD241-441
    Subject code 540
    Language English
    Publishing date 2023-01-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Synthesis of Novel Biologically Active Proflavine Ureas Designed on the Basis of Predicted Entropy Changes

    Ladislav Janovec / Eva Kovacova / Martina Semelakova / Monika Kvakova / Daniel Kupka / David Jager / Maria Kozurkova

    Molecules, Vol 26, Iss 4860, p

    2021  Volume 4860

    Abstract: A novel series of proflavine ureas, derivatives 11a – 11i , were synthesized on the basis of molecular modeling design studies. The structure of the novel ureas was obtained from the pharmacological model, the parameters of which were determined from ... ...

    Abstract A novel series of proflavine ureas, derivatives 11a – 11i , were synthesized on the basis of molecular modeling design studies. The structure of the novel ureas was obtained from the pharmacological model, the parameters of which were determined from studies of the structure-activity relationship of previously prepared proflavine ureas bearing n -alkyl chains. The lipophilicity (Log P ) and the changes in the standard entropy (Δ S °) of the urea models, the input parameters of the pharmacological model, were determined using quantum mechanics and cheminformatics. The anticancer activity of the synthesized derivatives was evaluated against NCI-60 human cancer cell lines. The urea derivatives azepyl 11b , phenyl 11c and phenylethyl 11f displayed the highest levels of anticancer activity, although the results were only a slight improvement over the hexyl urea, derivative 11j , which was reported in a previous publication. Several of the novel urea derivatives displayed GI 50 values against the HCT-116 cancer cell line, which suggest the cytostatic effect of the compounds azepyl 11b –0.44 μM, phenyl 11c –0.23 μM, phenylethyl 11f –0.35 μM and hexyl 11j –0.36 μM. In contrast, the novel urea derivatives 11b , 11c and 11f exhibited levels of cytotoxicity three orders of magnitude lower than that of hexyl urea 11j or amsacrine.
    Keywords proflavine ureas ; molecular design ; cytostatic activity ; cytotoxicity ; Organic chemistry ; QD241-441
    Subject code 500
    Language English
    Publishing date 2021-08-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Acridine Based N -Acylhydrazone Derivatives as Potential Anticancer Agents

    Mária Vilková / Monika Hudáčová / Nikola Palušeková / Rastislav Jendželovský / Miroslav Almáši / Tibor Béres / Peter Fedoročko / Mária Kožurková

    Molecules, Vol 27, Iss 2883, p

    Synthesis, Characterization and ctDNA/HSA Spectroscopic Binding Properties

    2022  Volume 2883

    Abstract: A series of novel acridine N -acylhydrazone derivatives have been synthesized as potential topoisomerase I/II inhibitors, and their binding (calf thymus DNA—ctDNA and human serum albumin—HSA) and biological activities as potential anticancer agents on ... ...

    Abstract A series of novel acridine N -acylhydrazone derivatives have been synthesized as potential topoisomerase I/II inhibitors, and their binding (calf thymus DNA—ctDNA and human serum albumin—HSA) and biological activities as potential anticancer agents on proliferation of A549 and CCD-18Co have been evaluated. The acridine-DNA complex 3b (-F) displayed the highest K b value ( K b = 3.18 × 10 3 M −1 ). The HSA-derivatives interactions were studied by fluorescence quenching spectra. This method was used for the calculation of characteristic binding parameters. In the presence of warfarin, the binding constant values were found to decrease (K SV = 2.26 M −1 , K b = 2.54 M −1 ), suggesting that derivative 3a could bind to HSA at Sudlow site I. The effect of tested derivatives on metabolic activity of A549 cells evaluated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide or MTT assay decreased as follows 3b (-F) > 3a (-H) > 3c (-Cl) > 3d (-Br). The derivatives 3c and 3d in vitro act as potential dual inhibitors of hTopo I and II with a partial effect on the metabolic activity of cancer cells A594. The acridine-benzohydrazides 3a and 3c reduced the clonogenic ability of A549 cells by 72% or 74%, respectively. The general results of the study suggest that the novel compounds show potential for future development as anticancer agents.
    Keywords acridine ; benzohydrazide ; ctDNA ; HSA binding ; spectroscopic study ; Organic chemistry ; QD241-441
    Subject code 333
    Language English
    Publishing date 2022-04-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Tacrine-Coumarin Derivatives as Topoisomerase Inhibitors with Antitumor Effects on A549 Human Lung Carcinoma Cancer Cell Lines

    Eva Konkoľová / Monika Hudáčová / Slávka Hamuľaková / Rastislav Jendželovský / Jana Vargová / Juraj Ševc / Peter Fedoročko / Mária Kožurková

    Molecules, Vol 26, Iss 4, p

    2021  Volume 1133

    Abstract: A549 human lung carcinoma cell lines were treated with a series of new drugs with both tacrine and coumarin pharmacophores (derivatives 1a – 2c ) in order to test the compounds’ ability to inhibit both cancer cell growth and topoisomerase I and II ... ...

    Abstract A549 human lung carcinoma cell lines were treated with a series of new drugs with both tacrine and coumarin pharmacophores (derivatives 1a – 2c ) in order to test the compounds’ ability to inhibit both cancer cell growth and topoisomerase I and II activity. The ability of human topoisomerase I ( h TOPI) and II to relax supercoiled plasmid DNA in the presence of various concentrations of the tacrine-coumarin hybrid molecules was studied with agarose gel electrophoresis. The biological activities of the derivatives were studied using MTT assays, clonogenic assays, cell cycle analysis and quantification of cell number and viability. The content and localization of the derivatives in the cells were analysed using flow cytometry and confocal microscopy. All of the studied compounds were found to have inhibited topoisomerase I activity completely. The effect of the tacrine-coumarin hybrid compounds on cancer cells is likely to be dependent on the length of the chain between the tacrine and coumarin moieties ( 1c , 1d = tacrine-(CH 2 ) 8–9 -coumarin). The most active of the tested compounds, derivatives 1c and 1d , both display longer chains.
    Keywords tacrine-coumarin derivatives ; DNA ; topoisomerases I ; II ; cytotoxicity ; lung carcinoma cells ; A549 ; Organic chemistry ; QD241-441
    Subject code 540
    Language English
    Publishing date 2021-02-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: Synthesis of New Biscoumarin Derivatives, In Vitro Cholinesterase Inhibition, Molecular Modelling and Antiproliferative Effect in A549 Human Lung Carcinoma Cells

    Monika Hudáčová / Slávka Hamuľaková / Eva Konkoľová / Rastislav Jendželovský / Jana Vargová / Juraj Ševc / Peter Fedoročko / Ondrej Soukup / Jana Janočková / Veronika Ihnatova / Tomáš Kučera / Petr Bzonek / Nikola Novakova / Daniel Jun / Lucie Junova / Jan Korábečný / Kamil Kuča / Mária Kožurková

    International Journal of Molecular Sciences, Vol 22, Iss 3830, p

    2021  Volume 3830

    Abstract: A series of novel C4-C7-tethered biscoumarin derivatives ( 12a – e ) linked through piperazine moiety was designed, synthesized, and evaluated biological/therapeutic potential. Biscoumarin 12d was found to be the most effective inhibitor of both ... ...

    Abstract A series of novel C4-C7-tethered biscoumarin derivatives ( 12a – e ) linked through piperazine moiety was designed, synthesized, and evaluated biological/therapeutic potential. Biscoumarin 12d was found to be the most effective inhibitor of both acetylcholinesterase (AChE, IC 50 = 6.30 µM) and butyrylcholinesterase (BChE, IC 50 = 49 µM). Detailed molecular modelling studies compared the accommodation of ensaculin (well-established coumarin derivative tested in phase I of clinical trials) and 12d in the human recombinant AChE ( h AChE) active site. The ability of novel compounds to cross the blood–brain barrier (BBB) was predicted with a positive outcome for compound 12e . The antiproliferative effects of newly synthesized biscoumarin derivatives were tested in vitro on human lung carcinoma cell line (A549) and normal colon fibroblast cell line (CCD-18Co). The effect of derivatives on cell proliferation was evaluated by MTT assay, quantification of cell numbers and viability, colony-forming assay, analysis of cell cycle distribution and mitotic activity. Intracellular localization of used derivatives in A549 cells was confirmed by confocal microscopy. Derivatives 12d and 12e showed significant antiproliferative activity in A549 cancer cells without a significant effect on normal CCD-18Co cells. The inhibition of h AChE/human recombinant BChE ( h BChE), the antiproliferative activity on cancer cells, and the ability to cross the BBB suggest the high potential of biscoumarin derivatives. Beside the treatment of cancer, 12e might be applicable against disorders such as schizophrenia, and 12d could serve future development as therapeutic agents in the prevention and/or treatment of Alzheimer’s disease.
    Keywords biscoumarin ; Alzheimer’s disease ; blood–brain barrier ; cholinesterase ; antiproliferative activity ; A549 ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
    Subject code 610
    Language English
    Publishing date 2021-04-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: Neuroactive Multifunctional Tacrine Congeners with Cholinesterase, Anti-Amyloid Aggregation and Neuroprotective Properties

    Maria Kozurkova / Pavol Kristian / Helena Paulikova / Slavka Hamulakova / Zuzana Gazova

    Pharmaceuticals, Vol 4, Iss 2, Pp 382-

    2011  Volume 418

    Abstract: The review summarizes research into the highly relevant topics of cholinesterase and amyloid aggregation inhibitors connected to tacrine congeners, both of which are associated with neurogenerative diseases. Various opinions will be discussed regarding ... ...

    Abstract The review summarizes research into the highly relevant topics of cholinesterase and amyloid aggregation inhibitors connected to tacrine congeners, both of which are associated with neurogenerative diseases. Various opinions will be discussed regarding the dual binding site inhibitors which are characterized by increased inhibitor potency against acetylcholin/butyrylcholine esterase and amyloid formation. It is suggested that these compounds can both raise levels of acetylcholine by binding to the active site, and also prevent amyloid aggregation. In connection with this problem, the mono/dual binding of the multifunctional derivatives of tacrine, their mode of action and their neuroprotective activities are reported. The influence of low molecular compounds on protein amyloid aggregation, which might be considered as a potential therapeutic strategy in the treatment of Alzheimer’s disease is also reported. Finally, attention is paid to some physico-chemical factors, such as desolvation energies describing the transfer of the substrate solvated by water, the metal-chelating properties of biometals reacting with amyloid precursor protein, amyloid beta peptide and tau protein.
    Keywords tacrine ; acetylcholinesterase inhibitor ; amyloid aggregation ; Alzheimer’s disease ; Medicine ; R ; Pharmacy and materia medica ; RS1-441
    Subject code 500
    Language English
    Publishing date 2011-02-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article: Interaction of cholinesterase modulators with DNA and their cytotoxic activity

    Janockova, Jana / Jana Plsikova / Jaromir Mikes / Kamil Kuca / Kamil Musilek / Lubomir Culka / Maria Kozurkova / Peter Fedorocko / Zuzana Gulasova

    International journal of biological macromolecules. 2014 Mar., v. 64

    2014  

    Abstract: This research was focused on a study of the binding properties of a series of cholinesterase reactivators compounds K075 (1), K027 (2) and inhibitors compounds K524, K009 and 7-MEOTA (3–5) with calf thymus DNA. The nature of the interactions between ... ...

    Abstract This research was focused on a study of the binding properties of a series of cholinesterase reactivators compounds K075 (1), K027 (2) and inhibitors compounds K524, K009 and 7-MEOTA (3–5) with calf thymus DNA. The nature of the interactions between compounds 1–5 and DNA were studied using spectroscopic techniques (UV–vis, fluorescence spectroscopy and circular dichroism). The binding constants for complexes of cholinesterase modulators with DNA were determined from UV–vis spectroscopic titrations (K=0.5×104–8.9×105M−1). The ability of the prepared analogues to relax topoisomerase I was studied with electrophoretic techniques and it was proved that ligands 4 and 5 inhibited this enzyme at a concentration of 30μM. The biological activity of the novel compounds was assessed through an examination of changes in cell cycle distribution, mitochondrial membrane potential and cellular viability. Inhibitors 3–5 exhibited a cytotoxic effect on HL-60 (human acute promyelocytic leukaemia) cell culture, demonstrated a tendency to affect mitochondrial physiology and viability, and also forced cells to accumulate in the G1/G0-phase of the cell cycle. The cholinesterase reactivators 1 and 2 were found relatively save from the point of view of DNA binding, whereas cholinesterase inhibitors 3–5 resulted as strong DNA binding agents that limit their plausible use.
    Keywords binding agents ; binding properties ; calves ; cell culture ; cell cycle ; cholinesterase ; cholinesterase inhibitors ; circular dichroism spectroscopy ; cytotoxicity ; DNA ; DNA topoisomerase ; electrophoresis ; fluorescence emission spectroscopy ; humans ; leukemia ; ligands ; membrane potential ; mitochondria ; mitochondrial membrane ; thymus gland ; viability
    Language English
    Dates of publication 2014-03
    Size p. 53-62.
    Publishing place Elsevier B.V.
    Document type Article
    ZDB-ID 282732-3
    ISSN 1879-0003 ; 0141-8130
    ISSN (online) 1879-0003
    ISSN 0141-8130
    DOI 10.1016/j.ijbiomac.2013.11.022
    Database NAL-Catalogue (AGRICOLA)

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  8. Article: Novel tacrine/acridine anticholinesterase inhibitors with piperazine and thiourea linkers

    Hamulakova, Slavka / Ivan Danihel / Jan Imrich / Kamil Kuca / Ladislav Janovec / Maria Kozurkova / Miroslav Pohanka / Ondrej Holas / Pavol Kristian / Stanislav Böhm

    International journal of biological macromolecules. 2014 Sept., v. 70

    2014  

    Abstract: A new series of substituted tacrine/acridine and tacrine/tacrine dimers with aliphatic or alkylene-thiourea linkers was synthesized and the potential of these compounds as novel human acetylcholinesterase (hAChE) and human butyrylcholinesterase (hBChE) ... ...

    Abstract A new series of substituted tacrine/acridine and tacrine/tacrine dimers with aliphatic or alkylene-thiourea linkers was synthesized and the potential of these compounds as novel human acetylcholinesterase (hAChE) and human butyrylcholinesterase (hBChE) inhibitors with nanomolar inhibition activity was evaluated. The most potent AChE inhibitor was found to be homodimeric tacrine derivative 14a, which demonstrated an IC50 value of 2nM; this value indicates an activity rate which is 250-times higher than that of tacrine 1 and 7500-times higher than 7-MEOTA 15, the compounds which were used as standards in the study. IC50 values of derivatives 1, 9, 10, 14b and 15 were compared with the dissociation constants of the enzyme-inhibitor complex, Ki1, and the enzyme-substrate-inhibitor complex, Ki2, for. A dual binding site is presumed for the synthesized compounds which possess two tacrines or tacrine and acridine as terminal moieties show evidence of dual site binding. DFT calculations of theoretical desolvation free energies, ΔΔGtheor, and docking studies elucidate these suggestions in more detail.
    Keywords acetylcholinesterase ; binding sites ; cholinesterase ; dissociation ; humans ; inhibitory concentration 50 ; piperazine ; thiourea
    Language English
    Dates of publication 2014-09
    Size p. 435-439.
    Publishing place Elsevier B.V.
    Document type Article
    ZDB-ID 282732-3
    ISSN 1879-0003 ; 0141-8130
    ISSN (online) 1879-0003
    ISSN 0141-8130
    DOI 10.1016/j.ijbiomac.2014.06.064
    Database NAL-Catalogue (AGRICOLA)

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