123 results on '"Kaluzhny, Dmitry N."'
Search Results
2. Enhancement of intrinsic guanine fluorescence by protonation in DNA of various structures
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Tevonyan, Liana L., Bazhulina, Natalia P., and Kaluzhny, Dmitry N.
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- 2024
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Catalog
3. Synthesis and antitumor activity of cyclopentane-fused anthraquinone derivatives
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Tikhomirov, Alexander S., Sinkevich, Yuri B., Dezhenkova, Lyubov G., Kaluzhny, Dmitry N., Ilyinsky, Nikolay S., Borshchevskiy, Valentin I., Schols, Dominique, and Shchekotikhin, Andrey E.
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- 2024
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4. Heterocyclic ring expansion yields anthraquinone derivatives potent against multidrug resistant tumor cells
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Tikhomirov, Alexander S., Tsvetkov, Vladimir B., Volodina, Yulia L., Litvinova, Valeria A., Andreeva, Daria V., Dezhenkova, Lyubov G., Kaluzhny, Dmitry N., Treshalin, Ivan D., Shtil, Alexander A., and Shchekotikhin, Andrey E. more...
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- 2022
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5. Thiophene-2-carboxamide derivatives of anthraquinone: A new potent antitumor chemotype
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Volodina, Yulia L., Tikhomirov, Alexander S., Dezhenkova, Lyubov G., Ramonova, Alla A., Kononova, Anastasia V., Andreeva, Daria V., Kaluzhny, Dmitry N., Schols, Dominique, Moisenovich, Mikhail M., Shchekotikhin, Andrey E., and Shtil, Alexander A. more...
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- 2021
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6. Amides of pyrrole- and thiophene-fused anthraquinone derivatives: A role of the heterocyclic core in antitumor properties
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Tikhomirov, Alexander S., Litvinova, Valeria A., Andreeva, Daria V., Tsvetkov, Vladimir B., Dezhenkova, Lyubov G., Volodina, Yulia L., Kaluzhny, Dmitry N., Treshalin, Ivan D., Schols, Dominique, Ramonova, Alla A., Moisenovich, Mikhail M., Shtil, Alexander A., and Shchekotikhin, Andrey E. more...
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- 2020
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7. New anthra[2,3-b]furancarboxamides: A role of positioning of the carboxamide moiety in antitumor properties
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Volodina, Yulia L., Dezhenkova, Lyubov G., Tikhomirov, Alexander S., Tatarskiy, Victor V., Kaluzhny, Dmitry N., Moisenovich, Anastasia M., Moisenovich, Mikhail M., Isagulieva, Alexandra K., Shtil, Alexander A., Tsvetkov, Vladimir B., and Shchekotikhin, Andrey E. more...
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- 2019
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8. Tri-armed ligands of G-quadruplex on heteroarene-fused anthraquinone scaffolds: Design, synthesis and pre-screening of biological properties
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Tikhomirov, Alexander S., Tsvetkov, Vladimir B., Kaluzhny, Dmitry N., Volodina, Yulia L., Zatonsky, George V., Schols, Dominique, and Shchekotikhin, Andrey E.
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- 2018
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9. Synthesis and antiproliferative evaluation of glucosylated pyrazole analogs of K252c
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Douara, Bachir, Esvan, Yannick J., Pereira, Elisabeth, Giraud, Francis, Volodina, Yulia L., Kaluzhny, Dmitry N., Shtil, Alexander A., Anizon, Fabrice, and Moreau, Pascale
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- 2018
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10. Aminomethylation of heliomycin: Preparation and anticancer characterization of the first series of semi-synthetic derivatives
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Nadysev, Georgy Y., Tikhomirov, Alexander S., Lin, Ming-Hung, Yang, Ya-Ting, Dezhenkova, Lyubov G., Chen, Huei-Yu, Kaluzhny, Dmitry N., Schols, Dominique, Shtil, Alexander A., Shchekotikhin, Andrey E., and Chueh, Pin Ju more...
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- 2018
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11. Development and pharmaceutical evaluation of the anticancer Anthrafuran/Cavitron complex, a prototypic parenteral drug formulation
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Treshalina, Helen M., Romanenko, Vladimir I., Kaluzhny, Dmitry N., Treshalin, Michael I., Nikitin, Aleksey A., Tikhomirov, Alexander S., and Shchekotikhin, Andrey E.
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- 2017
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12. Quantitative parameters of complexes of tris(1-alkylindol-3-yl)methylium salts with serum albumin: Relevance for the design of drug candidates
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Durandin, Nikita A., Tsvetkov, Vladimir B., Bykov, Evgeny E., Kaluzhny, Dmitry N., Lavrenov, Sergey N., Tevyashova, Anna N., and Preobrazhenskaya, Maria N.
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- 2016
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13. Synthesis and biological activity of pyrazole analogues of the staurosporine aglycon K252c
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Esvan, Yannick J., Giraud, Francis, Pereira, Elisabeth, Suchaud, Virginie, Nauton, Lionel, Théry, Vincent, Dezhenkova, Lyubov G., Kaluzhny, Dmitry N., Mazov, Vsevolod N., Shtil, Alexander A., Anizon, Fabrice, and Moreau, Pascale more...
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- 2016
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14. Discovery of antitumor anthra[2,3-b]furan-3-carboxamides: Optimization of synthesis and evaluation of antitumor properties
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Shchekotikhin, Andrey E., Dezhenkova, Lyubov G., Tsvetkov, Vladimir B., Luzikov, Yuri N., Volodina, Yulia L., Tatarskiy, Victor V., Jr., Kalinina, Anastasia A., Treshalin, Michael I., Treshalina, Helen M., Romanenko, Vladimir I., Kaluzhny, Dmitry N., Kubbutat, Michael, Schols, Dominique, Pommier, Yves, Shtil, Alexander A., and Preobrazhenskaya, Maria N. more...
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- 2016
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15. Synthesis and evaluation of new antitumor 3-aminomethyl-4,11-dihydroxynaphtho[2,3-f]indole-5,10-diones
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Shchekotikhin, Andrey E., Glazunova, Valeria A., Dezhenkova, Lyubov G., Luzikov, Yuri N., Buyanov, Vladimir N., Treshalina, Helena M., Lesnaya, Nina A., Romanenko, Vladimir I., Kaluzhny, Dmitry N., Balzarini, Jan, Agama, Keli, Pommier, Yves, Shtil, Alexander A., and Preobrazhenskaya, Maria N. more...
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- 2014
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16. Novel multi-targeting anthra[2,3-b]thiophene-5,10-diones with guanidine-containing side chains: Interaction with telomeric G-quadruplex, inhibition of telomerase and topoisomerase I and cytotoxic properties
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Ilyinsky, Nikolay S., Shchyolkina, Anna K., Borisova, Olga F., Mamaeva, Olga K., Zvereva, Maria I., Azhibek, Dulat M., Livshits, Mikhail A., Mitkevich, Vladimir A., Balzarini, Jan, Sinkevich, Yuri B., Luzikov, Yuri N., Dezhenkova, Lybov G., Kolotova, Ekaterina S., Shtil, Alexander A., Shchekotikhin, Andrey E., and Kaluzhny, Dmitry N. more...
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- 2014
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17. 5‐Substituted Uridines with Activity against Gram‐Positive Bacteria.
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Makarov, Dmitry A., Negrya, Sergey D., Jasko, Maxim V., Karpenko, Inna L., Solyev, Pavel N., Chekhov, Vladimir O., Kaluzhny, Dmitry N., Efremenkova, Olga V., Vasilyeva, Byazilya F., Chizhov, Alexander O., Avdanina, Darya A., Zhgun, Alexander A., Kochetkov, Sergey N., and Alexandrova, Liudmila A. more...
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- 2023
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18. New Boron Containing Acridines: Synthesis and Preliminary Biological Study.
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Druzina, Anna A., Dudarova, Nadezhda V., Ananyev, Ivan V., Antonets, Anastasia A., Kaluzhny, Dmitry N., Nazarov, Alexey A., Sivaev, Igor B., and Bregadze, Vladimir I.
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ACRIDINE derivatives ,BIOSYNTHESIS ,ACRIDINES ,BORON-neutron capture therapy ,COPPER ,MOLECULAR structure - Abstract
The synthesis of the first conjugates of acridine with cobalt bis(dicarbollide) are reported. A novel 9-azido derivative of acridine was prepared through the reaction of 9-methoxyacridine with Nscript>3CH
2 CH2 NH2 , and its solid-state molecular structure was determined via single-crystal X-ray diffraction. The azidoacridine was used in a copper (I)-catalyzed azide-alkyne cycloaddition reaction with cobalt bis(dicarbollide)-based terminal alkynes to give the target 1,2,3-triazoles. DNA interaction studies via absorbance spectroscopy showed the weak binding of the obtained conjugates with DNA. The antiproliferative activity (IC50 ) of the boronated conjugates against a series of human cell lines was evaluated through an MTT assay. The results suggested that acridine derivatives of cobalt bis(dicarbollide) might serve as a novel scaffold for the future development of new agents for boron neutron capture therapy (BNCT). [ABSTRACT FROM AUTHOR] more...- Published
- 2023
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19. Changes in Hemoglobin Properties in Complex with Glutathione and after Glutathionylation.
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Kuleshova, Iuliia D., Zaripov, Pavel I., Poluektov, Yuri M., Anashkina, Anastasia A., Kaluzhny, Dmitry N., Parshina, Evgeniia Yu., Maksimov, Georgy V., Mitkevich, Vladimir A., Makarov, Alexander A., and Petrushanko, Irina Yu. more...
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QUATERNARY structure ,HEMOGLOBINS ,ERYTHROCYTES ,BLOOD proteins ,CIRCULAR dichroism ,SERUM albumin ,OXYGEN carriers ,MYOGLOBIN - Abstract
Hemoglobin is the main protein of red blood cells that provides oxygen transport to all cells of the human body. The ability of hemoglobin to bind the main low-molecular-weight thiol of the cell glutathione, both covalently and noncovalently, is not only an important part of the antioxidant protection of red blood cells, but also affects its affinity for oxygen in both cases. In this study, the properties of oxyhemoglobin in complex with reduced glutathione (GSH) and properties of glutathionylated hemoglobin bound to glutathione via an SS bond were characterized. For this purpose, the methods of circular dichroism, Raman spectroscopy, infrared spectroscopy, tryptophan fluorescence, differential scanning fluorimetry, and molecular modeling were used. It was found that the glutathionylation of oxyhemoglobin caused changes in the secondary structure of the protein, reducing the alpha helicity, but did not affect the heme environment, tryptophan fluorescence, and the thermostability of the protein. In the noncovalent complex of oxyhemoglobin with reduced glutathione, the secondary structure of hemoglobin remained almost unchanged; however, changes in the heme environment and the microenvironment of tryptophans, as well as a decrease in the protein's thermal stability, were observed. Thus, the formation of a noncovalent complex of hemoglobin with glutathione makes a more significant effect on the tertiary and quaternary structure of hemoglobin than glutathionylation, which mainly affects the secondary structure of the protein. The obtained data are important for understanding the functioning of glutathionylated hemoglobin, which is a marker of oxidative stress, and hemoglobin in complex with GSH, which appears to deposit GSH and release it during deoxygenation to increase the antioxidant protection of cells. [ABSTRACT FROM AUTHOR] more...
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- 2023
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20. Synthesis, characterization and in vitro activity of thrombin-binding DNA aptamers with triazole internucleotide linkages
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Varizhuk, Anna M., Tsvetkov, Vladimir B., Tatarinova, Olga N., Kaluzhny, Dmitry N., Florentiev, Vladimir L., Timofeev, Edward N., Shchyolkina, Anna K., Borisova, Olga F., Smirnov, Igor P., Grokhovsky, Sergei L., Aseychev, Anton V., and Pozmogova, Galina E. more...
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- 2013
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21. Preferential DNA photocleavage potency of Zn(II) over Ni(II) derivatives of carboxymethyl tetracationic porphyrin: the role of the mode of binding to DNA
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Kovaleva, Oxana A., Tsvetkov, Vladimir B., Mamaeva, Olga K., Ol’shevskaya, Valentina A., Makarenkov, Anton V., Dezhenkova, Lyubov G., Semeikin, Alexander S., Borisova, Olga F., Shtil, Alexander A., Shchyolkina, Anna K., and Kaluzhny, Dmitry N. more...
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- 2014
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22. Taq-Polymerase Stop Assay to Determine Target Selectivity of G4 Ligands in Native Promoter Sequences of MYC , TERT , and KIT Oncogenes.
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Chashchina, Galina V., Tevonyan, Liana L., Beniaminov, Artemy D., and Kaluzhny, Dmitry N.
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LIGANDS (Biochemistry) ,ONCOGENES ,LIGAND binding (Biochemistry) ,POTASSIUM ions ,HUMAN genome - Abstract
Computational and high-throughput experimental methods predict thousands of potential quadruplex sequences (PQSs) in the human genome. Often these PQSs contain more than four G-runs, which introduce additional uncertainty into the conformational polymorphism of the G4 DNA. G4-specific ligands, which are currently being actively developed as potential anticancer agents or tools for studying G4 structures in genomes, may preferentially bind to specific G4 structures over the others that can be potentially formed in the extended G-rich genomic region. We propose a simple technique that identifies the sequences that tend to form G4 in the presence of potassium ions or a specific ligand. Thermostable DNA Taq-polymerase stop assay can detect the preferential position of the G4 –ligand binging within a long PQS-rich genomic DNA fragment. This technique was tested for four G4 binders PDS, PhenDC3, Braco-19, and TMPyP4 at three promoter sequences of MYC, KIT, and TERT that contain several PQSs each. We demonstrate that the intensity of polymerase pausing reveals the preferential binding of a ligand to particular G4 structures within the promoter. However, the strength of the polymerase stop at a specific site does not always correlate with the ligand-induced thermodynamic stabilization of the corresponding G4 structure. [ABSTRACT FROM AUTHOR] more...
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- 2023
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23. Mechanisms of Phototoxic Effects of Cationic Porphyrins on Human Cells In Vitro.
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Yegorov, Yegor E., Vishnyakova, Khava S., Pan, Xiaowen, Egorov, Anton E., Popov, Konstantin V., Tevonyan, Liana L., Chashchina, Galina V., and Kaluzhny, Dmitry N.
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PORPHYRINS ,TRYPAN blue ,POISONS ,CELL permeability ,PHOTODYNAMIC therapy - Abstract
The toxic effects of four cationic porphyrins on various human cells were studied in vitro. It was found that, under dark conditions, porphyrins are almost nontoxic, while, under the action of light, the toxic effect was observed starting from nanomolar concentrations. At a concentration of 100 nM, porphyrins caused inhibition of metabolism in the MTT test in normal and cancer cells. Furthermore, low concentrations of porphyrins inhibited colony formation. The toxic effect was nonlinear; with increasing concentrations of various porphyrins, up to about 1 μM, the effect reached a plateau. In addition to the MTT test, this was repeated in experiments examining cell permeability to trypan blue, as well as survival after 24 h. The first visible manifestation of the toxic action of porphyrins is blebbing and swelling of cells. Against the background of this process, permeability to porphyrins and trypan blue appears. Subsequently, most cells (even mitotic cells) freeze in this swollen state for a long time (24 and even 48 h), remaining attached. Cellular morphology is mostly preserved. Thus, it is clear that the cells undergo mainly necrotic death. The hypothesis proposed is that the concentration dependence of membrane damage indicates a limited number of porphyrin targets on the membrane. These targets may be any ion channels, which should be considered in photodynamic therapy. [ABSTRACT FROM AUTHOR] more...
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- 2023
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24. The role of carboxymethyl substituents in the interaction of tetracationic porphyrins with DNA
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Kovaleva, Oxana A., Tsvetkov, Vladimir B., Shchyolkina, Anna K., Borisova, Olga F., Ol’shevskaya, Valentina A., Makarenkov, Anton V., Semeikin, Alexander S., Shtil, Alexander A., and Kaluzhny, Dmitry N. more...
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- 2012
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25. Synthesis and biological activities of new pyrrolocarbazole-imidazobenzimidazole conjugates
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Anizon, Fabrice, Giraud, Francis, Ivanova, Ekaterina S., Kaluzhny, Dmitry N., Shtil, Alexander A., Cisnetti, Federico, and Moreau, Pascale
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- 2020
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26. Isolating Linum usitatissimum L. Nuclear DNA Enabled Assembling High-Quality Genome.
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Dvorianinova, Ekaterina M., Bolsheva, Nadezhda L., Pushkova, Elena N., Rozhmina, Tatiana A., Zhuchenko, Alexander A., Novakovskiy, Roman O., Povkhova, Liubov V., Sigova, Elizaveta A., Zhernova, Daiana A., Borkhert, Elena V., Kaluzhny, Dmitry N., Melnikova, Nataliya V., and Dmitriev, Alexey A. more...
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NUCLEAR DNA ,FLAX ,GENOMES ,PLANT yields ,PLANT DNA - Abstract
High-quality genome sequences help to elucidate the genetic basis of numerous biological processes and track species evolution. For flax (Linum usitatissimum L.)—a multifunctional crop, high-quality assemblies from Oxford Nanopore Technologies (ONT) data were unavailable, largely due to the difficulty of isolating pure high-molecular-weight DNA. This article proposes a scheme for gaining a contiguous L. usitatissimum assembly using Nanopore data. We developed a protocol for flax nuclei isolation with subsequent DNA extraction, which allows obtaining about 5 μg of pure high-molecular-weight DNA from 0.5 g of leaves. Such an amount of material can be collected even from a single plant and yields more than 30 Gb of ONT data in two MinION runs. We performed a comparative analysis of different genome assemblers and polishers on the gained data and obtained the final 447.1-Mb assembly of L. usitatissimum line 3896 genome using the Canu—Racon (two iterations)—Medaka combination. The genome comprised 1695 contigs and had an N50 of 6.2 Mb and a completeness of 93.8% of BUSCOs from eudicots_odb10. Our study highlights the impact of the chosen genome construction strategy on the resulting assembly parameters and its eligibility for future genomic studies. [ABSTRACT FROM AUTHOR] more...
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- 2022
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27. Differential Impact of Random GC Tetrad Binding and Chromatin Events on Transcriptional Inhibition by Olivomycin A.
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Isagulieva, Alexandra K., Kaluzhny, Dmitry N., Beniaminov, Artemy D., Soshnikova, Nataliya V., and Shtil, Alexander A.
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TRANSCRIPTION factors , *RNA polymerase II , *GENETIC transcription regulation , *CHROMATIN , *BINDING sites , *GENE expression , *REPORTER genes - Abstract
Olivomycin A (OA), an antibiotic of the aureolic acid family, interferes with gene transcription upon forming complexes with GC-rich regions in the DNA minor groove. We demonstrate that the mechanism of transcriptional deregulation is not limited to OA interaction with GC-containing binding sites for transcription factors. Using electrophoretic mobility shift assays and DNAse I footprinting of cytomegalovirus (CMV) promoter fragments carrying OA-preferred GC tetrads (CMVwt), we showed OA binding specifically to GC islands. Replacement of G for A in these tetrads (CMVmut) abrogated OA binding. Furthermore, OA decreased RNA polymerase II (RNAPII) binding to the CMVwt promoter and inhibited the reporter gene expression. In line with the absence of OA binding sites in CMVmut DNA, the expression driven from this promoter was weakly sensitive to OA. In the endogenous genes OA decreased RNAPII on promoters and coding regions. In certain cases this phenomenon was concomitant with the increased histone 3 abundance. However, the sensitivity to OA did not correlate with GC patterns around transcription start sites, suggesting that certain GC stretches play unequal roles in OA-induced transcriptional perturbations. Thus, OA affects transcription via complex mechanisms in which GC tetranucleotide binding causes RNAPII/chromatin alterations differentially manifested in individual gene contexts. [ABSTRACT FROM AUTHOR] more...
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- 2022
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28. Study of Structure–Activity Relationships of the Marine Alkaloid Fascaplysin and Its Derivatives as Potent Anticancer Agents.
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Zhidkov, Maxim E., Kaune, Moritz, Kantemirov, Alexey V., Smirnova, Polina A., Spirin, Pavel V., Sidorova, Maria A., Stadnik, Sergey A., Shyrokova, Elena Y., Kaluzhny, Dmitry N., Tryapkin, Oleg A., Busenbender, Tobias, Hauschild, Jessica, Rohlfing, Tina, Prassolov, Vladimir S., Bokemeyer, Carsten, Graefen, Markus, von Amsberg, Gunhild, and Dyshlovoy, Sergey A. more...
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Marine alkaloid fascaplysin and its derivatives are known to exhibit promising anticancer properties in vitro and in vivo. However, toxicity of these molecules to non-cancer cells was identified as a main limitation for their clinical use. Here, for the very first time, we synthesized a library of fascaplysin derivatives covering all possible substituent introduction sites, i.e., cycles A, C and E of the 12H-pyrido[1-2-a:3,4-b']diindole system. Their selectivity towards human prostate cancer versus non-cancer cells, as well as the effects on cellular metabolism, membrane integrity, cell cycle progression, apoptosis induction and their ability to intercalate into DNA were investigated. A pronounced selectivity for cancer cells was observed for the family of di- and trisubstituted halogen derivatives (modification of cycles A and E), while a modification of cycle C resulted in a stronger activity in therapy-resistant PC-3 cells. Among others, 3,10-dibromofascaplysin exhibited the highest selectivity, presumably due to the cytostatic effects executed via the targeting of cellular metabolism. Moreover, an introduction of radical substituents at C-9, C-10 or C-10 plus C-3 resulted in a notable reduction in DNA intercalating activity and improved selectivity. Taken together, our research contributes to understanding the structure–activity relationships of fascaplysin alkaloids and defines further directions of the structural optimization. [ABSTRACT FROM AUTHOR] more...
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- 2022
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29. Recombination R-triplex: H-bonds contribution to stability as revealed with minor base substitutions for adenine
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Shchyolkina, Anna K., Kaluzhny, Dmitry N., Arndt-Jovin, Donna J., Jovin, Thomas M., and Zhurkin, Victor B.
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- 2006
30. Anomeric DNA quadruplexes: Modified thrombin aptamers
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Kolganova, Natalia A, Varizhuk, Anna M, Novikov, Roman A, Florentiev, Vladimir L, Pozmogova, Galina E, Borisova, Olga F, Shchyolkina, Anna K, Smirnov, Igor P, Kaluzhny, Dmitry N, and Timofeev, Edward N more...
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- 2014
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31. Formation of an intramolecular triple-stranded DNA structure monitored by fluorescence of 2-aminopurine or 6-methylisoxanthopterin
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Shchyolkina, Anna K., Kaluzhny, Dmitry N., Borisova, Olga F., Hawkins, Mary E., Jernigan, Robert L., Jovin, Thomas M., Arndt-Jovin, Donna J., and Zhurkin, Victor B.
- Published
- 2004
32. Recurrent Potential G-Quadruplex Sequences in Archaeal Genomes.
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Chashchina, Galina V., Shchyolkina, Anna K., Kolosov, Simon V., Beniaminov, Artemy D., and Kaluzhny, Dmitry N.
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GENOMES ,POTASSIUM ions ,GENOMICS ,ARTIFICIAL chromosomes ,HAIRPIN (Genetics) ,CIRCULAR dichroism ,ARCHAEBACTERIA - Abstract
Evolutionary conservation or over-representation of the potential G-quadruplex sequences (PQS) in genomes are usually considered as a sign of the functional relevance of these sequences. However, uneven base distribution (GC-content) along the genome may along the genome may result in seeming abundance of PQSs over average in the genome. Apart from this, a number of other conserved functional signals that are encoded in the GC-rich genomic regions may inadvertently result in emergence of G-quadruplex compatible sequences. Here, we analyze the genomes of archaea focusing our search to repetitive PQS (rPQS) motifs within each organism. The probability of occurrence of several identical PQSs within a relatively short archaeal genome is low and, thus, the structure and genomic location of such rPQSs may become a direct indication of their functionality. We have found that the majority of the genomes of Methanomicrobiaceae family of archaea contained multiple copies of the interspersed highly similar PQSs. Short oligonucleotides corresponding to the rPQS formed the G-quadruplex (G4) structure in presence of potassium ions as demonstrated by circular dichroism (CD) and enzymatic probing. However, further analysis of the genomic context for the rPQS revealed a 10–12 nt cytosine-rich track adjacent to 3'-end of each rPQS. Synthetic DNA fragments that included the C-rich track tended to fold into alternative structures such as hairpin structure and antiparallel triplex that were in equilibrium with G4 structure depending on the presence of potassium ions in solution. Structural properties of the found repetitive sequences, their location in the genomes of archaea, and possible functions are discussed. [ABSTRACT FROM AUTHOR] more...
- Published
- 2021
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33. Deep Sequencing Revealed a CpG Methylation Pattern Associated With ALDH1L1 Suppression in Breast Cancer.
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Beniaminov, Artemy D., Puzanov, Grigory A., Krasnov, George S., Kaluzhny, Dmitry N., Kazubskaya, Tatiana P., Braga, Eleonora A., Kudryavtseva, Anna V., Melnikova, Nataliya V., and Dmitriev, Alexey A.
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BREAST cancer ,CPG nucleotides ,DNA methylation - Abstract
Hypermethylation of promoter CpG islands is generally recognized epigenetic mechanism responsible for gene silencing in cancer. However, molecular details on how this epigenetic mark triggers the process of gene downregulation are still elusive. Here, we used deep bisulfite sequencing and qPCR analysis to investigate the pattern of CpG methylation of ALDH1L1 promoter region and its association with the gene expression level in 16 paired breast cancer (BC) samples of different clinical stages. Expression of ALDH1L1 gene was suppressed in all examined BC samples up to 200-fold, and average hypermethylation level of the promoter region correlated positively with ALDH1L1 downregulation. We determined the role of every individual CpG site within the ALDH1L1 promoter, including upstream untranscribed region, first untranslated exon, and the start of the first intron, in aberrant gene expression by correlation analysis. The search revealed CpG sites which methylation has the highest impact on intensity of gene transcription. The majority of such CpG sites are located in a compact region in the first intron of the ALDH1L1 gene. These results assist in unraveling of dynamic nature of CpG promoter hypermethylation as well as demonstrate the efficiency of deep bisulfite sequencing in search for novel epigenetic markers in cancer. [ABSTRACT FROM AUTHOR] more...
- Published
- 2018
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34. Divalent cations are dispensable for binding to DNA of a novel positively charged olivomycin A derivative.
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Beniaminov, Artemy D., Dezhenkova, Lyubov G., Mamaeva, Olga K., Shchyolkina, Anna K., Tevyashova, Anna N., Kaluzhny, Dmitry N., and Shtil, Alexander A.
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CARRIER proteins ,CHEMICAL derivatives ,ANTINEOPLASTIC antibiotics ,MOLECULAR weights ,ELECTROSTATIC interaction - Abstract
The current model of binding of the antitumor antibiotic olivomycin A (1) to GC-rich DNA regions presumes that coordination of the magnesium divalent cation with drug dimers is necessary for binding of 1 into the minor groove of the DNA duplex. Previously we have synthesized the derivatives of 1 termed ‘short acid’ (2) and its N,N-dimethylaminoethylamide (3). The latter compound demonstrated an improved tolerance in vivo compared to 1 and good therapeutic potency in animal models. We herein report that compound 3 is able to form stable complexes with DNA in the absence of Mg
2+ , in striking contrast to 1 whose binding to the DNA absolutely requires Mg2+ . The mode of binding of 3 to DNA is similar in the presence or absence of Mg2+ as determined by circular dichroism. The affinity to DNA of 3 in Mg2+ -free solution was similar to that of 1 or 3 in the presence of Mg2+ at low ionic strength. Non-electrostatic contributions to total free energy of binding of 1 and 3 to DNA were comparable for Mg2+ -free complexes. Our data strongly suggest that electrostatic interaction of the positively charged 3 can compensate for the absence of divalent ions in complexes with DNA. This new property of the olivomycin A derivative expands the mechanistic knowledge of the modes of interaction with DNA of small molecular weight drug candidates. [ABSTRACT FROM AUTHOR] more...- Published
- 2018
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35. Light-induced oxidation of the telomeric G4 DNA in complex with Zn(II) tetracarboxymethyl porphyrin.
- Author
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Beniaminov, Artemy D., Novikov, Roman A., Mamaeva, Olga K., Mitkevich, Vladimir A., Smirnov, Igor P., Livshits, Mikhail A., Shchyolkina, Anna K., and Kaluzhny, Dmitry N.
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- 2016
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36. Anomeric DNA quadruplexes.
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Kolganova, Natalia A., Varizhuk, Anna M., Novikov, Roman A., Florentiev, Vladimir L., Pozmogova, Galina E., Borisova, Olga F., Shchyolkina, Anna K., Smirnov, Igor P., Kaluzhny, Dmitry N., and Timofeev, Edward N. more...
- Subjects
THROMBIN ,APTAMERS ,ANOMERIC effect ,NUCLEASES ,ANTICOAGULANTS - Abstract
Thrombin-binding aptamer (TBa) is a 15-nt DNa oligomer that efficiently inhibits thrombin. It has been shown that TBa folds into an anti-parallel unimolecular G-quadruplex. Its three-dimensional chair-like structure consists of two G-tetrads connected by TT and TGT loops. TBa undergoes fast degradation by nucleases in vivo. To improve the nuclease resistance of TBa, a number of modified analogs have been proposed. here, we describe anomeric modifications of TBa. Non-natural α anomers were used to replace selected nucleotides in the loops and core. significant stabilization of the quadruplex was observed for the anomeric modification of TT loops at T4 and T13. Replacement of the core guanines either prevents quadruplex assembly or induces rearrangement in G-tetrads. It was found that the anticoagulant properties of chimeric aptamers could be retained only with intact TT loops. On the contrary, modification of the TGT loop was shown to substantially increase nuclease resistance of the chimeric aptamer without a notable disturbance of its anticoagulant activity. [ABSTRACT FROM AUTHOR] more...
- Published
- 2014
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37. Synthesis of Triazole-Linked Oligonucleotides with High Affinity to DNA Complements and an Analysis of Their Compatibility with Biosystems.
- Author
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Varizhuk, Anna M., Kaluzhny, Dmitry N., Novikov, Roman A., Chizhov, Alexandr O., Smirnov, Igor P., Chuvilin, Andrey N., Tatarinova, Olga N., Fisunov, Gleb Y., Pozmogova, Galina E., and Florentiev, Vladimir L. more...
- Subjects
- *
TRIAZOLES , *AZOLES , *OLIGONUCLEOTIDES , *NUCLEOTIDES , *DNA - Abstract
New oligonucleotide analogues with triazole internucleotide linkages were synthesized, and their hybridization properties were studied. The analogues demonstrated DNA binding affinities similar to those of unmodified oligonucleotides. The modification was shown to protect the oligonucleotides from nuclease hydrolysis. The modified oligonucleotides were tested as PCR primers. Modifications remote from the 3'-terminus were tolerated by polymerases. Our results suggest that these new oligonucleotide analogues are among the most promising triazole DNA mimics characterized to date. [ABSTRACT FROM AUTHOR] more...
- Published
- 2013
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38. Diverse modes of 5′-[4-(aminoiminomethyl)phenyl]-[2,2′-bifuran]-5-carboximidamide (DB832) interaction with multi-stranded DNA structures.
- Author
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Kaluzhny, Dmitry N., Borisova, Olga F., and Shchyolkina, Anna K.
- Published
- 2010
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39. Novel Antitumor L-Arabinose Derivative of Indolocarbazole with High Affinity to DNA.
- Author
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Kaluzhny, Dmitry N., Tatarskiy, Victor V., Dezhenkova, Lyubov G., Plikhtyak, Irina L., Miniker, Tatyana D., Shchyolkina, Anna K., Strel'tsov, Sergey A., Chilov, Ghermes G., Novikov, Fedor N., Kubasova, Irina Yu., Smirnova, Zoya S., Mel'nik, Stalina Ya., Livshits, Mikhail A., Borisova, Olga F., and Shtil, Alexander A. more...
- Published
- 2009
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40. Discrimination between G/C Binding Sites by Olivomycin A Is Determined by Kinetics of the Drug-DNA Interaction.
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Beniaminov, Artemy D., Chashchina, Galina V., Livshits, Mikhail A., Kechko, Olga I., Mitkevich, Vladimir A., Mamaeva, Olga K., Tevyashova, Anna N., Shtil, Alexander A., Shchyolkina, Anna K., and Kaluzhny, Dmitry N. more...
- Subjects
BINDING sites ,ISOTHERMAL titration calorimetry ,ANALYTICAL mechanics ,CIRCULAR dichroism - Abstract
Olivomycin A (OA) exerts its cytotoxic potency due to binding to the minor groove of the G/C-rich DNA and interfering with replication and transcription. Screening of the complete set of tetranucleotide G/C sites by electrophoretic mobility gel shift assay (EMSA) revealed that the sites containing central GC or GG dinucleotides were able to bind OA, whereas the sites with the central CG dinucleotide were not. However, studies of equilibrium OA binding in solution by fluorescence, circular dichroism and isothermal titration calorimetry failed to confirm the sequence preference of OA, indicating instead a similar type of complex and comparable affinity of OA to all G/C binding sites. This discrepancy was resolved by kinetics analysis of the drug–DNA interaction: the dissociation rate significantly differed between SGCS, SGGS and SCGS sites (S stands for G or C), thereby explaining the disintegration of the complexes during EMSA. The functional relevance of the revealed differential kinetics of OA–DNA interaction was demonstrated in an in vitro transcription assay. These findings emphasize the crucial role of kinetics in the mechanism of OA action and provide an important approach to the screening of new drug candidates. [ABSTRACT FROM AUTHOR] more...
- Published
- 2020
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41. The English (H6R) Mutation of the Alzheimer's Disease Amyloid-β Peptide Modulates Its Zinc-Induced Aggregation.
- Author
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Radko, Sergey P., Khmeleva, Svetlana A., Kaluzhny, Dmitry N., Kechko, Olga I., Kiseleva, Yana Y., Kozin, Sergey A., Mitkevich, Vladimir A., and Makarov, Alexander A.
- Subjects
AMYLOID beta-protein ,ALZHEIMER'S disease ,ZINC ions ,CIRCULAR dichroism ,LIGHT scattering ,OPTICAL properties - Abstract
The coordination of zinc ions by histidine residues of amyloid-beta peptide (Aβ) plays a critical role in the zinc-induced Aβ aggregation implicated in Alzheimer's disease (AD) pathogenesis. The histidine to arginine substitution at position 6 of the Aβ sequence (H6R, English mutation) leads to an early onset of AD. Herein, we studied the effects of zinc ions on the aggregation of the Aβ42 peptide and its isoform carrying the H6R mutation (H6R-Aβ42) by circular dichroism spectroscopy, dynamic light scattering, turbidimetric and sedimentation methods, and bis-ANS and thioflavin T fluorescence assays. Zinc ions triggered the occurrence of amorphous aggregates for both Aβ42 and H6R-Aβ42 peptides but with distinct optical properties. The structural difference of the formed Aβ42 and H6R-Aβ42 zinc-induced amorphous aggregates was also supported by the results of the bis-ANS assay. Moreover, while the Aβ42 peptide demonstrated an increase in the random coil and β-sheet content upon complexing with zinc ions, the H6R-Aβ42 peptide showed no appreciable structural changes under the same conditions. These observations were ascribed to the impact of H6R mutation on a mode of zinc/peptide binding. The presented findings further advance the understanding of the pathological role of the H6R mutation and the role of H6 residue in the zinc-induced Aβ aggregation. [ABSTRACT FROM AUTHOR] more...
- Published
- 2020
- Full Text
- View/download PDF
42. Untitled.
- Author
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Andreeva, Daria V., Tikhomirov, Alexander S., Dezhenkova, Lyubov G., Kaluzhny, Dmitry N., Mamaeva, Olga K., Solovyova, Svetlana E., Sinkevich, Yuri B., and Shchekotikhin, Andrey E.
- Abstract
A divergent route for the synthesis of new derivatives of 4,11-diaminoanthra[2,3- b ]thiophene-5,10-dione was developed based on the introduction of cyclic amines to the terminal positions of 4,11-aminoalkyl groups. Modification of the side chains of anthra[2,3-b ]-thiophene-5,10-dione increases the affinity of ligands to DNA duplex and decreases the affinity to G-quadruplexes. An analysis of the structure–activity relationship showed that 2-(piperidin-1-yl)ethylamine is the most promising side chain fragment for the development of new double-stranded DNA ligands. The ability of new ligands to bind to DNA duplex correlates with inhibition of tumor cell growth, which indicates the prospects for a further search for new antitumor compounds or chemical probes for duplex-forming nucleic acid sequences among 4,11-diaminoanthra[2,3-b ]thiophene-5,10-diones.A divergent route for the synthesis of new derivatives of 4,11-diaminoanthra[2,3- b ]thiophene-5,10-dione was developed based on the introduction of cyclic amines to the terminal positions of 4,11-aminoalkyl groups. Modification of the side chains of anthra[2,3-b ]-thiophene-5,10-dione increases the affinity of ligands to DNA duplex and decreases the affinity to G-quadruplexes. An analysis of the structure–activity relationship showed that 2-(piperidin-1-yl)ethylamine is the most promising side chain fragment for the development of new double-stranded DNA ligands. The ability of new ligands to bind to DNA duplex correlates with inhibition of tumor cell growth, which indicates the prospects for a further search for new antitumor compounds or chemical probes for duplex-forming nucleic acid sequences among 4,11-diaminoanthra[2,3-b ]thiophene-5,10-diones.A divergent route for the synthesis of new derivatives of 4,11-diaminoanthra[2,3- b ]thiophene-5,10-dione was developed based on the introduction of cyclic amines to the terminal positions of 4,11-aminoalkyl groups. Modification of the side chains of anthra[2,3-b ]-thiophene-5,10-dione increases the affinity of ligands to DNA duplex and decreases the affinity to G-quadruplexes. An analysis of the structure–activity relationship showed that 2-(piperidin-1-yl)ethylamine is the most promising side chain fragment for the development of new double-stranded DNA ligands. The ability of new ligands to bind to DNA duplex correlates with inhibition of tumor cell growth, which indicates the prospects for a further search for new antitumor compounds or chemical probes for duplex-forming nucleic acid sequences among 4,11-diaminoanthra[2,3-b ]thiophene-5,10-diones.A divergent route for the synthesis of new derivatives of 4,11-diaminoanthra[2,3- b ]thiophene-5,10-dione was developed based on the introduction of cyclic amines to the terminal positions of 4,11-aminoalkyl groups. Modification of the side chains of anthra[2,3-b ]-thiophene-5,10-dione increases the affinity of ligands to DNA duplex and decreases the affinity to G-quadruplexes. An analysis of the structure–activity relationship showed that 2-(piperidin-1-yl)ethylamine is the most promising side chain fragment for the development of new double-stranded DNA ligands. The ability of new ligands to bind to DNA duplex correlates with inhibition of tumor cell growth, which indicates the prospects for a further search for new antitumor compounds or chemical probes for duplex-forming nucleic acid sequences among 4,11-diaminoanthra[2,3-b ]thiophene-5,10-diones.A divergent route for the synthesis of new derivatives of 4,11-diaminoanthra[2,3- b ]thiophene-5,10-dione was developed based on the introduction of cyclic amines to the terminal positions of 4,11-aminoalkyl groups. Modification of the side chains of anthra[2,3-b ]-thiophene-5,10-dione increases the affinity of ligands to DNA duplex and decreases the affinity to G-quadruplexes. An analysis of the structure–activity relationship showed that 2-(piperidin-1-yl)ethylamine is the most promising side chain fragment for the development of new double-stranded DNA ligands. The ability of new ligands to bind to DNA duplex correlates with inhibition of tumor cell growth, which indicates the prospects for a further search for new antitumor compounds or chemical probes for duplex-forming nucleic acid sequences among 4,11-diaminoanthra[2,3-b ]thiophene-5,10-diones.A divergent route for the synthesis of new derivatives of 4,11-diaminoanthra[2,3- b ]thiophene-5,10-dione was developed based on the introduction of cyclic amines to the terminal positions of 4,11-aminoalkyl groups. Modification of the side chains of anthra[2,3-b ]-thiophene-5,10-dione increases the affinity of ligands to DNA duplex and decreases the affinity to G-quadruplexes. An analysis of the structure–activity relationship showed that 2-(piperidin-1-yl)ethylamine is the most promising side chain fragment for the development of new double-stranded DNA ligands. The ability of new ligands to bind to DNA duplex correlates with inhibition of tumor cell growth, which indicates the prospects for a further search for new antitumor compounds or chemical probes for duplex-forming nucleic acid sequences among 4,11-diaminoanthra[2,3-b ]thiophene-5,10-diones.A divergent route for the synthesis of new derivatives of 4,11-diaminoanthra[2,3- b ]thiophene-5,10-dione was developed based on the introduction of cyclic amines to the terminal positions of 4,11-aminoalkyl groups. Modification of the side chains of anthra[2,3-b ]-thiophene-5,10-dione increases the affinity of ligands to DNA duplex and decreases the affinity to G-quadruplexes. An analysis of the structure–activity relationship showed that 2-(piperidin-1-yl)ethylamine is the most promising side chain fragment for the development of new double-stranded DNA ligands. The ability of new ligands to bind to DNA duplex correlates with inhibition of tumor cell growth, which indicates the prospects for a further search for new antitumor compounds or chemical probes for duplex-forming nucleic acid sequences among 4,11-diaminoanthra[2,3-b ]thiophene-5,10-diones.[ABSTRACT FROM AUTHOR] more... - Published
- 2020
- Full Text
- View/download PDF
43. Distinctive aspects of ligand binding to G4 DNA structure flanked by the double helix.
- Author
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Tevonyan LL, Fatkullin TM, Beniaminov AD, and Kaluzhny DN
- Abstract
Except for telomeres, G4 DNA structures in the human genome can be formed only within the context of double-stranded DNA. DNA duplexes flanking the G4 structure may potentially affect the G4 architecture and the binding of G4-specific ligands. Here, we examine the interaction of TMPyP4, NMM, and PDS ligands with three structures formed by the same DNA fragment containing the (GGGT)
4 sequence: the G4 in duplex (dsG4), G4 in single-stranded DNA (ssG4) and perfect duplex DNA (ds). To design a structure-specific fluorescent sensor, single thymine loops or proximal positions in DNA duplex were modified with FAM. Ligand-induced fluorescence quenching revealed a preferential binding of TMPyP4 and NMM with the dsG4 and ssG4 structures over the flanking duplex part or double-stranded DNA. PDS could not quench the fluorophores attached to single-nucleotide loops of the G4 DNA, although gel mobility assay confirmed tight binding of the ligand to the ssG4 or dsG4 structures. We hypothesize that the selectivity of the ligands for G4 loops compared to duplexes is responsible for the high quenching efficiency. Distinctive features of ligand interactions with G4 DNA in a duplex context suggest the potential for developing specific ligands for the genomic G4 structure., Competing Interests: Conflict of interest We have no conflict of interest to declare., (Copyright © 2024 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.) more...- Published
- 2024
- Full Text
- View/download PDF
44. Novel Fluorinated Porphyrins Sensitize Tumor Cells to Photodamage in Normoxia and Hypoxia: Synthesis and Biocompatible Formulations.
- Author
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Belyaeva EV, Markova AA, Kaluzhny DN, Sigan AL, Gervitz LL, Ataeva AN, Chkanikov ND, and Shtil AA
- Subjects
- Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Biocompatible Materials chemical synthesis, Biocompatible Materials chemistry, Cell Proliferation drug effects, Cell Survival drug effects, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, HCT116 Cells, Humans, Hydrocarbons, Fluorinated chemical synthesis, Hydrocarbons, Fluorinated chemistry, Hypoxia metabolism, Molecular Structure, Oxygen metabolism, Photosensitizing Agents chemical synthesis, Photosensitizing Agents chemistry, Porphyrins chemistry, Structure-Activity Relationship, Tumor Cells, Cultured, Antineoplastic Agents pharmacology, Biocompatible Materials pharmacology, Hydrocarbons, Fluorinated pharmacology, Photosensitizing Agents pharmacology, Porphyrins pharmacology
- Abstract
Background: Hypoxia renders tumor cells refractory to treatment. One way to overcome this problem is the design of drug delivery systems that contain the antitumor agent within an oxygen supply medium., Objective: to evaluate whether the perfluorocarbon liquids (capable of retaining up to 50% v/v amounts of O2 gas) can be tools for delivery of photosensitizers to hypoxic tumors., Method: We synthesized a series of compounds in which fluoroaliphatic or fluoroaromatic moieties were conjugated to the porphyrin ring in meso-positions. Two derivatives were tested as the solutions prepared either from a dimethylformamide stock ('free' formulation) or from a perfluorocarbon emulsion in which the photosensitizer is entrapped in the oxygenated medium., Results: In the emulsion the hydrophobic photosensitizer and the gas transporting liquid represented a biocompatible composition. Free formulations or perfluorocarbon emulsions of fluorinated porphyrins evoked little-to-null dark cytotoxicity. In contrast, each formulation triggered cell death upon light activation. Photodamage in the presence of fluorinated porphyrins was achievable not only at normoxic (20.9% O2 v/v) conditions but also in hypoxia (0.5% O2). With new compounds dissolved in the medium the cell photodamage in hypoxia was negligible whereas a significant photodamage was achieved with the emulsions of fluorinated porphyrins. The derivative with the fluoroalkyl substituent was more potent than its structurally close analog carrying the fluoroaryl moiety., Conclusion: Our new fluorinated porphyrin derivatives, especially their emulsions in which the photosensitizer and the oxygenated medium are coupled into one phase, can be perspective for photoelimination of hypoxic tumor cells., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.) more...
- Published
- 2018
- Full Text
- View/download PDF
45. The Oxime Derivatives of 1-R-1H-Naphtho[2,3-d][1,2,3]triazole-4,9-dione 2-oxides: Synthesis and Properties.
- Author
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Gornostaev LM, Tsvetkov VB, Markova AA, Lavrikova TI, Khalyavina YG, Kuznetsova AS, Kaluzhny DN, Shunayev AV, Tsvetkova MV, Glazunova VA, Chernyshev VV, and Shtil AA
- Subjects
- Antineoplastic Agents chemical synthesis, Cell Line, Tumor, Cell Proliferation drug effects, Drug Screening Assays, Antitumor, Humans, Molecular Docking Simulation, Spectrum Analysis methods, Structure-Activity Relationship, Triazoles chemical synthesis, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Oximes chemistry, Triazoles chemistry, Triazoles pharmacology
- Abstract
Objective: To synthesize a novel chemotype based on the naphthoquinone scaffold with retained cytotoxicity and provisionally low intracellular oxidation potential., Background: Derivatives of naphthoquinone, although potent anticancer agents, can exert heart toxicity due to generation of free oxygen species., Methods: In this study, we modified the scaffold by replacing one carbonyl group with the oxime moiety. Interestingly, only one carbonyl group in 1-R-1H-naphtho[2,3-d][1,2,3]triazole-4,9-dione 2-oxides reacted with hydroxylamine. The spatial structure was determined by X-ray analysis. New compounds were tested for the ability to form stable complexes with double stranded DNA by spectroscopy and molecular docking and to induce death of tumor cell lines and non-malignant counterparts., Results: The resulting 1-R-1H-naphtho[2,3-d][1,2,3]triazole-4,9-dione 4-oxime 2-oxides were further acylated to produce a series of 1-R-1H-naphtho[2,3-d][1,2,3]triazole-4,9-dione 4-(O-acyloxime) 2-oxides. Newly synthesized compounds demonstrated a higher (in submicromolar or low micromolar range) cytotoxic potency against human colon and breast adenocarcinoma cell lines than to non-malignant skin fibroblasts. Spectroscopic measurements revealed that, unlike other classes of quinone derivatives, new naphthotriazoledione oxides did not form stable complexes with double stranded DNA regardless of their fitting to the DNA minor groove (as determined by molecular modeling)., Conclusion: Thus, our chemical modifications yielded a new chemotype with good cytotoxic properties and yet-to-be-identified intracellular target(s)., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.) more...
- Published
- 2017
- Full Text
- View/download PDF
46. Conformational variability of recombination R-triplex formed by the mammalian telomeric sequence.
- Author
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Shchyolkina AK, Kaluzhny DN, Borisova OF, Arndt-Jovin DJ, Jovin TM, and Zhurkin VB
- Subjects
- Base Sequence, Circular Dichroism, Hydrogen Bonding, Oligonucleotides chemistry, Thermodynamics, DNA chemistry, Models, Molecular, Nucleic Acid Conformation, Telomere chemistry, Telomere genetics
- Abstract
Alignment of three nucleic acids strands, in which the third strand is identical to one of the DNA duplex strands, occurs in various cellular systems. In the case of telomeric t-loops, recognition between the DNA duplex and the homologous single strand is likely to be mediated by proteins through formation of the transient recombination-type R-triplex. Earlier, using 2-aminopurine as a fluorescent reporting base, we evaluated the thermodynamic characteristics of intramolecular R-triplex formed by a mixed nucleotide sequence. Here, we used this approach to explore a propensity of the telomeric TTAGGG repeat to form the R-triplex. The circular dichroism spectral changes detected upon formation of the R-triplex suggest that this process is accompanied by specific conformational changes in DNA, including a local destabilization of the target duplex next to a GGG run revealed by the fluorescence of the reporting 2-aminopurine base. Surprisingly, stability of the R-triplex formed by telomeric sequence depends strikingly on the counter ion, being higher for Na(+) than for Li(+). Taken together these findings indicate a significant conformational variability of telomeric DNA in the context of recombination-type R-triplex, a phenomenon of possible biological relevance. more...
- Published
- 2016
- Full Text
- View/download PDF
47. New potent and selective inhibitor of Pim-1/3 protein kinases sensitizes human colon carcinoma cells to doxorubicin.
- Author
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Moreau P, Dezhenkova LG, Anizon F, Nauton L, Thery V, Liang S, Kaluzhny DN, and Shtil AA
- Subjects
- Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Carbazoles chemical synthesis, Carbazoles chemistry, Drug Resistance, Neoplasm drug effects, Drug Screening Assays, Antitumor, HCT116 Cells, Humans, Models, Molecular, Protein Kinase Inhibitors chemical synthesis, Protein Kinase Inhibitors chemistry, Protein Serine-Threonine Kinases metabolism, Proto-Oncogene Proteins metabolism, Proto-Oncogene Proteins c-pim-1 metabolism, Pyrroles chemical synthesis, Pyrroles chemistry, Structure-Activity Relationship, Topoisomerase Inhibitors pharmacology, Antineoplastic Agents pharmacology, Carbazoles pharmacology, Doxorubicin pharmacology, Protein Kinase Inhibitors pharmacology, Protein Serine-Threonine Kinases antagonists & inhibitors, Proto-Oncogene Proteins antagonists & inhibitors, Proto-Oncogene Proteins c-pim-1 antagonists & inhibitors, Pyrroles pharmacology
- Abstract
The Pim protein kinases (provirus insertion site of Moloney murine leukemia virus) have been identified as important actors involved in tumor cell survival, proliferation, migration and invasion. Therefore, inhibition of Pim activity by low molecular weight compounds is under investigation as a part of anticancer therapeutic strategies. We have synthesized a series of pyrrolo[2,3-a]carbazole derivatives that significantly inhibited Pim protein kinases at submicromolar concentrations. Particularly, benzodiazocine derivative 1 potently inhibited Pim-1 and -3 isoforms in in vitro kinase assays (IC50 8 nM and 13 nM, respectively), whereas Pim-2 activity was less affected (IC50 350 nM). We show here that no inhibitory effect of 1 was detectable at 1 µM against other 22 serine/threonine and tyrosine kinases. In addition, 1, possessing a planar pyrrolocarbazole scaffold, demonstrated no significant binding to DNA, nor was it a potent topoisomerase I inhibitor, suggesting that 1 is likely to be highly selective for Pim-1 and -3. Importantly, whereas 1 exerted a negligible cytotoxicity for human colon carcinoma HCT116 cell line at concentrations >10 µM within 72 h of cell exposure, it synergized at nontoxic concentrations with the antitumor drug doxorubicin (Dox) in killing HCT116 cells: IC50 of Dox alone and Dox+1 were ~200 nM and ~25 nM, respectively. These data strongly suggest that 1 emerges as a prospective antitumor drug candidate due to its selectivity to individual Pim protein kinases and the ability to potentiate the efficacy of conventional chemotherapeutics. more...
- Published
- 2014
- Full Text
- View/download PDF
48. Melting of model HIV-1 stem-loop 1 RNA dimers monitored by 2-aminopurine fluorescence.
- Author
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Livshits MA, Kaluzhny DN, and Minyat EE
- Subjects
- 2-Aminopurine chemistry, Dimerization, Fluorescence, HIV-1 metabolism, Nucleic Acid Denaturation, RNA, Viral genetics, RNA, Viral metabolism, Sequence Analysis, RNA, HIV-1 genetics, Inverted Repeat Sequences genetics, Nucleic Acid Conformation, RNA, Viral chemistry
- Abstract
Viral maturation of HIV-1 involves refolding of its genomic RNA, which is believed to include a rearrangement of the SL1 stem-loop from a metastable conformation called kissing loop dimer (KD) to a stable one termed extended dimer (ED). To investigate this rearrangement in vitro we have studied the thermal melting of the RNA dimers formed by slightly modified 23-nucleotide SL1 RNA of HIV-1 Mal. Local structural changes in the RNA dimers during the melting were monitored by changes in the fluorescence of 2-aminopurine (2AP) incorporated in predetermined positions of RNA. We have shown that the stem regions of both preformed KD and ED melt in the temperature interval from 75 ° C to 90 ° C. Kissing loop interface of the KD RNA is found to be disrupted at lower temperatures from 20 ° C to 55 ° C, at which the stem regions remain intact. Conversion of the preformed KD to ED overcoming the kinetic barrier occurs between 55 ° C and 65 ° C. The melting of "loop-loop" regions in both preformed and newly formed EDs takes place around 70 ° C. Our finding that thermoinduced KD-to-ED conversion is preceded by transient dissociation of loop-loop interface disagrees with a common idea of strand exchange without disruption of loop-loop-contact. more...
- Published
- 2011
- Full Text
- View/download PDF
49. Novel Indolocarbazole Derivative 12-(α-L-arabinopyranosyl)indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7-dione Is a Preferred c-Myc Guanine Quadruplex Ligand.
- Author
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Kaluzhny DN, Shchyolkina AK, Ilyinsky NS, Borisova OF, and Shtil AA
- Abstract
The indolocarbazole derivative 12-(α-L-arabinopyranosyl)indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7-dione (AIC) has demonstrated a high potency (at nanomolar to submicromolar concentrations) towards the NCI panel of human tumor cell lines and transplanted tumors. Intercalation into the DNA double helix has been identified as an important prerequisite for AIC cytotoxicity. In this study, we provide evidence for preferential binding to the G-quadruplex derived from the c-Myc oncogene promoter (Pu18 d(AG(3)TG(4))(2); G-c-Myc). The association constant for AIC:G-c-Myc complex was ~100 times and 10 times greater than the respective values for the complexes AIC:c-Myc duplex and AIC:telomeric d(TTAGGG)(4) G-quadruplex. The concentrations at which AIC formed complexes with G-c-Myc were close to those that attenuated the steady-state level of the c-Myc mRNA in the human HCT116 colon carcinoma cell line. We suggest that preferential binding of AIC to G-c-Myc rather than to the c-Myc duplex might favor the quadruplex formation in the cells, thereby contributing to downregulation of the c-Myc expression by AIC. more...
- Published
- 2011
- Full Text
- View/download PDF
50. Intramolecular recombination R-triplex in solution: stabilization by bis-intercalator YOYO.
- Author
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Kaluzhny DN, Timoshin VV, Borisova OF, Zhurkin VB, Florentiev VL, and Shchyolkina AK
- Subjects
- Base Sequence, Molecular Structure, Nucleic Acid Conformation, Nucleic Acid Denaturation, Oligonucleotides chemistry, Thermodynamics, Benzoxazoles chemistry, DNA chemistry, Fluorescent Dyes chemistry, Intercalating Agents chemistry, Quinolinium Compounds chemistry
- Abstract
Recognition of double-stranded DNA with a mixed nucleotide sequence by oligonucleotide is a long-term challenge. This aim can be achieved via formation of the recombination R-triplex, accommodating two identical DNA strands in parallel orientation, and antiparallel complementary strand. In the absence of proteins the R-triplex stability is low, however, so that intermolecular R-triplex is not formed by three DNA strands in a ligand-free system. Recently, recognition of DNA with mixed base sequence by single-stranded oligonucleotide in the presence of bis-intercalator YOYO was reported. Here, we describe thermodynamic characteristics of YOYO complexes with the model oligonucleotides 5'-GT-2AP-GACTGAG TTTT CTCAGTCTACGC GAA GCGTAGACTGAG-3' (R(2AP)CW) bearing a single reporting 2-aminopurine (2AP) in place of adenine and 5'-CTCAGTCTACGC GAA GCGTAGACTGAG-3' (CW). We found that each oligonucleotide is able to bind two YOYO molecules via intercalation mode in 0.5 M LiCl. Fluorescence intensity of YOYO intercalated in triplex R(2AP)CW and in CW hairpin increased 40-fold compared to the free YOYO. Remarkably, the melting temperature of the triplex (determined using temperature dependence of the 2AP fluorescence) increased from 19 degrees C to 33 degrees C upon binding two YOYO molecules. Further increase in the YOYO concentration resulted in binding of up to five YOYO molecules to R(2AP)CW triplex and up to six YOYO molecules to CW hairpin. more...
- Published
- 2008
- Full Text
- View/download PDF
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