8 results on '"Skvortsov, Dmitry A."'
Search Results
2. [4+2]-Cycloaddition to 5-Methylidene-Hydantoins and 5-Methylidene-2-Thiohydantoins in the Synthesis of Spiro-2-Chalcogenimidazolones.
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Shybanov, Dmitry E., Kukushkin, Maxim E., Hrytseniuk, Yanislav S., Grishin, Yuri K., Roznyatovsky, Vitaly A., Tafeenko, Viktor A., Skvortsov, Dmitry A., Zyk, Nikolai V., and Beloglazkina, Elena K.
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ESCHERICHIA coli ,DIELS-Alder reaction ,RING formation (Chemistry) ,CYCLOHEXADIENE ,NITRILE oxides ,ALKYLATION - Abstract
Novel hydantion and thiohydantoin-based spiro-compounds were prepared via theDiels–Alder reactions between 5-methylidene-hydantoins or 5-methylidene-2-thiohydantoins and 1,3-dienes (cyclopentadiene, cyclohexadiene, 2,3-dimethylbutadiene, isoprene). It was shown that the cycloaddition reactions proceed regioselectively and stereoselectively with the formation of exo-isomers in the reactions with cyclic dienes andthe less sterically hindered products in the reactions with isoprene. Reactions of methylideneimidazolones with cyclopentadiene proceed viaco-heating the reactants; reactions with cyclohexadiene, 2,3-dimethylbutadiene, and isoprene require catalysis by Lewis acids. It was demonstrated that ZnI
2 is an effective catalyst in the Diels–Alder reactions of methylidenethiohydantoins with non-activated dienes. The possibility of alkylation and acylation of the obtained spiro-hydantoinsat the N(1)nitrogen atoms with PhCH2 Cl or Boc2 O and the alkylation of the spiro-thiohydantoinsat the S atoms with MeI or PhCH2 Cl in high yields have been demonstrated. The preparativetransformation of spiro-thiohydantoins into corresponding spiro-hydantoinsin mild conditions by treating with 35% aqueous H2 O2 or nitrile oxide has been carried out. The obtained compounds show moderate cytotoxicity in the MTT test on MCF7, A549, HEK293T, and VA13 cell lines. Some of the tested compounds demonstrated some antibacterial effect against Escherichia coli (E. coli) BW25113 DTC-pDualrep2 but were almost inactive against E. coli BW25113 LPTD-pDualrep2. [ABSTRACT FROM AUTHOR]- Published
- 2023
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3. Synthesis and Biological Evaluation of Novel Dispiro -Indolinones with Anticancer Activity.
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Ivanenkov, Yan A., Kukushkin, Maxim E., Beloglazkina, Anastasia A., Shafikov, Radik R., Barashkin, Alexander A., Ayginin, Andrey A., Serebryakova, Marina S., Majouga, Alexander G., Skvortsov, Dmitry A., Tafeenko, Viktor A., and Beloglazkina, Elena K.
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BIOSYNTHESIS ,ANTINEOPLASTIC agents ,DRUG target ,MOLECULAR docking ,CONFOCAL microscopy ,FLUORESCENT dyes - Abstract
Novel variously substituted thiohydantoin-based dispiro-indolinones were prepared using a regio- and diastereoselective synthetic route from 5-arylidene-2-thiohydantoins, isatines, and sarcosine. The obtained molecules were subsequently evaluated in vitro against the cancer cell lines LNCaP, PC3, HCT
wt , and HCT(−/−) . Several compounds demonstrated a relatively high cytotoxic activity vs. LNCaP cells (IC50 = 1.2–3.5 µM) and a reasonable selectivity index (SI = 3–10). Confocal microscopy revealed that the conjugate of propargyl-substituted dispiro-indolinone with the fluorescent dye Sulfo-Cy5-azide was mainly localized in the cytoplasm of HEK293 cells. P388-inoculated mice and HCT116-xenograft BALB/c nude mice were used to evaluate the anticancer activity of compound 29 in vivo. Particularly, the TGRI value for the P388 model was 93% at the final control timepoint. No mortality was registered among the population up to day 31 of the study. In the HCT116 xenograft model, the compound (170 mg/kg, i.p., o.d., 10 days) provided a T/C ratio close to 60% on day 8 after the treatment was completed. The therapeutic index—estimated as LD50 /ED50 —for compound 29 in mice was ≥2.5. Molecular docking studies were carried out to predict the possible binding modes of the examined molecules towards MDM2 as the feasible biological target. However, such a mechanism was not confirmed by Western blot data and, apparently, the synthesized compounds have a different mechanism of cytotoxic action. [ABSTRACT FROM AUTHOR]- Published
- 2023
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4. Synthesis and Biological Evaluation of S-, O- and Se-Containing Dispirooxindoles.
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Kukushkin, Maksim, Novotortsev, Vladimir, Filatov, Vadim, Ivanenkov, Yan, Skvortsov, Dmitry, Veselov, Mark, Shafikov, Radik, Moiseeva, Anna, Zyk, Nikolay, Majouga, Alexander, and Beloglazkina, Elena
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BIOSYNTHESIS ,YLIDES ,CHALCOGENS ,RING formation (Chemistry) ,COLORECTAL cancer ,CELL lines ,DOUBLE bonds - Abstract
A series of novel S-, O- and Se-containing dispirooxindole derivatives has been synthesized using 1,3-dipolar cycloaddition reaction of azomethine ylide generated from isatines and sarcosine at the double C=C bond of 5-indolidene-2-chalcogen-imidazolones (chalcogen was oxygen, sulfur or selenium). The cytotoxicity of these dispiro derivatives was evaluated in vitro using different tumor cell lines. Several molecules have demonstrated a considerable cytotoxicity against the panel and showed good selectivity towards colorectal carcinoma HCT116 p53
+/+ over HCT116 p53−/− cells. In particular, good results have been obtained for LNCaP prostate cell line. The performed in silico study has revealed MDM2/p53 interaction as one of the possible targets for the synthesized molecules. However, in contrast to selectivity revealed during the cell-based evaluation and the results obtained in computational study, no significant p53 activation using a reporter construction in p53wt A549 cell line was observed in a relevant concentration range. [ABSTRACT FROM AUTHOR]- Published
- 2021
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5. Anticancer activity of G4-targeting phenoxazine derivatives in vitro.
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Lizunova, Sofia A., Tsvetkov, Vladimir B., Skvortsov, Dmitry A., Kamzeeva, Polina N., Ivanova, Olga M., Vasilyeva, Lilja A., Chistov, Alexey A., Belyaev, Evgeny S., Khrulev, Alexei A., Vedekhina, Tatiana S., Bogomazova, Alexandra N., Lagarkova, Maria A., Varizhuk, Anna M., and Aralov, Andrey V.
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ANTINEOPLASTIC agents , *CELL nuclei , *NUCLEOSIDE derivatives , *LIVER cells , *PROMOTERS (Genetics) , *POISONS , *CANCER cells - Abstract
G4-stabilizing ligands are now being considered as anticancer, antiviral and antibacterial agents. Phenoxazine is a promising scaffold for the development of G4 ligands. Here, we profiled two known phenoxazine-based nucleoside analogs and five new nucleoside and non-nucleoside derivatives against G4 targets from telomere repeats and the KIT promoter region. Leading new derivatives exhibited remarkably high G4-stabilizing effects (comparable or superior to the effects of the commonly used selective G4 ligands PDS and NMM) and selectivity toward G4s over duplex (superior to BRACO-19). All phenoxazine-based ligands inhibited cellular metabolic activity. The phenoxazine derivatives were particularly toxic for lung adenocarcinoma cells A549' and human liver cancer cells HepG2 (CC 50 of the nucleoside analogues in the nanomolar range), but also affected breast cancer cells MCF7, as well as immortalized fibroblasts VA13 and embryonic kidney cells HEK293t (CC 50 in the micromolar range). Importantly, the CC 50 values varied mostly in accordance with G4-binding affinities and G4-stabilizing effects, and the phenoxazine derivatives localized in the cell nuclei, which corroborates G4-mediated mechanisms of action. • Phenoxazine-based derivatives were probed as G4 ligands. • Some derivatives exhibited remarkably high G4-stabilizing effects and selectivity. • All phenoxazine-based ligands inhibited cellular metabolic activity. • The ligands were particularly toxic for lung adenocarcinoma cells. • Localization in the cell nuclei corroborated G4-mediated mechanisms of action. [ABSTRACT FROM AUTHOR]
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- 2022
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6. Dispirooxindoles Based on 2-Selenoxo-Imidazolidin-4-Ones: Synthesis, Cytotoxicity and ROS Generation Ability.
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Novotortsev, Vladimir K., Kukushkin, Maxim E., Tafeenko, Viktor A., Skvortsov, Dmitry A., Kalinina, Marina A., Timoshenko, Roman V., Chmelyuk, Nelly S., Vasilyeva, Liliya A., Tarasevich, Boris N., Gorelkin, Petr V., Erofeev, Alexander S., Majouga, Alexander G., Zyk, Nikolai V., Beloglazkina, Elena K., and Plano Amatriain, Daniel
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REACTIVE oxygen species ,INDOLINE ,ISOXAZOLIDINES ,FORMALDEHYDE ,SCHIFF bases ,TETRAZOLIUM ,YLIDES ,SPIRO compounds - Abstract
A regio- and diastereoselective synthesis of two types of dispiro derivatives of 2-selenoxoimidazolidin-4-ones, differing in the position of the nitrogen atom in the central pyrrolidine ring of the spiro-fused system—namely, 2-selenoxodispiro[imidazolidine-4,3′-pyrrolidine-2′,3″-indoline]-2″,5-diones (5a-h) and 2-senenoxodispiro[imidazolidine-4,3′-pyrrolidine-4′,3″-indoline]-2″,5-diones (6a-m)—were developed based on a 1,3-dipolar cycloaddition of azomethine ylides generated from isatin and sarcosine or formaldehyde and sarcosine to 5-arylidene or 5-indolidene-2-selenoxo-tetrahydro-4H-imidazole-4-ones. Selenium-containing dispiro indolinones generally exhibit cytotoxic activity near to the activity of the corresponding oxygen and sulfur-containing derivatives. Compounds 5b, 5c, and 5e demonstrated considerable in vitro cytotoxicity in the 3-(4,5-dimethylthiazol-2-yl)2,5-diphenyl tetrazolium bromide (MTT) test (concentration of compounds that caused 50% death of cells (CC
50 ) 7.6–8.7 μM) against the A549 cancer cell line with the VA13/A549 selectivity index 5.2–6.9; some compounds (5 and 6) increased the level of intracellular reactive oxygen species (ROS) in the experiment on A549 and PC3 cells using platinized carbon nanoelectrode. The tests for p53 activation for compounds 5 and 6 on the transcriptional reporter suggest that the investigated compounds can only have an indirect p53-dependent mechanism of action. For the compounds 5b, 6b, and 6l, the ROS generation may be one of the significant mechanisms of their cytotoxic action. [ABSTRACT FROM AUTHOR]- Published
- 2021
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7. Synthesis and biological activity of 5-aryliden-2-thiohydantoin S-aryl derivatives.
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Finko, Alexander V., Skvortsov, Dmitry A., Laikov, Dimitri N., Averochkin, Gleb M., Dlin, Egor A., Kalinina, Marina A., Aladinskiy, Vladimir A., Vorobyeva, Nataliya S., Mironov, Andrei V., Beloglazkina, Elena K., Zyk, Nikolay V., Ivanenkov, Yan A., and Majouga, Alexander G.
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BIOSYNTHESIS , *ARYL iodides , *ANDROGEN receptors , *BIOACTIVE compounds , *ALLOSTERIC regulation , *MOLECULAR docking - Abstract
• Three suggested methods of synthesis are mutually complementing. • Two hits caused activation of androgen receptor, but not P53. • Allosteric regulation of the androgen receptor by the hits has been concluded. • One hit to significant activation of the P53 cascade, but not AR. • P53 activation due to hit interaction with MDM2 has been concluded. Three new and complementary approaches to S-arylation of 2-thiohydantoins have been developed: copper-catalyzed cross coupling with either arylboronic acids or aryl iodides under mild conditions, or direct nucleophilic substitution in activated aryl halides. For 38 diverse compounds, reaction yields for all three methods have been determined. Selected by molecular docking, they have been tested on androgen receptor activation, and p53-Mdm2 regulation, and A549, MCF7, VA13, HEK293T, PC3, LnCAP cell lines for cytotoxicity, Two of them turned out to be promising as androgen receptor activators (likely by allosteric regulation), and another one is shown to activate the p53 cascade. It is hoped that 2-thiohydantoin S-arylidenes are worth further studies as biologically active compounds. [ABSTRACT FROM AUTHOR]
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- 2020
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8. Synthesis, characterisation, cytotoxicity and antibacterial activity of ruthenium(II) and rhodium(III) complexes with sulfur-containing terpyridines.
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Beloglazkina, Elena K., Manzheliy, Eugeniy A., Moiseeva, Anna A., Maloshitskaya, Olga A., Zyk, Nikolai V., Skvortsov, Dmitry A., Osterman, Ilya A., Sergiev, Petr V., Dontsova, Olga A., Ivanenkov, Yan A., Veselov, Mark S., and Majouga, Alexander G.
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CELL-mediated cytotoxicity , *ANTIBACTERIAL agents , *RUTHENIUM catalysts , *RHODIUM compounds synthesis , *PYRIDINE synthesis - Abstract
The synthesis and characterisation of novel thioacetyl-functionalised terpyridine ligands and their ruthenium and rhodium complexes [Ru(tpy) 2 ](PF 6 ) 2 , [Rh(tpy) 2 ](PF 6 ) 3 , [Ru(phen)(tpy)Cl](PF 6 ), [Rh(phen)(tpy)Cl](PF 6 ) 2 (phen = phenanthroline; tpy = S-[ω-(2,2:6′,2″-terpyridin-4′-yl)phenoxy]alkyl ethanethioate) have been described. Ligands and complexes were characterised by 1 H NMR spectroscopy, mass spectrometry, elemental analysis and cyclic voltammetry data. The crystal structure of the complex [Rh(phen)(tpy)Cl](PF 6 ) 2 (phen = phenanthroline; tpy = 4′-phenyl-2,2′:6′,2″-terpyridine) ( 21 ), have been determined by X-ray crystallography. Complex 21 show a distorted octahedral geometry around the ruthenium centre. Antimicrobial activity toward Escherichia coli at concentrations as low as 5 μM was found for some of the studied complexes. For complexes [Rh(tpy C 6 H 4 O(CH 2 ) 8 SCOCH 3 ) 2 ](PF 6 ) 3 ( 19 ), [Rh(phen)(tpy C 6 H 4 O (CH 2 ) 8 SCOCH 3 )Cl](PF 6 ) 2 ( 31 ) and [Rh(phen)(tpy C 6 H 4 O (CH 2 ) 11 SCOCH 3 )Cl](PF 6 ) 2 ( 32 ), a strong inhibition of in vitro protein synthesis was observed using firefly luciferase. An investigation of cytotoxicity of the complexes against human embryonic kidney cells (HEK293 line) by the MTT assay demonstrates that the toxicity of all tested compounds is of similar magnitude, with IC 50 values of 3–30 μM. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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