9 results on '"Džubák, Petr"'
Search Results
2. Novel 7-Chloro-(4-thioalkylquinoline) Derivatives: Synthesis and Antiproliferative Activity through Inducing Apoptosis and DNA/RNA Damage.
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Gutiérrez, Joyce E., Fernandez-Moreira, Esteban, Rodríguez, Miguel A., Mijares, Michael R., De Sanctis, Juan Bautista, Gurská, Soňa, Džubák, Petr, Hajdůch, Marián, Bruno-Colmenarez, Julia, Rojas, Luis, Deffieux, Denis, Pouységu, Laurent, Quideau, Stéphane, Charris, Jaime, and Ramírez, Hegira
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DNA synthesis ,DNA ,RNA ,CANCER cells ,CELL lines ,SULFONYL compounds - Abstract
A series of 78 synthetic 7-chloro-(4-thioalkylquinoline) derivatives were investigated for cytotoxic activity against eight human cancer as well as 4 non-tumor cell lines. The results showed, with some exceptions, that sulfanyl 5–40 and sulfinyl 41–62 derivatives exhibited lower cytotoxicity for cancer cell lines than those of well-described sulfonyl N-oxide derivatives 63–82. As for compound 81, the most pronounced selectivity (compared against BJ and MRC-5 cells) was observed for human cancer cells from HCT116 (human colorectal cancer with wild-type p53) and HCT116p53−/− (human colorectal cancer with deleted p53), as well as leukemia cell lines (CCRF-CEM, CEM-DNR, K562, and K562-TAX), lung (A549), and osteosarcoma cells (U2OS). A good selectivity was also detected for compounds 73 and 74 for leukemic and colorectal (with and without p53 deletion) cancer cells (compared to MRC-5). At higher concentrations (5 × IC
50 ) against the CCRF-CEM cancer cell line, we observe the accumulation of the cells in the G0/G1 cell phase, inhibition of DNA and RNA synthesis, and induction of apoptosis. In addition, X-ray data for compound 15 is being reported. These results provide useful scientific data for the development of 4-thioalkylquinoline derivatives as a new class of anticancer candidates. [ABSTRACT FROM AUTHOR]- Published
- 2022
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3. Steroid Glycosides Hyrcanoside and Deglucohyrcanoside: On Isolation, Structural Identification, and Anticancer Activity.
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Rimpelová, Silvie, Zimmermann, Tomáš, Drašar, Pavel B., Dolenský, Bohumil, Bejček, Jiří, Kmoníčková, Eva, Cihlářová, Petra, Gurská, Soňa, Kuklíková, Lucie, Hajdůch, Marián, Ruml, Tomáš, Opletal, Lubomír, Džubák, Petr, and Jurášek, Michal
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STEROID glycosides ,CARDIAC glycosides ,OUABAIN ,CELL cycle ,METABOLITES - Abstract
Cardiac glycosides (CGs) represent a group of sundry compounds of natural origin. Most CGs are potent inhibitors of Na
+ /K+ -ATPase, and some are routinely utilized in the treatment of various cardiac conditions. Biological activities of other lesser known CGs have not been fully explored yet. Interestingly, the anticancer potential of some CGs was revealed and thereby, some of these compounds are now being evaluated for drug repositioning. However, high systemic toxicity and low cancer cell selectivity of the clinically used CGs have severely limited their utilization in cancer treatment so far. Therefore, in this study, we have focused on two poorly described CGs: hyrcanoside and deglucohyrcanoside. We elaborated on their isolation, structural identification, and cytotoxicity evaluation in a panel of cancerous and noncancerous cell lines, and on their potential to induce cell cycle arrest in the G2/M phase. The activity of hyrcanoside and deglucohyrcanoside was compared to three other CGs: ouabain, digitoxin, and cymarin. Furthermore, by in silico modeling, interaction of these CGs with Na+ /K+ -ATPase was also studied. Hopefully, these compounds could serve not only as a research tool for Na+ /K+ -ATPase inhibition, but also as novel cancer therapeutics. [ABSTRACT FROM AUTHOR]- Published
- 2021
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4. Antimicrobial and cytotoxic activity of (thio)alkyl hexopyranosides, nonionic glycolipid mimetics.
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Džubák, Petr, Gurská, Soňa, Bogdanová, Kateřina, Uhríková, Daniela, Kanjaková, Nina, Combet, Sophie, Klunda, Tomáš, Kolář, Milan, Hajdúch, Marian, and Poláková, Monika
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GLYCOLIPIDS , *GALACTOSE , *EUKARYOTIC cells , *ENTEROCOCCUS faecalis , *GALACTOSIDES , *CELL lines , *GLYCOSIDES - Abstract
A series of 19 synthetic alkyl and thioalkyl glycosides derived from d -mannose, d -glucose and d -galactose and having C 10 –C 16 aglycone were investigated for cytotoxic activity against 7 human cancer and 2 non-tumor cell lines as well as for antimicrobial potential on 12 bacterial and yeast strains. The most potent compounds were found to be tetradecyl and hexadecyl β- d -galactopyranosides (18, 19), which showed the best cytotoxicity and therapeutic index against CCRF-CEM cancer cell line. Similar cytotoxic activity showed hexadecyl α- d -mannopyranoside (5) but it also inhibited non-tumor cell lines. Because these two galactosides (18, 19) were inactive against all tested bacteria and yeast strains, they could be a target-specific for eukaryotic cells. On the other hand, β-D-glucopyranosides with tetradecyl (11) and hexadecyl (12) aglycone inhibited only Gram-positive bacterial strain Enterococcus faecalis. The studied glycosides induce changes in the lipid bilayer thickness and lateral phase separation at high concentration, as derived from SAXS experiments on POPC model membranes. In general, glucosides and galactosides exhibit more specific properties. Those with longer aglycone show high cytotoxicity and therefore, they are more promising candidates for cancer cell line targeted inhibition. Image 1 • β-Hexopyranosides having C14-16 aglycone were the most potent glycosides. • Such two β-D-glucosides selectively inhibited a G+ strain Enterococcus faecalis. • Such two β- d -galactosides could be an agent specific for eukaryotic cells. • Tetradecyl β- d -galactoside was the most cytotoxic (IC 50 9.4 μM, CCRF-CEM line). [ABSTRACT FROM AUTHOR]
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- 2020
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5. Novel triterpenoid pyrones, phthalimides and phthalates are selectively cytotoxic in CCRF-CEM cancer cells – Synthesis, potency, and mitochondrial mechanism of action.
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Kazakova, Anna, Frydrych, Ivo, Jakubcová, Nikola, Pokorný, Jan, Lišková, Barbora, Gurská, Soňa, Džubák, Petr, Hajdúch, Marián, and Urban, Milan
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PHTHALIMIDES , *CANCER cells , *PHTHALATE esters , *CELL cycle , *MITOCHONDRIA , *TRITERPENOIDS , *TRIPHENYLAMINE , *DNA synthesis - Abstract
A series of triterpenoid pyrones was synthesized and subsequently modified to introduce phthalimide or phthalate moieties into the triterpenoid skeleton. These compounds underwent in vitro cytotoxicity screening, revealing that a subset of six compounds exhibited potent activity, with IC 50 values in the low micromolar range. Further biological evaluations, including Annexin V and propidium iodide staining experiment revealed, that all compounds induce selective apoptosis in cancer cells. Measurements of mitochondrial potential, cell cycle analysis, and the expression of pro- and anti-apoptotic proteins confirmed, that apoptosis was mediated via the mitochondrial pathway. These findings were further supported by cell cycle modulation and DNA/RNA synthesis studies, which indicated a significant increase in cell accumulation in the G0/G1 phase and a marked reduction in S-phase cells, alongside a substantial inhibition of DNA synthesis. The activation of caspase-3 and the cleavage of PARP, coupled with a decrease in the expression of Bcl-2 and Bcl-XL proteins, underscored the induction of apoptosis through the mitochondrial pathway. Given their high activity and pronounced effect on mitochondria function, trifluoromethyl pyrones 1f and 2f , and dihydrophthalimide 2h have been selected for further development. [Display omitted] • A set of novel triterpenoid pyrones, phthalimides and phthalates was synthesized. • Six compounds with high in vitro cytotoxicity in CCRF-CEM cells was identified. • All compounds induce apoptosis via the mitochondrial intrinsic pathway. • Pyrones 1f , 2f , and dihydrophthalimide 2h were selected for further development. [ABSTRACT FROM AUTHOR]
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- 2024
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6. Triazole-based estradiol dimers prepared via CuAAC from 17α-ethinyl estradiol with five-atom linkers causing G2/M arrest and tubulin inhibition.
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Jurášek, Michal, Řehulka, Jiří, Hrubá, Lenka, Ivanová, Aleksandra, Gurská, Soňa, Mokshyna, Olena, Trousil, Pavel, Huml, Lukáš, Polishchuk, Pavel, Hajdúch, Marián, Drašar, Pavel B., and Džubák, Petr
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METHOXY group , *CELL anatomy , *CELL cycle , *TUBULINS , *BENZYL group , *ESTRADIOL , *RNA synthesis , *DIMERS - Abstract
[Display omitted] • Triazole-Based Estradiol dimers inhibit tubulin assembly in vitro. • Triazole-Based Estradiol dimers reversibly disrupt microtubule structures in U2OS cells. • Triazole-Based Estradiol dimers show cytotoxic activities on cancer cell lines, arrest cells in the G2/M phase of the cell cycle and attenuate DNA/RNA synthesis. • Structural changes in the bridge are essential for the activity of estradiol dimers at the cytoskeletal level. • Simple linkers seem more suitable than more complex ones, bulky groups (benzyl pendants), are reducing the activity. Microtubule dynamic is exceptionally sensitive to modulation by small-molecule ligands. Our previous work presented the preparation of microtubule-targeting estradiol dimer (ED) with anticancer activity. In the present study, we explore the effect of selected linkers on the biological activity of the dimer. The linkers were designed as five-atom chains with carbon, nitrogen or oxygen in their centre. In addition, the central nitrogen was modified by a benzyl group with hydroxy or methoxy substituents and one derivative possessed an extended linker length. Thirteen new dimers were subjected to cytotoxicity assay and cell cycle profiling. Dimers containing linker with benzyl moiety substituted with one or more methoxy groups and longer branched ones were found inactive, whereas other structures had comparable efficacy as the original ED (e.g. D1 with IC 50 = 1.53 µM). Cell cycle analysis and immunofluorescence proved the interference of dimers with microtubule assembly and mitosis. The proposed in silico model and calculated binding free energy by the MM-PBSA method were closely correlated with in vitro tubulin assembly assay. [ABSTRACT FROM AUTHOR]
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- 2023
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7. Lupane derivatives containing various aryl substituents in the position 3 have selective cytostatic effect in leukemic cancer cells including resistant phenotypes.
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Borková, Lucie, Frydrych, Ivo, Vránová, Barbora, Jakubcová, Nikola, Lišková, Barbora, Gurská, Soňa, Džubák, Petr, Pavliš, Petr, Hajdúch, Marián, and Urban, Milan
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BETULINIC acid , *CELL permeability , *CANCER cells , *MICROSOMES , *CELL cycle , *CELL lines - Abstract
In this work, a large set of betulinic acid derivatives modified with various aromatic substituents at the position C-3 were prepared via Suzuki-Myiaura cross-coupling. All compounds were tested for their in vitro cytotoxic activity in 8 cancer and 2 healthy cell lines. Derivatives 6h , 6i , and 6o had the lowest IC 50 in the CCRF-CEM cell line (0.69–4.0 μM) and had high selectivity. In addition, 6h and 6i also showed significant activity in daunorubicin-resistant CEM and taxol-resistant K562 cell lines; therefore, they were selected for the evaluation of the mechanism of action. First, the effect of 6h , 6i , and 6o on cell death induction was studied. To our surprise, we have not detected almost any apoptotic cells, even following a long-time exposure of CCRF-CEM cells to the compounds. On the other hand, a dramatic cell number decrease was observed, proportional to the time of the compound's exposure. Based on this data it was concluded that the effect of compounds is cytostatic rather than cytotoxic, which was further confirmed by subsequent studies of the impact of 6h , 6i , and 6o on the cell cycle. Detailed cell cycle analysis revealed a block in the G1 phase accompanied by reduced expression of phosphorylated forms of the RB protein as well as cyclin A protein. Evaluation of the pharmacological properties of the most promising compounds revealed their high stability in the presence of phosphate buffer, human plasma, and microsomes and limited permeability determined using permeability through artificial membrane (PAMPA) and cell permeability assay: Caco-2 and MDCK-MDR1 cell lines. Compounds 6h , 6i , and 6o were selected for further drug development; their cytostatic effect may be advantageous in this process since we expect fewer non-specific interactions and toxicity than in highly cytotoxic compounds. In addition, the activity of 6h and 6i against resistant CEM-DNR and K562-TAX leukemic cell lines makes them promising as a possible future alternative to currently used therapies. [Display omitted] • Arylated lupane derivatives were prepared and their cytotoxicity tested. • Pharmacological parameters and selectivity were measured. • Most active compounds were cytostatic against leukemic cells including resistant. • Compounds 6h , 6i , 6o were selected for further drug development. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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8. Substituted dienes prepared from betulinic acid – Synthesis, cytotoxicity, mechanism of action, and pharmacological parameters.
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Pokorný, Jan, Olejníková, Denisa, Frydrych, Ivo, Lišková, Barbora, Gurská, Soňa, Benická, Sandra, Šarek, Jan, Kotulová, Jana, Hajdúch, Marián, Džubák, Petr, and Urban, Milan
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BETULINIC acid , *WITTIG reaction , *DIOLEFINS , *CELL death , *CELL cycle , *CANCER cells - Abstract
A set of new substituted dienes were synthesized from betulinic acid by its oxidation to 30-oxobetulinic acid followed by the Wittig reaction. Cytotoxicity of all compounds was tested in vitro in eight cancer cell lines and two noncancer fibroblasts. Almost all dienes were more cytotoxic than betulinic acid. Compounds 4.22 , 4.30 , 4.33 , 4.39 had IC 50 below 5 μmol/L; 4.22 and 4.39 were selected for studies of the mechanism of action. Cell cycle analysis revealed an increase in the number of apoptotic cells at 5 × IC 50 concentration, where activation of irreversible changes leading to cell death can be expected. Both 4.22 and 4.39 led to the accumulation of cells in the G0/G1 phase with partial inhibition of DNA/RNA synthesis at 1 × IC 50 and almost complete inhibition at 5 × IC 50. Interestingly, compound 4.39 at 5 × IC 50 caused the accumulation of cells in the S phase. Higher concentrations of tested drugs probably inhibit more off-targets than lower concentrations. Mechanisms disrupting cellular metabolism can induce the accumulation of cells in the S phase. Both compounds 4.22 and 4.39 trigger selective apoptosis in cancer cells via intrinsic pathway, which we have demonstrated by changes in the expression of the crucial apoptosis-related protein. Pharmacological parameters of derivative 4.22 were superior to 4.39 , therefore 4.22 was the finally selected candidate for the development of anticancer drug. [Display omitted] • Forty new triterpenoids were prepared from 30-oxobetulinic acid by Wittig reaction • Four compounds had high selective cytotoxicity to cancer cells • Compounds 4.22 and 4.39 were selected for further development • Both compounds cause selective apoptosis in cancer cells via the intrinsic pathway • Diene 4.22 has appropriate pharmacological parameters and will be further developed [ABSTRACT FROM AUTHOR]
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- 2021
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9. Fluorinated derivatives of 2-phenyl-3-hydroxy-4(1H)-quinolinone as tubulin polymerization inhibitors.
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Řehulka, Jiří, Vychodilová, Kristýna, Krejčí, Petr, Gurská, Soňa, Hradil, Pavel, Hajdúch, Marián, Džubák, Petr, and Hlaváč, Jan
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TUBULINS , *CELL cycle , *POLYMERIZATION , *CELL analysis , *CELL imaging , *CELL lines , *PIPERAZINE - Abstract
We have synthesized a series of 2-phenyl-3-hydroxy-4(1 H)-quinolinone derivatives substituted with one or more fluorine atoms on the quinolone backbone as well as on phenyl ring. The derivatives bearing more fluorine atoms were subjected to modification by nucleophilic substitutions by thiophenol, morpholine, and piperazine derivative. We have tested the prepared compounds in cytotoxic activity assay against cancer cell lines. Four derivatives exhibited micromolar values of IC 50 against some of the cancer cell lines, and we have subjected them to cell cycle analysis on CCRF-CEM. Moreover, most active 7-fluoro-3-hydroxy-2-phenyl-6-(phenylthio)quinolin-4(1 H)-one inhibits mitosis progression. Cell cycle analysis, in vitro tubulin polymerization assay, and tubulin imaging in cells indicated that the anticancer activity of thiophenol derivative is associated with its ability to inhibit microtubule formation. Image 1 • Fluorine in 2-phenyl-3-hydroxy-4(1 H)-quinolinone improves biological activity. • Difluoroderivatives of 3-hydroxy-4(1 H)-quinolinone enable nucleophilic substitution. • 2-phenyl-3-hydroxy-4(1 H)-quinolinones can inhibit tubulin polymerization. [ABSTRACT FROM AUTHOR]
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- 2020
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