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 IC50 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.

• Klíčová slova
• Apoptosis, Cancer, Cytotoxicity, Heterocycle, Mitochondria, Pharmacology, Phthalate, Phthalimide, Pyrone, Triterpene,
• MeSH
• antitumorózní látky * terapeutické užití   MeSH
• apoptóza MeSH
• DNA metabolismus   MeSH
• ftalimidy farmakologie   MeSH
• kyseliny ftalové * MeSH
• membránový potenciál mitochondrií MeSH
• mitochondrie metabolismus   MeSH
• nádorové buněčné linie MeSH
• nádory * farmakoterapie   MeSH
• pyrony farmakologie   MeSH
• triterpeny * farmakologie   MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antitumorózní látky * MeSH
• DNA MeSH
• ftalimidy MeSH
• kyseliny ftalové * MeSH
• phthalic acid MeSH Prohlížeč
• pyrony MeSH
• triterpeny * MeSH

Cancer is one of the main causes of death worldwide. Chemotherapy, despite its severe side effects, is to date one of the leading strategies against cancer. Metal-based drugs present several potential advantages when compared to organic compounds and they have gained trust from the scientific community after the approval on the market of the drug cisplatin. Recently, we reported the ruthenium complex ([Ru(DIP)2 (sq)](PF6 ) (where DIP is 4,7-diphenyl-1,10-phenantroline and sq is semiquinonate) with a remarkable potential as chemotherapeutic agent against cancer, both in vitro and in vivo. In this work, we analyse a structurally similar compound, namely [Ru(DIP)2 (mal)](PF6 ), carrying the flavour-enhancing agent approved by the FDA, maltol (mal). To possess an FDA approved ligand is crucial for a complex, whose mechanism of action might include ligand exchange. Herein, we describe the synthesis and characterisation of [Ru(DIP)2 (mal)](PF6 ), its stability in solutions and under conditions that resemble the physiological ones, and its in-depth biological investigation. Cytotoxicity tests on different cell lines in 2D model and on HeLa MultiCellular Tumour Spheroids (MCTS) demonstrated that our compound has higher activity than cisplatin, inspiring further tests. [Ru(DIP)2 (mal)](PF6 ) was efficiently internalised by HeLa cells through a passive transport mechanism and severely affected the mitochondrial metabolism.

• Klíčová slova
• DNA, bioinorganic chemistry, cancer, medicinal inorganic chemistry, ruthenium,
• MeSH
• antitumorózní látky chemie   farmakologie   MeSH
• cisplatina chemie   farmakologie   MeSH
• HeLa buňky MeSH
• komplexní sloučeniny chemie   farmakologie   MeSH
• lidé MeSH
• ligandy MeSH
• molekulární struktura MeSH
• pyrony chemie   farmakologie   MeSH
• ruthenium chemie   farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antitumorózní látky MeSH
• cisplatina MeSH
• komplexní sloučeniny MeSH
• ligandy MeSH
• maltol MeSH Prohlížeč
• pyrony MeSH
• ruthenium MeSH

The aim of the present study is to evaluate the role of ATM (KU55933) and DNA-PK (NU7441) inhibitors in the repair of double-strand breaks and downstream signaling of DNA damage introduced by ionizing radiation. The irradiation of MCF-7 cells alone increased the proportion of cells in the G1 phase in comparison with mock-treated cells. After ATM inhibitor pretreatment, the cells were more accumulated in the G2 phase, whereas DNA-PK inhibitor application increased the percentage of cells in the G1 phase. ATM and DNA-PK inhibitor application alone increased the sensitivity of MCF-7 cells to ionizing radiation; however, combining both inhibitors together resulted in a further enhancement of cell death. Unexpectedly, combining both inhibitors decreased the percentage of senescent cells and increased G2 cell cycle arrest 3 days after treatment. After irradiation, the p21 protein was increased and Chk1 and Chk2 were activated. These proteins were not increased in cells pretreated with the ATM inhibitor prior to ionizing radiation exposure, albeit DNA-PK inhibitor application did not affect the amount of proteins detected. Formation of γH2AX was found to be ATM and DNA-PK dependent, application of the ATM inhibitor suppressed incidence of γH2AX, whereas DNA-PK caused persistence of γH2AX. Our results suggest that the further investigation of the ATM inhibitor in combination with the DNA-PK inhibitor as sensitizers preventing cell senescence and promoting cell death in breast carcinoma MCF-7 cells is warranted.

• MeSH
• ATM protein antagonisté a inhibitory   metabolismus   MeSH
• buněčná smrt účinky léků   MeSH
• checkpoint kinasa 1 MeSH
• checkpoint kinasa 2 metabolismus   MeSH
• chromony farmakologie   MeSH
• DNA vazebné proteiny antagonisté a inhibitory   MeSH
• G1 fáze účinky léků   MeSH
• G2 fáze účinky léků   MeSH
• histony MeSH
• inhibitor p21 cyklin-dependentní kinasy metabolismus   MeSH
• ionizující záření MeSH
• kontrolní body buněčného cyklu účinky léků   MeSH
• lidé MeSH
• MFC-7 buňky MeSH
• morfoliny farmakologie   MeSH
• nádorové buněčné linie MeSH
• oprava DNA účinky léků   MeSH
• poškození DNA účinky léků   MeSH
• proteinkinasa aktivovaná DNA antagonisté a inhibitory   metabolismus   MeSH
• proteinkinasy metabolismus   MeSH
• protokoly antitumorózní kombinované chemoterapie farmakologie   MeSH
• pyrony farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 2-morpholin-4-yl-6-thianthren-1-yl-pyran-4-one MeSH Prohlížeč
• 8-dibenzothiophen-4-yl-2-morpholin-4-yl-chromen-4-one MeSH Prohlížeč
• ATM protein, human MeSH Prohlížeč
• ATM protein MeSH
• CDKN1A protein, human MeSH Prohlížeč
• checkpoint kinasa 1 MeSH
• checkpoint kinasa 2 MeSH
• CHEK1 protein, human MeSH Prohlížeč
• CHEK2 protein, human MeSH Prohlížeč
• chromony MeSH
• DNA vazebné proteiny MeSH
• H2AX protein, human MeSH Prohlížeč
• histony MeSH
• inhibitor p21 cyklin-dependentní kinasy MeSH
• morfoliny MeSH
• proteinkinasa aktivovaná DNA MeSH
• proteinkinasy MeSH
• pyrony MeSH

We compared the effects of inhibitors of kinases ATM (KU55933) and ATR (VE-821) (incubated for 30 min before irradiation) on the radiosensitization of human promyelocyte leukaemia cells (HL-60), lacking functional protein p53. VE-821 reduces phosphorylation of check-point kinase 1 at serine 345, and KU55933 reduces phosphorylation of check-point kinase 2 on threonine 68 as assayed 4 h after irradiation by the dose of 6 Gy. Within 24 h after gamma-irradiation with a dose of 3 Gy, the cells accumulated in the G2 phase (67 %) and the number of cells in S phase decreased. KU55933 (10 μM) did not affect the accumulation of cells in G2 phase and did not affect the decrease in the number of cells in S phase after irradiation. VE-821 (2 and 10 μM) reduced the number of irradiated cells in the G2 phase to the level of non-irradiated cells and increased the number of irradiated cells in S phase, compared to irradiated cells not treated with inhibitors. In the 144 h interval after irradiation with 3 Gy, there was a considerable induction of apoptosis in the VE-821 group (10 μM). The repair of the radiation damage, as observed 72 h after irradiation, was more rapid in the group exposed solely to irradiation and in the group treated with KU55933 (80 and 77 % of cells, respectively, were free of DSBs), whereas in the group incubated with 10 μM VE-821, there were only 61 % of cells free of DSBs. The inhibition of kinase ATR with its specific inhibitor VE-821 resulted in a more pronounced radiosensitizing effect in HL-60 cells as compared to the inhibition of kinase ATM with the inhibitor KU55933. In contrast to KU55933, the VE-821 treatment prevented HL-60 cells from undergoing G2 cell cycle arrest. Taken together, we conclude that the ATR kinase inhibition offers a new possibility of radiosensitization of tumour cells lacking functional protein p53.

• MeSH
• akutní promyelocytární leukemie patologie   MeSH
• apoptóza účinky léků   MeSH
• ATM protein antagonisté a inhibitory   MeSH
• HL-60 buňky MeSH
• inhibitory proteinkinas farmakologie   MeSH
• kontrolní body fáze G2 buněčného cyklu účinky léků   MeSH
• lidé MeSH
• morfoliny farmakologie   MeSH
• oprava DNA účinky léků   MeSH
• pyraziny farmakologie   MeSH
• pyrony farmakologie   MeSH
• sulfony farmakologie   MeSH
• tolerance záření účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 2-morpholin-4-yl-6-thianthren-1-yl-pyran-4-one MeSH Prohlížeč
• 3-amino-6-(4-(methylsulfonyl)phenyl)-N-phenylpyrazine-2-carboxamide MeSH Prohlížeč
• ATM protein MeSH
• ATR protein, human MeSH Prohlížeč
• inhibitory proteinkinas MeSH
• morfoliny MeSH
• pyraziny MeSH
• pyrony MeSH
• sulfony MeSH

DNA lesions trigger the DNA damage response (DDR) machinery, which protects genomic integrity and sustains cellular survival. Increasing data underline the significance of the integrity of the DDR pathway in chemotherapy response. According to a recent work, persistent exposure of A549 lung carcinoma cells to doxorubicin induces an initial DDR-dependent checkpoint response, followed by a later DDR-independent, but p27(Kip1)-dependent one. Prompted by the above report and to better understand the involvement of the DDR signaling after chemotherapeutic stress, we examined the potential role of the canonical DDR pathway in A549 cells treated with doxorubicin. Exposure of A549 cells, prior to doxorubicin treatment, to ATM, ATR and DNA-PKcs inhibitors either alone or in various combinations, revealed that the earlier documented two-step response was DDR-dependent in both steps. Notably, inhibition of both ATM and ATR or selective inhibition of ATM or DNA-PKcs resulted in cell-cycle re-entry despite the increased levels of p27(Kip1) at all time points analyzed. We further investigated the regulation of p27(Kip1) protein levels in the particular setting. Our results showed that the protein status of p27(Kip1) is mainly determined by p38-MAPK, whereas the role of SKP2 is less significant in the doxoroubicin-treated A549 cells. Cumulatively, we provide evidence that the DNA damage signaling is responsible for the prolonged cell cycle arrest observed after persistent chemotherapy-induced genotoxic stress. In conclusion, precise identification of the molecular mechanisms that are activated during the chemotherapeutic cycles could potentially increase the sensitization to the therapy applied.

• Klíčová slova
• ATM, ATR, DNA damage response, DNA-PKcs, SKP2, cell cycle arrest, chemotherapy, p27Kip1, p38-MAPK,
• MeSH
• antitumorózní látky farmakologie   MeSH
• ATM protein antagonisté a inhibitory   MeSH
• buňky A549 MeSH
• chromony farmakologie   MeSH
• doxorubicin farmakologie   MeSH
• inhibitor p27 cyklin-dependentní kinasy fyziologie   MeSH
• kofein farmakologie   MeSH
• kontrolní body fáze G2 buněčného cyklu účinky léků   MeSH
• lidé MeSH
• mitogenem aktivované proteinkinasy p38 metabolismus   MeSH
• morfoliny farmakologie   MeSH
• poškození DNA MeSH
• proteinkinasa aktivovaná DNA antagonisté a inhibitory   MeSH
• proteiny asociované s kinázou S-fáze metabolismus   MeSH
• pyrony farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 2-morpholin-4-yl-6-thianthren-1-yl-pyran-4-one MeSH Prohlížeč
• 8-dibenzothiophen-4-yl-2-morpholin-4-yl-chromen-4-one MeSH Prohlížeč
• antitumorózní látky MeSH
• ATM protein, human MeSH Prohlížeč
• ATM protein MeSH
• CDKN1B protein, human MeSH Prohlížeč
• chromony MeSH
• doxorubicin MeSH
• inhibitor p27 cyklin-dependentní kinasy MeSH
• kofein MeSH
• mitogenem aktivované proteinkinasy p38 MeSH
• morfoliny MeSH
• proteinkinasa aktivovaná DNA MeSH
• proteiny asociované s kinázou S-fáze MeSH
• pyrony MeSH

The effect of protein kinase C (PKC) inhibitors on porcine oocyte activation by calcium ionophore A23187 was studied. Calcium ionophore applied in a 50 microM concentration for 10 min induced activation in 74% of oocytes matured in vitro. When the ionophore-treated oocytes were exposed to the effect of bisindolylmaleimide I, which inhibits calcium-dependent PKC isotypes (PKC-alpha, -beta(I), -beta(II), -gamma,) and calcium-independent PKC isotypes (PKC-delta, -epsilon), the portion of activated oocytes decreased (at a concentration of 100 nM, 2% of the oocytes were activated). Go6976, the inhibitor of calcium-dependent PKC isotypes PKC-alpha, -beta(I) did not prevent the action of the oocytes treated with calcium ionophore in concentrations from 1 to 100 microM. The inhibitor of PKC-beta(I) and beta(II) isotypes, hispidin, in a concentration of 2 microM-2 mM, was not effective either. The inhibitor of PKC-delta isotype, rottlerin, suppressed activation of the oocytes by calcium ionophore (no oocyte was activated at 10 microM concentration). The PKC-delta isotype in matured porcine oocytes, studied by Western blot analysis, appeared as non-truncated PKC-delta of 77.5 kDa molecular weight, on the one hand, and as truncated PKC-delta, which was present in the form of a doublet of approximately 62.5 and 68 kDa molecular weight, on the other hand. On the basis of these results, it can be supposed that PKC participates in the regulation of processes associated with oocyte activation. Calcium-dependent PKC-alpha, -beta isotypes do not seem to play any significant role in calcium activation. The activation seems to depend on the activity of the calcium-independent PKC-delta isoform.

• MeSH
• acetofenony farmakologie   MeSH
• benzopyrany farmakologie   MeSH
• calcimycin farmakologie   MeSH
• indoly farmakologie   MeSH
• inhibitory proteinkinas farmakologie   MeSH
• ionofory farmakologie   MeSH
• izoenzymy antagonisté a inhibitory   klasifikace   fyziologie   MeSH
• karbazoly farmakologie   MeSH
• maleimidy farmakologie   MeSH
• oocyty účinky léků   fyziologie   MeSH
• prasata fyziologie   MeSH
• proteinkinasa C antagonisté a inhibitory   klasifikace   fyziologie   MeSH
• pyrony farmakologie   MeSH
• techniky in vitro MeSH
• vápník fyziologie   MeSH
• western blotting MeSH
• zvířata MeSH
• Check Tag
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• acetofenony MeSH
• benzopyrany MeSH
• bisindolylmaleimide I MeSH Prohlížeč
• calcimycin MeSH
• Go 6976 MeSH Prohlížeč
• hispidin MeSH Prohlížeč
• indoly MeSH
• inhibitory proteinkinas MeSH
• ionofory MeSH
• izoenzymy MeSH
• karbazoly MeSH
• maleimidy MeSH
• proteinkinasa C MeSH
• pyrony MeSH
• rottlerin MeSH Prohlížeč
• vápník MeSH

Since members of hydroxypyrone series posses iron chelating properties, kojic acid (KA), 5-hydroxy-2-(hydroxymethyl)-4H-pyran-one, a fungal metabolite of natural origin, has been suggested to might play a role in iron-overload diseases and in oxidative stress conditions involving transition metal. In our experiments in vivo models of iron-overload were used to study iron-chelating properties of KA and its effect on oxidative damage in mice and rats. The treatment of iron-preloaded rats (25 mg Fe x kg(-1) b.w., i.p., daily for five days) with 0.5% KA in drinking water for four weeks did not lower the iron concentration accumulated in the liver, neither diminished the induced hepatic lipid peroxidation in iron-loaded rats. The GSH level decreased in KA-treated group. Similarly, in iron-loaded mice model experiment, the following oral treatment with KA (100 mg x kg(-1)) daily for 7 days did not decrease the level of Fe accumulated in the liver and the lipid peroxidation even enhanced after KA treatment. Though in our experiments in vivo the ability of kojic acid to affect iron kinetics in the organism could not be proved, kojic acid as a molecule of natural origin may serve as a template for the preparation of new biologically active derivatives possessing capability of chelating iron.

• MeSH
• aplikace orální MeSH
• chelátory železa farmakologie   MeSH
• deferoxamin farmakologie   MeSH
• játra metabolismus   MeSH
• krysa rodu Rattus MeSH
• myši MeSH
• peroxidace lipidů MeSH
• potkani Wistar MeSH
• přetížení železem farmakoterapie   MeSH
• pyrony farmakologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• chelátory železa MeSH
• deferoxamin MeSH
• kojic acid MeSH Prohlížeč
• pyrony MeSH

Kojic acid (5-hydroxy-2-hydroxymethyl-4-pyranone) represents an attractive polyfunctional skeleton for development of biologically active compounds. The authors prepared a great variety of kojic acid derivatives and selected biological properties have been studied. Thus, kojic acid derivatives are promising compounds that might advantageously be used in human and/or veterinary medicine and also in preparation of new, even more biologically active preparations.

• MeSH
• antifungální látky chemická syntéza   farmakologie   MeSH
• antitumorózní látky chemická syntéza   farmakologie   MeSH
• leukemie L1210 farmakoterapie   MeSH
• lidé MeSH
• pyrony chemie   farmakologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antifungální látky MeSH
• antitumorózní látky MeSH
• kojic acid MeSH Prohlížeč
• pyrony MeSH

Azidometalkojates of the general formula MX2 (M = Cu, Mn, Mg, Zn or Ni and X = 5-hydroxy-2-azidomethyl-4H-pyran-4-one) were prepared and tested for antibacterial, antifungal and cytotoxic effects. The mangan and zinc derivatives are not active against any the tested microorganisms. A weak antibacterial activity was found with the copper derivative. The strongest antifungal effects were shown by the nickel derivative while the highest cytotoxic effect on HeLa cells was manifested by the zinc derivative.

• MeSH
• antibakteriální látky chemická syntéza   chemie   farmakologie   MeSH
• antifungální látky chemická syntéza   chemie   farmakologie   MeSH
• antitumorózní látky chemická syntéza   chemie   farmakologie   MeSH
• Bacteria účinky léků   MeSH
• HeLa buňky účinky léků   MeSH
• houby účinky léků   MeSH
• kationty MeSH
• lidé MeSH
• měď MeSH
• mikrobiální testy citlivosti MeSH
• molekulární struktura MeSH
• pyrony chemie   farmakologie   MeSH
• racionální návrh léčiv MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• srovnávací studie MeSH
• Názvy látek
• 5-hydroxy-2-azidomethyl-4H-pyran-4-one MeSH Prohlížeč
• antibakteriální látky MeSH
• antifungální látky MeSH
• antitumorózní látky MeSH
• kationty MeSH
• kojic acid MeSH Prohlížeč
• měď MeSH
• pyrony MeSH

The present paper investigates the antibiotic properties of the novel antifungal antibiotic agent cortalceron and its semisynthetic derivative cortalceron 7-diphenylhydrazone. The MIC values were assayed by the agar diffusion method. Cortalceron was found to weakly inhibit the growth of E. coli and B. subtilis. The growth of yeast was not influenced. On i.v. administration to mice [correction of rats], the agent produced breathing disorders and convulsions which later disappeared. The diphenylhydrazine derivative of cortalceron inhibited the growth of most yeasts tested as well.

• MeSH
• antibakteriální látky farmakologie   toxicita   MeSH
• antifungální látky farmakologie   MeSH
• Bacteria účinky léků   MeSH
• houby účinky léků   MeSH
• hydrazony farmakologie   toxicita   MeSH
• mikrobiální testy citlivosti MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• pyrony farmakologie   toxicita   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• anglický abstrakt MeSH
• časopisecké články MeSH
• Názvy látek
• 2-hydroxy-2H-pyran-3(6H)-one-2-carboxaldehyde diphenylhydrazone MeSH Prohlížeč
• antibakteriální látky MeSH
• antifungální látky MeSH
• cortalcerone MeSH Prohlížeč
• hydrazony MeSH
• pyrony MeSH