The novel copper complex [Cu(phen)2(salubrinal)](ClO4)2 (C0SAL) has been synthesised and characterised. Copper(ii) is coordinated by salubrinal through the thionic group, as shown by the UV-Vis, IR, ESI-MS and tandem mass results, together with the theoretical calculations. The formed complex showed a DPPH radical scavenging ability higher than that of salubrinal alone. Studies on lipid oxidation inhibition showed that the C0SAL concentration, required to inhibit the enzyme, was lower than that of salubrinal. The inhibition of the enzyme could take place via allosteric modulation, as suggested by docking calculations. C0SAL showed a good cytotoxic activity on A2780 cells, 82 fold higher than that of the precursor salubrinal and 1.4 fold higher than that of [Cu(phen)2(H2O)](ClO4)2. Treatment with C0SAL in SKOV3 ovarian cancer cells induced expression of GRP-78 and DDIT3 regulators of ER-stress response. The cytotoxic effect of C0SAL was reverted in the presence of TUDCA, suggesting that C0SAL induces cell death through ER-stress. In A2780 cells treated with C0SAL γ-H2AX was accumulated, suggesting that DNA damage was also involved.
- MeSH
- antivirové látky farmakologie MeSH
- cinnamáty farmakologie MeSH
- fenantroliny farmakologie MeSH
- kyselina taurochenodeoxycholová farmakologie MeSH
- lidé MeSH
- magnetická rezonanční spektroskopie MeSH
- měď farmakologie MeSH
- molekulární struktura MeSH
- nádorové buněčné linie MeSH
- peroxidace lipidů účinky léků MeSH
- poškození DNA účinky léků genetika MeSH
- thiomočovina analogy a deriváty farmakologie MeSH
- transkripční faktor CHOP genetika metabolismus MeSH
- transmisní elektronová mikroskopie MeSH
- viabilita buněk účinky léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The synthesis of novel imidazole derivatives via immobilized α-acylamino ketones is reported in this article. The key intermediates were prepared from the Wang-piperazine resin-supported Fmoc-amino acids. After their sulfonylation with 4-nitrobenzenesulfonyl chloride (4-Nos-Cl), followed by alkylation with α-bromoketones and cleavage of Nos group, the resulting α-acylamino ketones were reacted with Fmoc-isothiocyanate. The corresponding Fmoc-thioureas were subjected to the Fmoc-cleavage and spontaneous ring-closure to imidazole scaffold. The resulting imidazole-thiones were alkylated with alkyl halides and oxidized using meta-chloroperbenzoic acid ( mCPBA). Trifluoroacetic acid (TFA)-mediated cleavage yielded the corresponding trisubstituted 2-alkylsulfonyl imidazoles in good crude purity and acceptable overall yields. In the case of sulfides, prepared from alkyl bromides, the unexpected products brominated at the C4 position of the imidazole were obtained.
- MeSH
- alkylace MeSH
- aminokyseliny chemie MeSH
- cyklizace MeSH
- fluoreny chemie MeSH
- halogenace MeSH
- imidazoly chemická syntéza MeSH
- ketony chemie MeSH
- kyselina trifluoroctová chemie MeSH
- molekulární struktura MeSH
- oxidace-redukce MeSH
- piperazin chemie MeSH
- sulfony chemie MeSH
- techniky syntézy na pevné fázi MeSH
- thioketony chemie MeSH
- thiomočovina analogy a deriváty chemie MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
BACKGROUND: The possible use of acridines as anticancer agents was first considered in the 1920´s. Since then, a large number of acridine drugs have been tested as antitumour agents, including compounds containing sulphur on the acridine chromophore. In this review, we will discuss recent studies which have investigated the anticancer activity of this class of acridine derivatives. METHODS: We present the results both of our own decade-long research and also of existing research literature into the anticancer activity of acridine derivatives containing sulphur. The evidence of specific tumor-cell killing properties displayed by these compounds suggest the potential of using such molecules as anticancer therapeutics. RESULTS: During the last decade, a number of acridine analogs have been developed by modifying the position and the nature of the substituent on the acridine core. In this paper, we published results on the anticancer activity of acridine derivatives containing sulfur (acridine thioureas, acridine thiazolidine/thiazoidinone, and acridine thiosemicarbazones/ thiosemicarbazides). In cancer chemotherapy, the mechanism of the drugs is complex, although the study of the anticancer activity of acridines has yielded exciting results. CONCLUSION: In this review we have summarized recent literature on the anticancer activity of acridine derivatives containing sulfur. A considerable amount of published data suggests that these compounds exhibit promising anticancer activity against selected cancer cell lines. The obtained results can be helpful in the development of new pharmaceutical agents.
- MeSH
- akridiny farmakologie MeSH
- antitumorózní látky farmakologie MeSH
- léky antitumorózní - screeningové testy MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- thiazolidiny farmakologie MeSH
- thiomočovina analogy a deriváty farmakologie MeSH
- thiosemikarbazony farmakologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
AIMS: The diverse physiological functions of histamine are mediated through distinct histamine receptors. In this study we investigated the role of H2R and H4R in the effects of histamine on the production of reactive oxygen species by phagocytes in whole blood. MAIN METHODS: Changes in reactive oxygen species (ROS) production by whole blood phagocytes after treatment with histamine, H4R agonists (4-methylhistamine, VUF8430), H2R agonist (dimaprit) and their combinations with H4R antagonist (JNJ10191584) and H2R antagonist (ranitidine) were determined using the chemiluminescence (CL) assay. To exclude the direct scavenging effects of the studied compounds on the CL response, the antioxidant properties of all compounds were measured using several methods (TRAP, ORAC, and luminol-HRP-H2O2 based CL). KEY FINDINGS: Histamine, 4-methylhistamine, VUF8430 and dimaprit inhibited the spontaneous and OZP-activated whole blood CL in a dose-dependent manner. On the other hand, only VUF8430 was able to inhibit PMA-activated whole blood CL. Ranitidine, but not JNJ10191584, completely reduced the effects of histamine, 4-methylhistamine and dimaprit. The direct scavenging ability of tested compounds was negligible. SIGNIFICANCE: Our results demonstrate that the inhibitory effects of histamine on ROS production in whole blood phagocytes were caused by H2R. Our results also suggest that H4R agonists in concentrations higher than 10(-6)M may also influence ROS production via binding to H2R.
- MeSH
- agonisté histaminu farmakologie MeSH
- benzimidazoly farmakologie MeSH
- dimaprit farmakologie MeSH
- fagocyty účinky léků metabolismus MeSH
- guanidiny farmakologie MeSH
- histamin fyziologie MeSH
- lidé MeSH
- methylhistaminy farmakologie MeSH
- reaktivní formy kyslíku krev MeSH
- receptory histaminu H2 metabolismus MeSH
- receptory histaminu metabolismus MeSH
- receptory spřažené s G-proteiny agonisté metabolismus MeSH
- thiomočovina analogy a deriváty farmakologie MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Tyreostatiká sú relatívne jednoduché molekuly známe ako tionamidy, obsahujú sulfhydrylovú skupinu a polovičný podiel thiourey v heterocyklickej štruktúre. Propylthiouracyl (6-propyl‐2-sulfanylidén‐1,2,3,4-tetrahydropyrimidín‐4-jeden) a metimazol (1-metyl‐2,3-dihydro‐1H‐imidazol‐2-thión) sú tyreostatiká, ktoré sa používajú v USA. Metimazol sa častejšie používa v Európe a Ázii a karbimazol – analóg metimazolu sa používa vo Veľkej Británii a častiach britského Commonwealthu. Primárnym účinkom je inhibícia syntézy tyreoidálnych hormónov následkom interferencie s tyreoperoxidázou, ktorá umožňuje jodidáciu tyrozínových reziduí v tyreoglobulíne a je dôležitým krokom v syntéze tyroxínu a trijódotyronínu. Propyltiouracyl (nie však metimazol a carbimazol) blokuje konverziu tyroxínu na trijódotyronín v štítnej žľaze a periférnych tkanivách. Tyreostatiká majú klinicky dôležité imunosupresívne účinky. Nežiadúce účinky tionamidov sú zvyčajne mierne, závažné neočakávané účinky sa pozorujú v menej ako 5 % prípadov, častejšie sa vyskytujú v úvodnej fáze liečby, kedy je denná dávka lieku najvyššia.
Antithyroid drugs are relatively simple molecules known as thionamides, which contain a sulfhydryl group and a thiourea moiety within a heterocyclic structure. Propylthiouracil (6-propyl‐2-sulfanylidene‐1,2,3,4-tetrahydropyrimidin‐4-one) and methimazole (1-metyl‐2,3-dihydro‐1H‐imidazole‐2-thione) are the antithyroid drugs used in the United States. Methimazole is used in most of Europe and Asia, and carbimazole – methimazole analogue, is used in the United Kingdom and parts of the former British Commonwealth. Their primary effect is to inhibit thyroid hormone synthesis by interfering with thyroid peroxidase‐mediated iodination of tyrosine residues in thyroglobulin and is an important step in the synthesis of thyroxine and triiodothyronine. Propylthiouracil (but not methimazole or carbimazole), can block the conversion of thyroxine to triiodothyronine within the thyroid and in peripheral tissues. Antithyroid drugs may have clinically important immunosuppressive effects. Side effects of thionamides are usually mild, serious untoward effects are observed in < 5% of cases, more frequently during the initial phases of treatment, when the drug daily dose is higher.
- MeSH
- abnormality vyvolané léky MeSH
- beta blokátory škodlivé účinky terapeutické užití MeSH
- hypertyreóza farmakoterapie MeSH
- jodidy farmakologie škodlivé účinky terapeutické užití MeSH
- komplikace těhotenství farmakoterapie MeSH
- lidé MeSH
- methimazol * aplikace a dávkování farmakologie škodlivé účinky MeSH
- nemoci jater etiologie MeSH
- propylthiouracil * farmakologie škodlivé účinky terapeutické užití MeSH
- radioizotopy jodu farmakologie škodlivé účinky terapeutické užití MeSH
- těhotenství MeSH
- thiomočovina analogy a deriváty terapeutické užití MeSH
- thyreostatika * aplikace a dávkování škodlivé účinky terapeutické užití MeSH
- Check Tag
- lidé MeSH
- těhotenství MeSH
- Publikační typ
- přehledy MeSH
The aim of this study was to find out whether opening of mitochondrial large-conductance Ca(2+)-activated potassium channels (BK(Ca)) protects cardiomyocytes against injury caused by simulated ischemia and reperfusion. This study also aimed to determine whether the protective mechanism involves signaling by reactive oxygen species (ROS) and phosphatidylinositol-3-kinase (PI3K). We used isolated ventricular myocytes, which are believed to contain no functional BK(Ca) channels in the sarcolemma. Cells were isolated from the left ventricles of adult male Wistar rats and subjected to 25-min metabolic inhibition with NaCN and 2-deoxyglucose followed by 30-min re-energization. NS11021 (0.1 μmol/L), a novel BK(Ca) channel opener, or hydrogen peroxide (2 μmol/L) added at re-energization, increased cell survival (the number of rod-shaped cells) and markedly reduced the release of lactate dehydrogenase (LDH). These cytoprotective effects of NS11021 were completely abolished by paxilline, a BK(Ca) inhibitor, or tempol, an antioxidant, but not by wortmannin, an inhibitor of PI3K. NS11021 slightly but significantly increased the fluorescence signal in 2'7'-dichlorodihydrofluorescein diacetate (DCF-DA)-loaded myocytes, indicating an increased ROS formation. The NS11021-induced ROS formation was abolished by paxilline or tempol. NS13558 (0.1 μmol/L), an inactive structural analogue of NS11021, affected neither cell survival/LDH release nor DCF-DA fluorescence. These results suggest that pharmacological activation of mitochondrial BK(Ca) channels effectively protects isolated cardiomyocytes against injury associated with simulated reperfusion. The mechanism for this form of protection requires ROS signaling, but not the activation of the PI3K pathway.
- MeSH
- kardiomyocyty účinky léků fyziologie MeSH
- kardiovaskulární látky metabolismus MeSH
- krysa rodu rattus MeSH
- L-laktátdehydrogenasa analýza MeSH
- peroxid vodíku metabolismus MeSH
- potkani Wistar MeSH
- reperfuzní poškození myokardu patologie prevence a kontrola MeSH
- tetrazoly metabolismus MeSH
- thiomočovina analogy a deriváty metabolismus MeSH
- vápníkem aktivované draslíkové kanály s vysokou vodivostí - alfa-podjednotky agonisté metabolismus MeSH
- viabilita buněk účinky léků MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- MeSH
- arginin analogy a deriváty MeSH
- citrulin analogy a deriváty MeSH
- dieta s nízkým obsahem soli MeSH
- finanční podpora výzkumu jako téma MeSH
- krysa rodu rattus MeSH
- ledviny fyziologie MeSH
- synthasa oxidu dusnatého biosyntéza fyziologie MeSH
- thiomočovina analogy a deriváty MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
