A series of new heteroleptic copper(II) complexes of the composition [Cu(L)(bpy)]NO3·2MeOH (1), [Cu(L)(dimebpy)]NO3·2H2O (2), [Cu(L)(phen)]NO3·2MeOH (3), [Cu(L)(bphen)]NO3·MeOH (4), [Cu(L)(dppz)]NO3·MeOH (5) was prepared, where HL = 3-(3,4-dihydroxyphenyl)-5-hydroxy-8,8-dimethyl-6-(3-methylbut-2-ene-1-yl)-4H,8H-benzo[1,2-b:3,4-b']dipyran-4-one, (pomiferin) and bpy = 2,2'-bipyridine, dimebpy = 4,4'-dimethyl-2,2'-bipyridine, phen = 1,10-phenanthroline, bphen = 4,7-diphenyl-1,10-phenanthroline, and dppz = dipyrido[3,2-a:2',3'-c]phenazine. The complexes were characterized using elemental analysis, infrared and UV/Vis spectroscopies, mass spectrometry, thermal analysis and conductivity measurements. The in vitro cytotoxicity, screened against eight human cancer cell lines (breast adenocarcinoma (MCF-7), osteosarcoma (HOS), lung adenocarcinoma (A549), prostate adenocarcinoma (PC-3), ovarian carcinoma (A2780), cisplatin-resistant ovarian carcinoma (A2780R), colorectal adenocarcinoma (Caco-2) and monocytic leukemia (THP-1), revealed the complexes as effective antiproliferative agents, with the IC50 values of 2.2-13.0 μM for the best performing complexes 3 and 5. All the complexes 1-5 showed the best activity against the A2780R cells (IC50 = 2.2-6.6 μM), and moreover, the complexes demonstrated relatively low toxicity on healthy human hepatocytes, with IC50 > 100 μM. The complexes were evaluated by the Annexin V/propidium iodide apoptosis assay, induction of cell cycle modifications in A2780 cells, production of reactive oxygen species (ROS), perturbation of mitochondrial membrane potential, inhibition of apoptosis and inflammation-related signaling pathways (NF-κB/AP-1 activity, NF-κB translocation, TNF-α secretion), and tested for nuclease mimicking activity. The obtained results revealed the corresponding complexes to be effective antiproliferative and anti-inflammatory agents.
- MeSH
- antiflogistika farmakologie MeSH
- apoptóza účinky léků MeSH
- benzopyrany chemie farmakologie MeSH
- flavonoidy metabolismus farmakologie MeSH
- isoflavony chemie farmakologie MeSH
- komplexní sloučeniny chemie farmakologie MeSH
- lidé MeSH
- měď chemie metabolismus farmakologie MeSH
- nádorové buněčné linie MeSH
- proliferace buněk účinky léků MeSH
- protinádorové látky farmakologie MeSH
- reaktivní formy kyslíku metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
This work presents a deeper pharmacological evaluation of two formerly prepared and characterized, and highly in vitro cytotoxic platinum(II) oxalato complexes [Pt(ox)(L1)2] (1) and [Pt(ox)(L2)2] (2), containing the derivatives of cyclin-dependent kinase inhibitor (CDKi) seliciclib ((R)-roscovitine, CYC202) coordinating as N-donor carrier ligands, i.e., 2-(1-ethyl-2-hydroxyethylamino)-N6-(4-methoxybenzyl)-9-isopropyladenine (L1) and 2-chloro-N6-(2,4-dimethoxybenzyl)-9-isopropyladenine (L2). The positive results of in vitro cytotoxicity screening on human cancer cell lines (HeLa, HOS, A2780, A2780R, G361 and MCF7 with IC50 at low micromolar levels) published previously, motivated us to perform extended preclinical in vitro experiments to reveal the mechanisms associated with the induction of cancer cell death. In addition, the in vivo antitumor activity was evaluated using the mouse lymphocytic leukaemia L1210 model. The obtained results revealed that complex 1 exceeds the antitumor effect of cisplatin (as for the extension of life-span of mice) and shows far less adverse effects as compared to reference drug cisplatin. The in vitro and ex vivo studies of cellular effects and molecular mechanisms of cell death induction showed that the mechanism of action of complex 1 is essentially different from that of cisplatin. The obtained results showed a possible way how to obtain antitumor active platinum(II) oxalato complexes with better therapeutic profile than contemporary used platinum-based therapeutics.
- MeSH
- apoptóza účinky léků MeSH
- cisplatina škodlivé účinky MeSH
- lidé MeSH
- lymfom patologie MeSH
- myši inbrední DBA MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- organoplatinové sloučeniny chemie MeSH
- oxaláty chemie MeSH
- protinádorové látky chemie farmakologie MeSH
- roskovitin chemie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
We report in vitro and in vivo anti-inflammatory activities of a series of copper(II)-lawsone complexes of the general composition [Cu(Law)2(LN)x(H2O)(2-x)]·yH2O; where HLaw = 2-hydroxy-1,4-naphthoquinone, x = 1 when LN = pyridine (1) and 2-aminopyridine (3) and x = 2 when LN = imidazole (2), 3-aminopyridine (4), 4-aminopyridine (5), 3-hydroxypyridine (6), and 3,5-dimethylpyrazole (7). The compounds were thoroughly characterized by physical techniques, including single crystal X-ray analysis of complex 2. Some of the complexes showed the ability to suppress significantly the activation of nuclear factor κB (NF-κB) both by lipopolysaccharide (LPS) and TNF-alpha (complexes 3-7 at 100 nM level) in the similar manner as the reference drug prednisone (at 1 μM level). On the other hand, all the complexes 1-7 decreased significantly the levels of the secreted TNF-alpha after the LPS activation of THP-1 cells, thus showing the anti-inflammatory potential via both NF-κB moderation and by other mechanisms, such as influence on TNF-alpha transcription and/or translation and/or secretion. In addition, a strong intracellular pro-oxidative effect of all the complexes has been found at 100 nM dose in vitro. The ability to suppress the inflammatory response, caused by the subcutaneous application of λ-carrageenan, has been determined by in vivo testing in hind-paw edema model on rats. The most active complexes 1-3 (applied in a dose corresponding to 40 μmol Cu/kg), diminished the formation of edema simalarly as the reference drug indomethacine (applied in 10 mg/kg dose). The overall effect of the complexes, dominantly 1-3, shows similarity to anti-inflammatory drug benoxaprofen, known to induce intracellular pro-oxidative effects.
- MeSH
- antiflogistika terapeutické užití MeSH
- edém farmakoterapie MeSH
- hmotnostní spektrometrie s elektrosprejovou ionizací MeSH
- krysa rodu rattus MeSH
- krystalografie rentgenová MeSH
- lidé MeSH
- měď chemie terapeutické užití MeSH
- nádorové buněčné linie MeSH
- naftochinony chemie terapeutické užití MeSH
- NF-kappa B antagonisté a inhibitory MeSH
- potkani Wistar MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- zánět farmakoterapie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
The platinum(II) iodido complexes 1-5 of the general formula cis-[PtI2(Ln)2], where Ln stands for O-substituted 9-deazahypoxanthine derivatives, were prepared and thoroughly characterized by various techniques, including multinuclear 1D and 2D NMR spectroscopy. The complexes were screened for their anticancer potential in vitro on ten human cancer cell lines, concretely breast adenocarcinoma (MCF7), osteosarcoma (HOS), lung carcinoma (A549), cervix epithelioid carcinoma (HeLa), malignant melanoma (G-361), prostate carcinoma (22Rv1, PC-3), hepatocellular carcinoma (HepG2), ovarian carcinoma (A2780) and cisplatin-resistant ovarian carcinoma (A2780R). The complexes exhibited significant wide-spectrum anticancer activity in vitro against all the employed cell lines, with IC50≈0.5-24.0μM. Very good correlation between the lipophilicity parameter log P and IC50 values of anticancer activity in vitro were obtained by simple QSAR analysis. The most lipophilic complexes 2, 4 and 5 showed the best results, as they reached the sub-micromolar IC50 values against the A2780 and A2780R sub-lines, with the best result equal 0.5±0.1μM on A2780 for complex 5. The in vivo testing of the representative complexes 1, 4 and 5 (applied at the same dose of Pt as 2mg/kg dose of cisplatin) on a L1210 leukaemia model revealed their positive effect on the prolongation of the mean survival time, even if it was lower than that of cisplatin. The 1H NMR interaction study revealed the ability of complexes to interact with glutathione (GSH) and 5'-guanosine monophosphate (GMP) and overall higher stability of the complexes 1-5 as compared to cisplatin. The electrospray-ionization mass spectrometry experiments with complex 1 identified the formation of a rich collection of hydrolytic species in water-containing media after 24h and the interaction intermediates with sulfur-containing biomolecule l-cysteine, but not with the reduced glutathione at physiologically relevant concentration levels.
- MeSH
- apoptóza účinky léků MeSH
- buňky Hep G2 MeSH
- HeLa buňky MeSH
- hypoxanthiny chemie MeSH
- jod chemie MeSH
- Kaplanův-Meierův odhad MeSH
- komplexní sloučeniny chemie terapeutické užití toxicita MeSH
- lidé MeSH
- MFC-7 buňky MeSH
- myši inbrední DBA MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- nádory farmakoterapie mortalita patologie MeSH
- platina chemie MeSH
- protinádorové látky chemie terapeutické užití toxicita MeSH
- screeningové testy protinádorových léčiv MeSH
- transplantace heterologní MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
A series of anionic heavy lanthanide complexes, involving the N-salicylideneglycinato(2-) Schiff base ligand (salgly) and having the general formula K[Ln(salgly)₂(H₂O)₂]∙H₂O (1-6), where Ln stands for Gd, Tb, Dy, Ho, Er and Tm, was prepared using the one-pot template synthesis. The complexes were thoroughly characterized by elemental and Thermogravimetric/Differential Thermal Analyses (TG/DTA), Fourier Transform Infrared Spectroscopy (FT-IR), and photoluminescence spectroscopies, electrospray-ionization mass spectrometry, and their magnetic properties were studied by temperature-dependent dc magnetic measurements using the superconducting quantum interference device (SQUID). The X-ray structure of the terbium(III) complex (2), representing the unique structure between the lanthanide complexes of N-salicylideneamino acids, was determined. The results of spectral and structural studies revealed the isostructural nature of the prepared complexes, in which the lanthanide ion is octacoordinated by two O,N,O-donor salgly ligands and two aqua ligands. The analysis of magnetic data confirmed that the complexes behave as paramagnets obeying the Curie law. The results of photoluminescence spectral studies of the complexes showed the different origin in their luminescent properties between the solid state and solution. An antenna effect of the Schiff base ligand was observed in a powder form of the complex only, while it acts as a fluorophore in a solution.
- MeSH
- chemické modely MeSH
- fotochemické procesy MeSH
- glycin chemie MeSH
- hmotnostní spektrometrie s elektrosprejovou ionizací MeSH
- komplexní sloučeniny chemie MeSH
- krystalografie rentgenová MeSH
- kyselina salicylová chemie MeSH
- lanthanoidy chemie MeSH
- ligandy MeSH
- luminescentní proteiny chemie MeSH
- luminiscence MeSH
- magnetismus MeSH
- prášky, zásypy, pudry MeSH
- spektroskopie infračervená s Fourierovou transformací MeSH
- teplota MeSH
- termogravimetrie MeSH
- vodíková vazba MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The gold(I) mixed-ligand complexes involving O-substituted derivatives of 9-deazahypoxanthine (HLn) and triphenylphosphine (PPh3) with the general formula [Au(Ln)(PPh3)] (1-5) were prepared and thoroughly characterized by elemental analysis, FT-IR and multinuclear NMR spectroscopy, ESI+ mass spectrometry, single crystal X-ray (HL5 and complex 2) and TG/DTA analyses. Complexes 1-5 were evaluated for their in vitro antitumor activity against nine human cancer lines, i.e. MCF7 (breast carcinoma), HOS (osteosarcoma), A549 (adenocarcinoma), G361 (melanoma), HeLa (cervical cancer), A2780 (ovarian carcinoma), A2780R (ovarian carcinoma resistant to cisplatin), 22Rv1 (prostate cancer) and THP-1 (monocytic leukaemia), for their in vitro anti-inflammatory activity using a model of LPS-activated macrophages, and for their in vivo antiedematous activity by λ-carrageenan-induced hind paw edema model on rats. The results showed that the complexes 1-5 exhibit selective in vitro cytotoxicity against MCF7, HOS, 22Rv1, A2780 and A2780R, with submicromolar IC50 values for 2 against the MCF7 (0.6 µM) and HOS (0.9 µM). The results of in vitro cytotoxicity screening on primary culture of human hepatocytes (HEP220) revealed up to 30-times lower toxicity of compounds against healthy cells as compared with cancer cells. Additionally, the complexes 1-5 significantly influence the secretion and expression of pro-inflammatory cytokines TNF-α and IL-1β by a similar manner as a commercially used anti-arthritic drug Auranofin. The tested complexes also significantly influence the rate and overall volume of the edema, caused by the intraplantar application of λ-carrageenan polysaccharide to rats. Based on these promising results, the presented compounds could qualify to become feasible candidates for advanced testing as potential antitumor and anti-inflammatory drug-like compounds.
- MeSH
- antiflogistika chemie farmakologie terapeutické užití MeSH
- edém farmakoterapie MeSH
- hepatocyty účinky léků MeSH
- hypoxanthiny chemie farmakologie terapeutické užití MeSH
- krysa rodu rattus MeSH
- lidé MeSH
- modely nemocí na zvířatech MeSH
- nádorové buněčné linie MeSH
- nádory farmakoterapie MeSH
- protinádorové látky chemie farmakologie terapeutické užití MeSH
- spektroskopie infračervená s Fourierovou transformací MeSH
- zánět farmakoterapie MeSH
- zlato chemie farmakologie terapeutické užití MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
A series of copper(II) and zinc(II) complexes involving a tridentate O,N,O'-donor Schiff base derived from salicylaldehyde and beta-alanine {i.e. N-salicylidene-beta-alanine(2-), (L)}, having the composition [Cu(2)(L)(2)(H(2)O)].H(2)O (1), [Cu(L)(H(2)O)](n) (2), and [Zn(L)(H(2)O)](n) (3), have been prepared and characterized by elemental analyses, UV-visible (UV-VIS), FT-IR and ESI-MS spectra, and thermal analyses. Complexes 1 and 2 have been investigated by single crystal X-ray analysis and also by temperature dependent magnetic susceptibility measurements (294-80K). All prepared complexes have been evaluated by the antiperoxynitrite activity assay and alloxan-induced diabetes model. The significant antioxidant and antidiabetic activities have been found in the case of both copper(II) complexes 1 and 2. In spite of first two complexes, the zinc(II) complex 3, as well as the potassium salt of the ligand (KHL) showed only insignificant protective effect against the tyrosine nitration in vitro.
- MeSH
- aldehydy chemie MeSH
- beta-alanin chemie MeSH
- experimentální diabetes mellitus prevence a kontrola MeSH
- financování organizované MeSH
- hmotnostní spektrometrie s elektrosprejovou ionizací MeSH
- hypoglykemika farmakologie chemická syntéza chemie MeSH
- krystalografie rentgenová MeSH
- měď chemie MeSH
- molekulární modely MeSH
- molekulární struktura MeSH
- myši MeSH
- scavengery volných radikálů farmakologie chemická syntéza chemie MeSH
- spektrofotometrie ultrafialová MeSH
- spektroskopie infračervená s Fourierovou transformací MeSH
- zinek chemie MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
Databázový systém Beilstein CrossFire je jedným z najznámejších, najobsiahlejších a najprepracovanejšíchinformačných systémov spracúvajúcich informácie o chemických látkach aj liečiváchpokrývajúce tak základné identifikačné, fyzikálno-chemické, ako aj ekologické a neposlednom radefarmakologické dáta. Tento článok poskytuje prehľad historického vývoja databázového systémuBeilstein CrossFire od jeho zakladateľa prof. Friedricha Konrada Beilsteina až po opis dnešnýchtrendov prepojenia systému s full-textovými databázami. Poskytuje tiež prehľad o vývoji elektronickýchinformačných systémov na Slovensku a popis základných funkcií systému a príklad cielenéhovýberu aktívnych štruktúr podobných selektívnym inhibítomCOX-2 s preukázanou antiflogistickouaktivitou.
The Beilstein CrossFire database system is one of the most popular, most extensive, and mostaccomplished systems presenting information about chemical substances, including drugs, andcovering the basic identification, physico-chemical, ecological, and pharmacological data. Thepresent article offers an overviewof historical evaluation of the Beilstein CrossFire database system,beginning from its founder Prof. Friedrich Conrad Beilstein till the most recent prospects about theconnection of classical data with full-text databases. The article also offers a review of the developmentof electronic information systems in the Slovak Republic, a definition of basic functionality ofthe Beilstein CrossFire database system, and an example of targeted selection of active substancesstructurally similar to novel COX-2 inhibitors having an approved anti-inflammatory activity.
- MeSH
- databáze faktografické MeSH
- dějiny MeSH
- farmaceutická chemie MeSH
- informační systémy MeSH
- organická chemie dějiny MeSH
- Publikační typ
- biografie MeSH
- O autorovi
- Bejl'štejn, Fedor Fedorovič, 1838-1906 Autorita
