FLT3 tyrosine kinase is a potential drug target in acute myeloid leukemia (AML) because patients with FLT3-ITD mutations respond poorly to standard cytotoxic agents and there is a clear link between the disease and the oncogenic properties of FLT3. We present novel 2,6,9-trisubstituted purine derivatives with potent FLT3 inhibitory activity. The lead compound 7d displays nanomolar activity in biochemical assays and selectively blocks proliferation of AML cell lines harboring FLT3-ITD mutations, whereas other transformed and normal human cells are several orders of magnitude less sensitive. The MV4-11 cells treated with 7d suppressed the phosphorylation of FLT3 and its downstream signaling pathways, with subsequent G1 cell cycle arrest and apoptosis. Additionally, a single dose of 7d in mice with subcutaneous MV4-11 xenografts caused sustained inhibition of FLT3 and STAT5 phosphorylation over 48 h, in contrast to the shorter effect observed after administration of the reference FLT3 inhibitor quizartinib.
- MeSH
- akutní myeloidní leukemie genetika patologie MeSH
- antitumorózní látky chemie metabolismus farmakologie MeSH
- diaminy chemie metabolismus farmakologie MeSH
- inhibitory proteinkinas chemie metabolismus farmakologie MeSH
- konformace proteinů MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- objevování léků * MeSH
- simulace molekulového dockingu MeSH
- tyrosinkinasa 3 podobná fms antagonisté a inhibitory chemie genetika metabolismus MeSH
- vztahy mezi strukturou a aktivitou MeSH
- xenogenní modely - testy antitumorózní aktivity MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
How the proliferation of the urothelium is regulated is known to a little degree. E. coli lipopolysaccharide (LPS) activates the innate immune response of the urinary bladder via the Toll-like receptor 4 (TLR4) on the urothelium but induces also urothelial proliferation. We wanted to assess whether muscarinic receptors are involved in the regulation of urothelial proliferation triggered by LPS stimulation. Female Fischer 344 rats were instilled with LPS or saline (control) in the urinary bladder in the absence or presence of muscarinic receptor blockade with atropine and regeneration of the urothelium was assessed 4h and 24h later. In the Fischer 344 bladder, urothelial thinning and urothelial caspase 3 up-regulation occurred at 4h after LPS urinary bladder instillation, which were totally blocked in rats pre-treated with atropine. TLR4 was only expressed in blood vessels in the Fischer 344 bladder, while it was also expressed in umbrella cells in the Sprague-Dawley bladder. Proliferation (Ki67 incorporation) of the human urothelial cell line UROtsa was reduced in the presence of the muscarinic receptor antagonists methoctramine (M2/M4-selective) and pirenzepine (M1/M4-selective), while proliferation instead was enhanced in the presence of atropine. In UROtsa cells exposed to LPS for 24h, 4-DAMP (M3/M1/M5-selective) inhibited instead proliferation. In conclusion, muscarinic receptors regulate urothelial proliferation and LPS may induce urothelial apoptosis via muscarinic receptor-dependent pathways. Our findings also suggest that species differences exist in the expressional pattern of TLR4 in the urothelium.
- MeSH
- apoptóza MeSH
- atropin farmakologie MeSH
- buněčné linie MeSH
- cholinergní látky farmakologie MeSH
- diaminy farmakologie MeSH
- Escherichia coli imunologie MeSH
- kaspasa 3 metabolismus MeSH
- krysa rodu rattus MeSH
- lidé MeSH
- lipopolysacharidy imunologie MeSH
- pirenzepin farmakologie MeSH
- potkani inbrední F344 MeSH
- potkani Sprague-Dawley MeSH
- přirozená imunita MeSH
- proliferace buněk MeSH
- receptory muskarinové metabolismus MeSH
- toll-like receptor 4 metabolismus MeSH
- urotel patologie fyziologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Sulfate-reducing bacteria (SRB) are most likely involved in both the initiation and maintenance of inflammatory bowel disease (IBD); unfortunately present antibacterial chemotherapeutics used in the treatment of IBD have been ineffective. Thus, the antimicrobial activity of salicylamide derivatives against two different genera of intestinal SRB, Desulfovibrio and Desulfomicrobium, was investigated. Six 2-(phenylcarbamoyl)phenyl N-[(benzyloxy)carbonyl]alkanoates and three 2-hydroxy-N-[(2S)-1-oxo-1-(phenylamino)alkan-2-yl]benzamides showed MIC values in the range from 0.22 to 0.35 μM against Desulfovibrio piger Vib-7 and in the range from 0.27 to 8.52 μM against Desulfomicrobium sp. Rod-9, while MIC values of ciprofloxacin were 41.2 μM and 39.3 μM. The highest potency against the two strains was observed for 4-chloro-N-{(2S)-1-[(3,4-dichlorophenyl)amino]-3-methyl-1-oxobutan-2-yl}-2-hydroxybenzamide (MIC 0.22 μM and 0.27 μM). 4-Chloro-2-[(4-nitrophenyl)carbamoyl]phenyl (2S)-2-{[(benzyloxy)carbonyl]amino}-3-methylbutanoate showed high activity against D. piger Vib-7 (MIC = 0.26 μM), while 4-chloro-2-[(4-methylphenyl)carbamoyl]phenyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(1H-indol-2-yl)propanoate expressed high activity against Desulfomicrobium sp. Rod-9 (MIC = 0.31 μM). Structure–activity relationships are discussed.
- MeSH
- antibakteriální látky farmakologie chemická syntéza chemie MeSH
- bakterie redukující síru účinky léků MeSH
- Desulfovibrio * účinky léků MeSH
- diaminy farmakologie chemická syntéza chemie MeSH
- mikrobiální testy citlivosti MeSH
- salicylamidy farmakologie chemická syntéza chemie MeSH
- salicylanilidy * farmakologie chemická syntéza chemie MeSH
- ulcerózní kolitida * farmakoterapie mikrobiologie MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Publikační typ
- práce podpořená grantem MeSH
Obidoxime, a weak acetylcholine-esterase (AChE) inhibitor, exerts muscarinic receptor antagonism with a significant muscarinic M2 receptor selective profile. The current examinations aimed to determine the functional significance of muscarinic M2 receptors in the state of AChE inhibition, elucidating muscarinic M2 and M3 receptor interaction. In the in vitro examinations, methacholine evoked concentration-dependent bladder contractile and atrial frequency inhibitory responses. Although atropine abolished both, methoctramine (1 μmol/L) only affected the cholinergic response in the atrial preparations. However, in the presence of methoctramine, physostigmine, an AChE inhibitor, increased the basal tension of the bladder strip preparations (+68%), as well as the contractile responses to low concentrations of methacholine (< 5 μmol/L; +90-290%). In contrast to physostigmine, obidoxime alone raised the basal tension (+58%) and the responses to low concentrations of methacholine (< 5 μmol/L; +80-450%). Physostigmine concentration-dependently increased methacholine-evoked responses, similarly to obidoxime at low concentrations. However, at large concentrations (> 5 μmol/L), obidoxime, because of its unselective muscarinic receptor antagonism, inhibited the methacholine bladder responses. In conclusion, the current results show that muscarinic M2 receptors inhibit muscarinic M3 receptor-evoked contractile responses to low concentrations of acetylcholine in the synaptic cleft. The muscarinic M2 and M3 receptor crosstalk could be a counteracting mechanism in the treatment of AChE inhibition when using reactivators, such as obidoxime.
- MeSH
- antagonisté muskarinových receptorů farmakologie MeSH
- atropin farmakologie MeSH
- cholinesterasové inhibitory farmakologie MeSH
- diaminy farmakologie MeSH
- fysostigmin farmakologie MeSH
- interakce mezi receptory a ligandy MeSH
- krysa rodu rattus MeSH
- methacholinchlorid farmakologie MeSH
- močový měchýř účinky léků enzymologie metabolismus MeSH
- obidoxim chlorid farmakologie MeSH
- receptor muskarinový M2 antagonisté a inhibitory MeSH
- receptor muskarinový M3 antagonisté a inhibitory MeSH
- srdeční síně účinky léků enzymologie metabolismus MeSH
- svalová kontrakce účinky léků MeSH
- techniky in vitro MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The ability of thorium uptake as well as responses to heavy metal stress were tested in tobacco cultivar La Burley 21. Thorium was accumulated preferentially in the root system. The presence of citric, tartaric and oxalic acids in hydroponic medium increased thorium accumulation in all plant organs. On the other hand, the addition of diamines and polyamines, the important antioxidants in plants, resulted in decrease of thorium accumulation, especially in the root system. Negative correlation was found between putrescine concentration and thorium accumulation. Nevertheless, the most important factor influencing the accumulation of thorium was the absence of phosphate ions in a hydroponic medium that caused more than 10-fold increase of thorium uptake in all plant parts. Accumulation and distribution of thorium was followed in six cultivars and 14 selected transformants. Cultivar La Barley 21 represented an average between the tested genotypes, having a very good distribution ratio between roots, stems and leaves.
- MeSH
- diaminy chemie farmakologie MeSH
- fosfáty chemie nedostatek MeSH
- genotyp MeSH
- hydroponie MeSH
- ionty chemie MeSH
- kořeny rostlin účinky léků metabolismus MeSH
- listy rostlin účinky léků metabolismus MeSH
- polyaminy chemie farmakologie MeSH
- putrescin chemie farmakologie MeSH
- stonky rostlin účinky léků metabolismus MeSH
- tabák metabolismus MeSH
- thorium chemie metabolismus MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
A selected chemical library of six platinum(II) complexes having 1,2-bis(aminomethyl)carbobicyclic ligands were synthesized after a rational design in order to evaluate their antiproliferative activity and the structure-activity relationships. The cytotoxicity studies were performed using cancer cell lines sensitive (A2780) and resistant (A2780R) to cisplatin. Excellent cytotoxicity was observed for most of complexes, which presented better resistance factors than cisplatin against the A2780R cell line. The interaction of these complexes with DNA, as the target biomolecule, was evaluated by several methods: DNA-platinum binding kinetics, changes in the DNA melting temperature, evaluation of the unwinding angle of supercoiled DNA, evaluation of the interstrand cross-links, and replication mapping. The kinetics of the interaction with glutathione was also investigated to better understand the resistant factors observed for the new complexes.
- MeSH
- adukty DNA chemie MeSH
- antitumorózní látky * farmakologie chemická syntéza chemie MeSH
- chelátory chemická syntéza chemie MeSH
- chemorezistence MeSH
- cisplatina farmakologie MeSH
- diaminy * farmakologie chemická syntéza chemie MeSH
- DNA chemie MeSH
- glutathion chemie MeSH
- kinetika MeSH
- léky antitumorózní - screeningové testy MeSH
- lidé MeSH
- ligandy MeSH
- můstkové bicyklické sloučeniny * farmakologie chemická syntéza chemie MeSH
- nádorové buněčné linie MeSH
- platina * MeSH
- reagencia zkříženě vázaná chemická syntéza chemie MeSH
- tranzitní teplota MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- práce podpořená grantem MeSH
This review reports on inhibitors of copper-containing amine oxidases and flavoprotein polyamine oxidases, which are structurally based on diamines. In the introduction, basic characteristics and classification of amine oxidases are described together with the significance of their synthetic inhibitors. The following text is divided into several chapters, which deal with diaminoketones, aza-diamines, unsaturated diamine analogs and diamines with heterocyclic substituents. Then it continues with diamine- and agmatine-based inhibitors of polyamine oxidases. Each chapter gives detailed information on the inhibition mode, potency and structural relationships. The conclusion points out possible roles of mechanism-based inhibitors of amine oxidases in physiological and medicinal research.
- MeSH
- agmatin farmakologie chemie MeSH
- aktivace enzymů fyziologie účinky léků MeSH
- diaminy farmakologie chemie MeSH
- financování organizované MeSH
- histaminasa antagonisté a inhibitory metabolismus MeSH
- inhibitory enzymů farmakologie chemie MeSH
- ketony farmakologie chemie MeSH
- lidé MeSH
- molekulární struktura MeSH
- oxidoreduktasy působící na CH-NH vazby antagonisté a inhibitory metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- přehledy MeSH
