Inhibitory SGLT2 (glifloziny) se v organismu metabolizují prakticky jen glukuronidací a jen minimálně oxidativní cestou. Současně jsou některé glifloziny substráty transportních systémů P‐glykoproteinu, BCRP a MRP‐2. Z těchto vlastností gliflozinů se odvozují jejich farmakokinetické lékové interakce. Z mechanismu účinku gliflozinů vyplývá, že zvyšují exkreci glukózy a natria močí, čímž zvyšují také exkreci vody. Kombinace gliflozinů s diuretiky působí synergicky na natriurézu a může vyvolat hypotenzi a dehydrataci. Kombinace gliflozinů s inzulinem nebo inzulinovými sekretagogy pak může zvýšit riziko vzniku hypoglykemických příhod. Glifloziny naproti tomu prakticky neovlivňují osud jiných léků v organismu a mají jen omezené množství klinicky relevantních lékových interakcí. Ke klinicky nejvýznamnějším patří indukce glukuronidace gliflozinů, synergický efekt při souběžném podávání diuretik a vliv gliflozinů na exkreci solí lithia.
SGLT2 inhibitors (gliflozins) are metabolized in the body practically mainly by glucuronidation and only minimally by the oxidative route. At the same time, some gliflozins are substrates of the P‐glycoprotein, BCRP and MRP‐2 transport systems. These properties of gliflozins indicate their pharmacokinetic drug interactions. The mechanism of action of gliflozins suggests that they increase glucose and sodium excretion in the urine, thereby also increasing water excretion. The combination of gliflozins with diuretics acts synergistically on sodium excretion and may cause hypotension and dehydration. Combining gliflozins with insulin or secretagogues may increase the risk of hypoglycemic episodes. Gliflozins, on the other hand, have virtually no effect on the fate of other drugs. Gliflozins have only a limited number of clinically relevant drug interactions, the most clinically important being the induction of gliflozin glucuronidation, the synergistic effect of co‐administered diuretics and the effect of gliflozins on lithium salt excretion.
- MeSH
- akutní poškození ledvin etiologie MeSH
- diuretika aplikace a dávkování škodlivé účinky terapeutické užití MeSH
- dospělí MeSH
- glifloziny * aplikace a dávkování farmakokinetika škodlivé účinky terapeutické užití MeSH
- glukuronosyltransferasa antagonisté a inhibitory MeSH
- hypoglykemie etiologie MeSH
- hypotenze etiologie MeSH
- inzulin aplikace a dávkování terapeutické užití MeSH
- kyselina niflumová aplikace a dávkování škodlivé účinky terapeutické užití MeSH
- kyselina valproová aplikace a dávkování škodlivé účinky terapeutické užití MeSH
- lékové interakce MeSH
- lidé MeSH
- lithium aplikace a dávkování škodlivé účinky terapeutické užití MeSH
- senioři MeSH
- výsledek terapie MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
Class I histone deacetylases (HDACs) are key regulators of cell proliferation and they are frequently dysregulated in cancer cells. We report here the synthesis of a novel series of class-I selective HDAC inhibitors (HDACi) containing a 2-aminobenzamide moiety as a zinc-binding group connected with a central (piperazin-1-yl)pyrazine or (piperazin-1-yl)pyrimidine moiety. Some of the compounds were additionally substituted with an aromatic capping group. Compounds were tested in vitro against human HDAC1, 2, 3, and 8 enzymes and compared to reference class I HDACi (Entinostat (MS-275), Mocetinostat, CI994 and RGFP-966). The most promising compounds were found to be highly selective against HDAC1, 2 and 3 over the remaining HDAC subtypes from other classes. Molecular docking studies and MD simulations were performed to rationalize the in vitro data and to deduce a complete structure activity relationship (SAR) analysis of this novel series of class-I HDACi. The most potent compounds, including 19f, which blocks HDAC1, HDAC2, and HDAC3, as well as the selective HDAC1/HDAC2 inhibitors 21a and 29b, were selected for further cellular testing against human acute myeloid leukemia (AML) and erythroleukemic cancer (HEL) cells, taking into consideration their low toxicity against human embryonic HEK293 cells. We found that 19f is superior to the clinically tested class-I HDACi Entinostat (MS-275). Thus, 19f is a new and specific HDACi with the potential to eliminate blood cancer cells of various origins.
- MeSH
- benzamidy chemická syntéza chemie farmakologie MeSH
- HEK293 buňky MeSH
- inhibitory histondeacetylas chemická syntéza chemie farmakokinetika farmakologie MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- ortoaminobenzoáty chemická syntéza chemie MeSH
- protinádorové látky chemická syntéza chemie farmakokinetika farmakologie MeSH
- protonová magnetická rezonanční spektroskopie MeSH
- pyraziny chemie MeSH
- pyridiny chemická syntéza chemie farmakologie MeSH
- simulace molekulového dockingu * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
The advantages of using mixtures of organic solvents for the separation of labeled oligosaccharides on the amide stationary phase under hydrophilic interaction liquid chromatography conditions are presented. The effect of the type of buffer as well as solvent or their mixtures on retention of uracil, saccharide labeling reagents (2-aminobenzoic acid, 2-aminobenzamide, ethyl 4-aminobenzoate, procainamide), and corresponding labeled saccharides were evaluated. The successful isocratic separation of labeled isomeric trisaccharides (maltotriose, panose, and isomaltotriose) was achieved in the mobile phase consisting of a 90% (v/v) mixture of organic solvents (methanol/acetonitrile 60:40) and 10% (v/v) 30 mM ammonium formate, pH 3.3. Changing the volume ratio between methanol/acetonitrile from 60:40 to 50:50 (v/v) allowed to obtain the separation of di-, tri-, and tetrasaccharides labeled by ethyl 4-aminobenzoate in less than 10.5 min.
- MeSH
- acetonitrily chemie MeSH
- amidy chemie MeSH
- chemické techniky analytické přístrojové vybavení metody MeSH
- chromatografie kapalinová * MeSH
- formiáty chemie MeSH
- hydrofobní a hydrofilní interakce MeSH
- isomerie MeSH
- oligosacharidy izolace a purifikace MeSH
- ortoaminobenzoáty chemie MeSH
- rozpouštědla chemie MeSH
- sacharidy chemie MeSH
- Publikační typ
- časopisecké články MeSH
Topical pain relief products differ in the type of drug, concentration, and formulation. All these factors influence the drug transit through the skin barrier, and its eventual retention in the skin as a reservoir for subsequent release. In addition, the drug potency can be different, which is important for the product efficacy. We studied here ex vivo human skin permeation and retention of five over-the-counter NSAID gels containing 2.32% diclofenac (DIC) and 5-10% etofenamate (ETF). The potency of the permeated/retained drug amounts were compared using a composite parameter, the Index of Relative Topical Anti-inflammatory Activity (IRTAA), which is calculated as the product of the skin permeation/retention and the drug relative potency. The IRTAAs of the DIC gel were 94-667-fold higher and 72-208-fold higher for transdermal delivery and skin retention, respectively, than IRTAAs of the ETF gels. These superior IRTAAs indicate that DIC delivered by this topical formulation would achieve a higher bioactivity and would form a potent drug reservoir relevant for its subsequent long-lasting release.
Two novel Co(II) fenamato complexes containing bathocuproine (bcp), namely [Co(bcp)(flu)2] (1) and [Co(bcp)(nif)2] (2) (flu = flufenamato, nif = niflumato) were synthesized and characterized by elemental analysis, single-crystal X-ray structure analysis as well as absorption and fluorescence spectroscopy. Investigation of their molecular structure revealed that both complexes are isostructural and form analogous complex molecules, with a Co(II) atom hexacoordinated by two nitrogen atoms of bcp and four oxygen atoms of two chelate bonded flu (1) and nif (2) ligands in a distorted octahedral arrangement. Surprisingly, the results of cytotoxicity experiments on four cancer cell lines (HeLa, HT-29, PC-3 and MCF-7) have revealed that despite similar structure of the complexes, the nif complex exhibits significantly higher activity, being the most effective against the PC-3 cell line (IC50 (MTT) = 6.11 ± 1.95 μM). Further studies performed on PC-3 cell line have shown that the mechanism of the cytotoxic action of nif complex (2) might involve activation of autophagic processes and apoptosis, while for its flu analogue (1) apoptosis was detected.
- MeSH
- apoptóza účinky léků MeSH
- autofagie účinky léků MeSH
- fenantroliny chemická syntéza farmakologie MeSH
- kobalt chemie MeSH
- komplexní sloučeniny chemická syntéza farmakologie MeSH
- kontrolní body fáze G1 buněčného cyklu účinky léků MeSH
- kyselina flufenamová analogy a deriváty farmakologie MeSH
- lidé MeSH
- ligandy MeSH
- molekulární struktura MeSH
- nádorové buněčné linie MeSH
- protinádorové látky chemická syntéza farmakologie MeSH
- screeningové testy protinádorových léčiv MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
distribution of auxin within plant tissues is of great importance for developmental plasticity, including root gravitropic growth. Auxin flow is directed by the subcellular polar distribution and dynamic relocalisation of auxin transporters such as the PIN-FORMED (PIN) efflux carriers, which can be influenced by the main natural plant auxin indole-3-acetic acid (IAA). Anthranilic acid (AA) is an important early precursor of IAA and previously published studies with AA analogues have suggested that AA may also regulate PIN localisation. Using Arabidopsis thaliana as a model species, we studied an AA-deficient mutant displaying agravitropic root growth, treated seedlings with AA and AA analogues and transformed lines to over-produce AA while inhibiting its conversion to downstream IAA precursors. We showed that AA rescues root gravitropic growth in the AA-deficient mutant at concentrations that do not rescue IAA levels. Overproduction of AA affects root gravitropism without affecting IAA levels. Treatments with, or deficiency in, AA result in defects in PIN polarity and gravistimulus-induced PIN relocalisation in root cells. Our results revealed a previously unknown role for AA in the regulation of PIN subcellular localisation and dynamics involved in root gravitropism, which is independent of its better known role in IAA biosynthesis.
- MeSH
- Arabidopsis účinky léků metabolismus MeSH
- chinolony farmakologie MeSH
- gravitropismus fyziologie MeSH
- kořeny rostlin anatomie a histologie účinky léků růst a vývoj fyziologie MeSH
- kyseliny indoloctové chemie metabolismus MeSH
- mutace genetika MeSH
- ortoaminobenzoáty chemie metabolismus farmakologie MeSH
- polarita buněk * účinky léků MeSH
- proteiny huseníčku metabolismus MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Rhomboid proteases form one of the most widespread intramembrane protease families. They have been implicated in variety of human diseases. The currently reported rhomboid inhibitors display some selectivity, but their construction involves multistep synthesis protocols. Here, we report benzoxazin-4-ones as novel inhibitors of rhomboid proteases with a covalent, but slow reversible inhibition mechanism. Benzoxazin-4-ones can be synthesized from anthranilic acid derivatives in a one-step synthesis, making them easily accessible. We demonstrate that an alkoxy substituent at the 2-position is crucial for potency and results in low micromolar inhibitors of rhomboid proteases. Hence, we expect that these compounds will allow rapid synthesis and optimization of inhibitors of rhomboids from different organisms.
- MeSH
- Bacillus subtilis enzymologie MeSH
- benzoxaziny chemická syntéza chemie farmakologie MeSH
- chymotrypsin antagonisté a inhibitory MeSH
- DNA vazebné proteiny antagonisté a inhibitory MeSH
- endopeptidasy MeSH
- enzymatické testy MeSH
- Escherichia coli enzymologie MeSH
- inhibitory serinových proteinas chemická syntéza chemie farmakologie MeSH
- inhibitory trypsinu chemická syntéza chemie farmakologie MeSH
- membránové proteiny antagonisté a inhibitory MeSH
- molekulární struktura MeSH
- ortoaminobenzoáty chemie MeSH
- proteiny z Escherichia coli antagonisté a inhibitory MeSH
- skot MeSH
- trypsin chemie MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- skot MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Natural pyrrolobenzodiazepines (PBDs) form a large and structurally diverse group of antitumour microbial metabolites produced through complex pathways, which are encoded within biosynthetic gene clusters. We sequenced the gene cluster of limazepines and proposed their biosynthetic pathway based on comparison with five available gene clusters for the biosynthesis of other PBDs. Furthermore, we tested two recombinant proteins from limazepine biosynthesis, Lim5 and Lim6, with the expected substrates in vitro. The reactions monitored by LC-MS revealed that limazepine biosynthesis involves a new way of 3-hydroxyanthranilic acid formation, which we refer to as the chorismate/DHHA pathway and which represents an alternative to the kynurenine pathway employed for the formation of the same precursor in the biosynthesis of other PBDs. The chorismate/DHHA pathway is presumably also involved in the biosynthesis of PBD tilivalline, several natural products unrelated to PBDs, and its part is shared also with phenazine biosynthesis. The similarities between limazepine and phenazine biosynthesis indicate tight evolutionary links between these groups of compounds.
- MeSH
- benzodiazepiny chemie metabolismus MeSH
- chromatografie kapalinová MeSH
- hmotnostní spektrometrie MeSH
- kyselina 3-hydroxyanthranilová metabolismus MeSH
- metabolické sítě a dráhy MeSH
- molekulární evoluce MeSH
- sekvenční analýza proteinů MeSH
- Streptomyces genetika metabolismus MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Insecticides usually present in low concentrations in streams are known to impair behaviour and development of non-target freshwater invertebrates. Moreover, there is growing awareness that the presence of natural stressors, such as predation risk may magnify the negative effects of pesticides. This is because perception of predation risk can by itself lead to changes on behaviour and physiology of prey species. To evaluate the potential combined effects of both stressors on freshwater detritivores we studied the behavioural and developmental responses of Chironomus riparius to chlorantraniliprole (CAP) exposure under predation risk. Also, we tested whether the presence of a shredder species would alter collector responses under stress. Trials were conducted using a simplified trophic chain: Alnus glutinosa leaves as food resource, the shredder Sericostoma vittatum and the collector C. riparius. CAP toxicity was thus tested under two conditions, presence/absence of the dragonfly predator Cordulegaster boltonii. CAP exposure decreased leaf decomposition. Despite the lack of significance for interactive effects, predation risk marginally modified shredder effect on leaf decomposition, decreasing this ecosystem process. Shredders presence increased leaf decomposition, but impaired chironomids performance, suggesting interspecific competition rather than facilitation. C. riparius growth rate was decreased independently by CAP exposure, presence of predator and shredder species. A marginal interaction between CAP and predation risk was observed regarding chironomids development. To better understand the effects of chemical pollution to natural freshwater populations, natural stressors and species interactions must be taken into consideration, since both vertical and horizontal species interactions play their role on response to stress.
- MeSH
- Chironomidae účinky léků růst a vývoj fyziologie MeSH
- hmyz účinky léků růst a vývoj fyziologie MeSH
- insekticidy toxicita MeSH
- larva účinky léků růst a vývoj fyziologie MeSH
- listy rostlin MeSH
- nymfa účinky léků růst a vývoj fyziologie MeSH
- olše MeSH
- ortoaminobenzoáty toxicita MeSH
- potravní řetězec * MeSH
- predátorské chování * MeSH
- stravovací zvyklosti účinky léků MeSH
- vážky růst a vývoj fyziologie MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Caddisflies have been included in ecotoxicological studies because of their sensitivity and ecological relevance. The present study aimed to assess the sublethal effects of an anthranilic diamide insecticide, chlorantraniliprole (CAP), to Sericostoma vittatum. Used worldwide, CAP is a persistent compound that has been found in surface waters at concentrations from 0.1 μg/L to 9.7 μg/L. It targets the ryanodine receptors, and the present ecotoxicological assessment focused on biomarkers related to neurotransmission, biotransformation, oxidative stress damage, and endpoints related to energy processing (feeding, energy reserves, and cellular metabolism). Six days of exposure trials revealed that feeding activity was significantly decreased in S. vittatum larvae exposed to 0.9 μg/L CAP. Concomitantly, a reduction in cellular metabolism and a significant decrease in protein content were also observed in caddisfly larvae exposed to CAP, suggesting metabolic depression. The results show that sublethal concentrations of CAP can cause detrimental sublethal effects on S. vittatum total glutathione content at concentrations as low as 0.2 μg/L. Bioenergetics can be used to assess physiological effects of contaminants, and the present results show that exposure to low, environmentally relevant, concentrations of CAP alter energy acquisition and metabolism in nontarget aquatic insects with potential population level effects. Environ Toxicol Chem 2017;36:1584-1591. © 2016 SETAC.
- MeSH
- biologické markery metabolismus MeSH
- energetický metabolismus účinky léků MeSH
- hmyz účinky léků metabolismus MeSH
- insekticidy MeSH
- larva účinky léků metabolismus MeSH
- ortoaminobenzoáty toxicita MeSH
- oxidační stres účinky léků MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
