Novel indolotacrine analogues were designed, synthesized, and evaluated as potential drugs for the treatment of Alzheimer's disease. By using a multitarget-directed ligand approach, compounds were designed to act simultaneously as cholinesterase (ChE) and monoamine oxidase (MAO) inhibitors. The compounds were also evaluated for antioxidant, cytotoxic, hepatotoxic, and blood-brain barrier (BBB) permeability properties. Indolotacrine 9 b (9-methoxy-2,3,4,6-tetrahydro-1H-indolo[2,3-b]quinolin-11-amine) showed the most promising results in the in vitro assessment; it is a potent inhibitor of acetylcholinesterase (AChE IC50 : 1.5 μm), butyrylcholinesterase (BChE IC50 : 2.4 μm) and MAO A (IC50 : 0.49 μm), and it is also a weak inhibitor of MAO B (IC50 : 53.9 μm). Although its cytotoxic (IC50 : 5.5±0.4 μm) and hepatotoxic (IC50 : 1.22±0.11 μm) profiles are not as good as those of the standard 7-methoxytacrine (IC50 : 63±4 and 11.50±0.77 μm, respectively), the overall improvement in the inhibitory activities and potential to cross the BBB make indolotacrine 9 b a promising lead compound for further development and investigation.
- MeSH
- acetylcholinesterasa chemie metabolismus MeSH
- Alzheimerova nemoc farmakoterapie MeSH
- buňky Hep G2 MeSH
- chinoliny chemická syntéza chemie metabolismus terapeutické užití toxicita MeSH
- cholinesterasové inhibitory chemická syntéza metabolismus terapeutické užití toxicita MeSH
- hematoencefalická bariéra metabolismus MeSH
- indoly chemická syntéza chemie metabolismus terapeutické užití toxicita MeSH
- inhibiční koncentrace 50 MeSH
- inhibitory MAO chemická syntéza metabolismus terapeutické užití toxicita MeSH
- lidé MeSH
- ligandy MeSH
- monoaminoxidasa chemie metabolismus MeSH
- racionální návrh léčiv * MeSH
- takrin chemie metabolismus terapeutické užití toxicita MeSH
- viabilita buněk účinky léků MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
- MeSH
- adjuvantní chemoterapie metody trendy využití MeSH
- chinoliny * škodlivé účinky terapeutické užití toxicita MeSH
- humanizované monoklonální protilátky terapeutické užití toxicita účinky léků MeSH
- klinické zkoušky, fáze III jako téma metody využití MeSH
- kongresy jako téma MeSH
- lidé MeSH
- nádory prsu * farmakoterapie genetika terapie MeSH
- přežití bez známek nemoci MeSH
- receptor erbB-2 * genetika imunologie účinky léků MeSH
- statistika jako téma MeSH
- výsledky a postupy - zhodnocení (zdravotní péče) MeSH
- Check Tag
- lidé MeSH
- MeSH
- akutní nemoc MeSH
- antibakteriální látky toxicita MeSH
- chemicky indukované poruchy MeSH
- chinoliny škodlivé účinky toxicita MeSH
- ciprofloxacin škodlivé účinky toxicita MeSH
- halucinace MeSH
- inhibitory topoisomerasy II škodlivé účinky toxicita MeSH
- lidé MeSH
- mladý dospělý MeSH
- nežádoucí účinky léčiv MeSH
- psychotické poruchy MeSH
- toxické psychózy MeSH
- Check Tag
- lidé MeSH
- mladý dospělý MeSH
- ženské pohlaví MeSH
- Publikační typ
- novinové články MeSH
The aim of this study was to compare the toxic effects of selected two- and three-ringed PAHs (naphthalene, phenanthrene, and anthracene) and their N-heterocyclic analogs with one (quinoline, acridine, and phenanthridine) or two (quinoxaline, phenazine, and 1,10-phenanthroline) nitrogen atoms on the survival and reproduction of Enchytraeus crypticus in artificial soil. Toxicity of compounds was recalculated to soil pore-water concentrations using the data of chemical analyses of 0.01 M CaCl(2) extracts of spiked soils. When toxicity was based on molar concentrations in pore water (μmol/L), it significantly increased with increasing K(ow) value. This relationship indicates nonpolar narcosis as the general toxicity mechanism of the tested compounds. In addition, significant correlation between the toxicity of PACs and their ionization potential has been identified by multidimensional QSAR models.
- MeSH
- akridiny toxicita MeSH
- anthraceny chemie toxicita MeSH
- chinoliny toxicita MeSH
- dusík toxicita MeSH
- fenantreny chemie toxicita MeSH
- fenantroliny chemie toxicita MeSH
- kvantitativní vztahy mezi strukturou a aktivitou MeSH
- látky znečišťující půdu chemie toxicita MeSH
- Oligochaeta účinky léků MeSH
- polycyklické aromatické uhlovodíky chemie toxicita MeSH
- půda analýza MeSH
- rozmnožování účinky léků MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Several health benefits, including protection from tumors at various anatomic sites, such as the lungs, stomach, and prostate gland, have been attributed to tomatoes and tomato-based products. Among tomato carotenoids, lycopene is the most active antioxidant, although it has many other biological effects, but data on its antimutagenic effects are scarce and often discrepant. The aim of our work was to determine the protective effects of lycopene, with regard to mutagenicity, via two indirect mutagens/carcinogens-2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and aflatoxin B₁ (AFB₁) and the direct mutagen/carcinogen N-nitroso-N-methylurea (MNU)--using the Ames and micronucleus tests. The significant, dose-dependent, antimutagenic effects of two concentrations of lycopene (30 μg and 300 μg per plate) were demonstrated at various concentrations of both AFB₁ and IQ in two strains of Salmonella typhimurium (TA98 and TA100). The protective effects of lycopene relative to MNU were lower in comparison to its protective effects relative to AFB₁ and IQ. Mice treated for 3 days with different doses of lycopene (either 25 or 50 mg/kg of body weight) prior to administration of individual mutagens resulted in a significant reduction of micronuclei numbers in the micronucleus test. Tomato purée (tested using the Ames test and AFB(1)) revealed a much stronger, dose-dependent, antimutagenic effect compared with corresponding doses of pure lycopene. Results indicate that lycopene has antimutagenic effects, although the effects are lower than that of tomato purée, which contains a complex mixture of bioactive phytochemicals. The antimutagenic effect is connected with the chemoprotective role of lycopene, tomatoes, and tomato products in the prevention of carcinogenesis.
- MeSH
- aflatoxin B1 antagonisté a inhibitory metabolismus toxicita MeSH
- antimutagenní látky analýza chemie farmakologie MeSH
- buňky kostní dřeně účinky léků MeSH
- chinoliny antagonisté a inhibitory metabolismus toxicita MeSH
- játra metabolismus MeSH
- karcinogeny antagonisté a inhibitory metabolismus toxicita MeSH
- karotenoidy analýza farmakologie MeSH
- krysa rodu rattus MeSH
- methylnitrosomočovina toxicita MeSH
- mikrojaderné testy MeSH
- mutageny metabolismus toxicita MeSH
- myši inbrední BALB C MeSH
- myši MeSH
- nádory prevence a kontrola MeSH
- ovoce chemie MeSH
- potkani Wistar MeSH
- Salmonella typhimurium účinky léků genetika MeSH
- Solanum lycopersicum chemie MeSH
- testy genotoxicity MeSH
- vztah mezi dávkou a účinkem léčiva 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
- srovnávací studie MeSH
Using the Ames bacterial mutagenicity test, the comet assay, and an in vivo micronucleus test, we investigated the effect of the chemoprotective substance phenethyl isothiocyanate (PEITC) on the mutagenic activity of indirect-acting mutagens and carcinogens aflatoxin B1 (AFB1) and 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), and direct-acting mutagen and carcinogen N-nitroso-N-methylurea (MNU). In the Ames test, the antimutagenic activity of PEITC was studied in the concentration range 0.3–300 µg/plate. PEITC at concentrations of 0.3, 3 and 30 µg/plate reduced dose-dependently mutagenicity of AFB1 and IQ in both S.typhimurium TA98 and TA100 strains. In the case of the direct mutagen MNU, the antimutagenic effect of PEITC was detected only at concentration of 30 µg/plate in the strain TA100. The PEITC concentration 300 µg/plate was toxic in the Ames test. The 24 h pre-treatment of HepG2 cells with PEITC at concentration 0.15 µg/ml resulted in a significant decrease of DNA breaks induced by MNU at concentrations 0.25 and 0.5 mM. Although a trend towards reduced strand break level were determined also at PEITC concentrations 0.035 and 0.07 µg/ml it did not reach the statistical significance. No effect, however, of PEITC on IQ-induced DNA breaks was observed. Chemopreventive effect of PEITC was revealed also in vivo. Pretreatment of mice with PEITC concentrations of 25 and 12.5 mg/kg b.w. administered to mice in three daily doses resulted in reduction of micronucleus formation in mice exposed to all three mutagens under study, with statistically significant effect at concentration of 25 mg/kg. Results of this study indicate that the strong PEITC antimutagenic properties may have an important role in the prevention of carcinogenesis and other chronic degenerative diseases that share some common pathogenetic mechanisms.
- MeSH
- aflatoxin B1 toxicita MeSH
- antimutagenní látky aplikace a dávkování farmakologie MeSH
- chinoliny toxicita MeSH
- financování organizované MeSH
- isothiokyanatany aplikace a dávkování farmakologie MeSH
- karcinogeny toxicita MeSH
- kultivované buňky MeSH
- lidé MeSH
- methylnitrosomočovina toxicita MeSH
- mutageny toxicita MeSH
- myši inbrední BALB C MeSH
- myši MeSH
- Salmonella typhimurium MeSH
- testy genotoxicity MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- zvířata MeSH
The aims of this study were: (i) to investigate the toxicity of N-heterocyclic polyaromatic hydrocarbons (NPAHs) quinoline, acridine, phenazine, and 1,10-phenanthroline to the soil invertebrates Eisenia fetida, Enchytraeus crypticus, Folsomia candida, and Caenorhabditis elegans, (ii) to compare the toxicity of four NPAHs and the species sensitivity, and (iii) to discuss possible risks of these compounds in soils. Different toxicities were found for the tested NPAHs which might be partially explained by their structure and properties. Effect concentrations expressed as soil pore-water concentrations were related to log K(ow), which indicated narcosis as the most probable mode of toxic action. The species sensitivity decreased in the rank: springtails >enchytraeids=earthworms> nematodes. Predicted no-effect concentration (PNEC) values were calculated for all tested species giving values from 0.5 to 6.8 mg/kg. It is unlikely that there is a risk for soil organisms in natural soils where lower NPAHs concentrations are expected.
- MeSH
- akridiny toxicita MeSH
- bezobratlí účinky léků MeSH
- Caenorhabditis elegans účinky léků MeSH
- chinoliny toxicita MeSH
- členovci účinky léků MeSH
- dusík toxicita MeSH
- fenantroliny toxicita MeSH
- fenaziny toxicita MeSH
- hodnocení rizik MeSH
- látky znečišťující půdu toxicita MeSH
- Oligochaeta účinky léků MeSH
- polycyklické aromatické uhlovodíky toxicita MeSH
- půda chemie MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
