Neurodegenerative diseases in which the decrease of the acetylcholine is observed are growing worldwide. In the present study, a series of new arylaminopropanone derivatives with N-phenylcarbamate moiety (1-16) were prepared as potential acetylcholinesterase and butyrylcholinesterase inhibitors. In vitro enzyme assays were performed; the results are expressed as a percentage of inhibition and the IC50 values. The inhibitory activities were compared with reference drugs galantamine and rivastigmine showing piperidine derivatives (1-3) as the most potent. A possible mechanism of action for these compounds was determined from a molecular modelling study by using combined techniques of docking, molecular dynamics simulations and quantum mechanics calculations.
- MeSH
- aktivace enzymů účinky léků MeSH
- cholinesterasové inhibitory chemická syntéza chemie farmakologie MeSH
- lidé MeSH
- molekulární konformace MeSH
- molekulární modely MeSH
- molekulární struktura MeSH
- propanolaminy chemická syntéza chemie farmakologie MeSH
- simulace molekulární dynamiky MeSH
- simulace molekulového dockingu MeSH
- vazba proteinů MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
PURPOSE: This study compared the pharmacokinetics, tissue distribution, and urinary excretion of platinum in rats after single oral doses of LA-12 and satraplatin. METHODS: Both platinum derivatives were administered to male Wistar rats as suspensions in methylcellulose at four equimolar doses within the range of 37.5-300 mg LA-12/kg body weight. Blood sampling was performed until 72 h, and plasma and plasma ultrafiltrate were separated. Moreover, urine was collected until 72 h, and kidney and liver tissue samples were obtained at several times after administration. Platinum was measured by atomic absorption spectrometry. The pharmacokinetics of platinum was analyzed by population modelling and post hoc Bayesian estimation as well as using non-compartmental pharmacokinetic analysis of the mean concentration-time curves. RESULTS: Platinum was detected in all plasma and ultrafiltrate samples 15 min after oral administration of both compounds and peaked between 3-4 h and 1-3 h, respectively. Similar for LA-12 and satraplatin, the C (max) and AUC values of plasma and ultrafiltrate platinum increased less than in proportion to dose. The mean C (max) and AUC values of plasma platinum observed after administration of LA-12 were from 0.84 to 2.5 mg/l and from 20.2 to 75.9 mg h/l. For ultrafiltrate platinum, the corresponding ranges were 0.16-0.78 mg/l and 0.63-1.8 mg h/l, respectively. The AUC of plasma platinum was higher after satraplatin (P < 0.001). However, administration of LA-12 resulted in significantly higher AUC values of ultrafiltrate platinum after the doses of 150 mg and 300 mg/kg (P < 0.01), respectively, and the C (max) values were significantly higher starting from the dose of 75 mg/kg LA-12 and upward (P < 0.01). Cumulative 72-h urinary recovery of platinum dose was below 5% for both compounds, and it decreased with the dose of satraplatin (P < 0.01), while a numerical decrease was observed after administration of LA-12 that did not reach statistical significance (P = 0.41). The renal clearance of free platinum was similar regardless of the dose and compound administered. Platinum concentrations in the liver homogenate exceeded those in the kidney. Distribution of platinum to tissues was higher after LA-12 compared to satraplatin. The difference in kidney platinum increased with dose and was twofold after 350 mg/kg LA-12. Liver platinum was twofold higher after LA-12 across all four doses. CONCLUSIONS: In conclusion, this first comparative pharmacokinetic study with LA-12 and satraplatin shows that characteristics of platinum exposure evaluated in the plasma, plasma ultrafiltrate and kidney and liver tissues increase less than in proportion to dose following a single-dose administration of 37.5-300 mg/kg to Wistar rats. These findings together with the dose-related elevation in the pharmacokinetic characteristics V/F and CL/F of platinum and ultrafiltrate platinum as well as a drop in platinum urinary recovery are consistent with a dose-related decrease in the extent of oral bioavailability most likely due to saturable intestinal absorption.
- MeSH
- amantadin aplikace a dávkování analogy a deriváty farmakokinetika moč MeSH
- aplikace orální MeSH
- Bayesova věta MeSH
- biologické modely MeSH
- krysa rodu rattus MeSH
- organoplatinové sloučeniny aplikace a dávkování farmakokinetika moč MeSH
- potkani Wistar MeSH
- protinádorové látky aplikace a dávkování farmakokinetika moč MeSH
- tkáňová distribuce MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- srovnávací studie MeSH
Transkarbam 12 (T12) is a novel transdermal penetration enhancer with high activity. Its polar head group is formed by carbamic acid salt that is unstable in acidic environment and releases CO(2). To find out whether this property influences its high activity, two series of compounds with CO(2) stronger bound in the polar head have been prepared-carbonic and carbamic acid esters. The carbamate salt in the polar head was found to be essential for the enhancing activity and its decomposition in an acidic environment suggested relating to the mode of action of T12.
- MeSH
- aplikace kožní MeSH
- estery MeSH
- financování organizované MeSH
- karbamáty farmakologie chemická syntéza chemie MeSH
- krysa rodu rattus MeSH
- kyselina uhličitá farmakologie chemická syntéza chemie MeSH
- permeabilita MeSH
- prasata MeSH
- vysokoúčinná kapalinová chromatografie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
- Publikační typ
- srovnávací studie MeSH
OBJECTIVES: The resistance of tumor cells to cisplatin remains a major cause of treatment failure in cancer patients. In this study, the ability of Pt(IV) complex with adamantylamine-LA-12 and its reduced counterpart with lower oxidation state Pt(II)-LA-9 to overcome intrinsic cisplatin resistance was investigated. METHODS: The ovarian adenocarcinoma SK-OV-3 cells were exposed to cisplatin, LA-9, or LA-12 for 72 h and the effects of drug concentrations that caused 10% or 50% inhibition of cell proliferation were determined. After 24-72 h of sustained exposure viability, apoptosis and inhibition of proliferation were analyzed. DNA synthesis and cell cycle analysis were performed simultaneously in order to determine the modulation of cell cycle after platinum complexes treatment. RESULTS: Lung Resistance-related Protein (LRP/MVP) was detected in SK-OV-3 cells but not in the other two ovarian cancer lines with different sensitivity to cisplatin. LRP/MVP overexpression may be an important factor contributing to intrinsic cisplatin resistance. Interestingly, Pt(IV) complex-LA-12 had approximately 2.7-fold lower IC(50) concentration than LA-9 or cisplatin in SK-OV-3 cells. Moreover, LA-12 caused persistent accumulation of cells in S-phase of the cell cycle while LA-9 and cisplatin treatment-induced S-phase arrest was transient and shifted to G(2)/M-phase at later intervals. Apoptosis seemed to be not the dominant type of cell death caused by such the derivatives, but it was the most intensive after LA-12 treatment. CONCLUSIONS: We found strong differences between effects of Pt(IV) complex-LA-12 and Pt(II) derivatives-LA-9 and cisplatin on cytokinetic parameters. Overall, LA-12 but not its reduced Pt(II) counterpart LA-9 is the compound effective in p53 null human ovarian cancer cells and it is able to overcome intrinsic cisplatin resistance in these cells.
- MeSH
- adenokarcinom farmakoterapie metabolismus patologie MeSH
- amantadin analogy a deriváty aplikace a dávkování MeSH
- buněčný cyklus účinky léků MeSH
- buňky - růstové procesy účinky léků MeSH
- chemorezistence MeSH
- cisplatina aplikace a dávkování MeSH
- DNA nádorová biosyntéza MeSH
- financování organizované MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- nádorové proteiny biosyntéza MeSH
- nádory vaječníků farmakoterapie metabolismus patologie MeSH
- organoplatinové sloučeniny aplikace a dávkování farmakologie MeSH
- poly(ADP-ribosa)polymerasy metabolismus MeSH
- protokoly protinádorové kombinované chemoterapie farmakologie MeSH
- vault ribonucleoprotein particles antagonisté a inhibitory MeSH
- western blotting MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Klíčová slova
- platinový derivát LA-12,
- MeSH
- buněčné linie MeSH
- buňky HT-29 * cytologie účinky léků MeSH
- cisplatina analogy a deriváty terapeutické užití toxicita MeSH
- farmakologické účinky MeSH
- farmakoterapie metody trendy využití MeSH
- kolorektální nádory farmakoterapie MeSH
- kultivační techniky MeSH
- lékařská onkologie metody trendy MeSH
- lidé MeSH
- organoplatinové sloučeniny terapeutické užití toxicita MeSH
- protinádorové látky * terapeutické užití toxicita MeSH
- techniky in vitro MeSH
- Check Tag
- lidé MeSH
The oral anti-tumor activity of a novel platinum(IV) complex, coded as LA-12, with a bulky adamantylamine ligand was evaluated and compared with another platinum(IV) complex satraplatin. The human carcinoma xenografts of colon HCT116, prostate PC3, and ovarian A2780 and A2780/cisR (resistant to cisplatin) were used to evaluate the in-vivo anti-tumor activity. The daily x 5 repeated dose regimen in equimolar doses of LA-12 and satraplatin, administered in 2 cycles, was selected for this evaluation. All doses of LA-12 and satraplatin were significantly effective in comparison with the control. The activities of LA-12 in all doses and all used tumor xenografts were higher than equimolar doses of satraplatin. The highest effect was reached with LA-12 at a dose of 60 mg/kg. The shapes of growth curves of ovarian carcinoma A2780 and its subline resistant to cisplatin after therapy with LA-12 were very similar. This shows that LA-12 is able to overcome resistance to cisplatin.
- MeSH
- amantadin analogy a deriváty terapeutické užití MeSH
- chemorezistence MeSH
- cisplatina škodlivé účinky MeSH
- financování organizované MeSH
- ligandy MeSH
- myši nahé MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- nádory prostaty farmakoterapie patologie prevence a kontrola MeSH
- nádory tračníku farmakoterapie patologie prevence a kontrola MeSH
- nádory vaječníků farmakoterapie patologie prevence a kontrola MeSH
- organoplatinové sloučeniny terapeutické užití MeSH
- protinádorové látky terapeutické užití MeSH
- transplantace heterologní MeSH
- viabilita buněk účinky léků MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- srovnávací studie MeSH
- MeSH
- amantadin analogy a deriváty škodlivé účinky terapeutické užití MeSH
- buňky HT-29 metabolismus účinky léků MeSH
- chemorezistence imunologie účinky léků MeSH
- cisplatina analogy a deriváty imunologie škodlivé účinky MeSH
- financování organizované MeSH
- hodnocení léčiv metody využití MeSH
- kolorektální nádory farmakoterapie imunologie metabolismus MeSH
- lékařská onkologie metody trendy MeSH
- lidé MeSH
- nádorové buněčné linie imunologie metabolismus účinky léků MeSH
- nežádoucí účinky léčiv MeSH
- organoplatinové sloučeniny terapeutické užití MeSH
- protinádorové látky škodlivé účinky terapeutické užití toxicita MeSH
- Check Tag
- lidé MeSH
- MeSH
- amantadin analogy a deriváty terapeutické užití MeSH
- chemorezistence imunologie účinky léků MeSH
- cisplatina analogy a deriváty imunologie škodlivé účinky MeSH
- financování organizované MeSH
- hodnocení léčiv metody využití MeSH
- lékařská onkologie metody trendy MeSH
- lidé MeSH
- nádorové buněčné linie imunologie metabolismus účinky léků MeSH
- nádory vaječníků farmakoterapie MeSH
- nežádoucí účinky léčiv MeSH
- organoplatinové sloučeniny škodlivé účinky terapeutické užití MeSH
- protinádorové látky škodlivé účinky terapeutické užití toxicita MeSH
- Check Tag
- lidé MeSH
