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.

• Klíčová slova
• N-phenylcarbamate, acetylcholinesterase, arylaminopropanone, butyrylcholinesterase, enzyme assays, molecular modelling,
• 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
• Názvy látek
• cholinesterasové inhibitory MeSH
• propanolaminy 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
• antitumorózní látky aplikace a dávkování   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
• tkáňová distribuce MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• srovnávací studie MeSH
• Názvy látek
• amantadin MeSH
• antitumorózní látky MeSH
• bis(acetato)(1-adamantylamine)amminedichloroplatinum(IV) MeSH Prohlížeč
• organoplatinové sloučeniny MeSH
• satraplatin MeSH Prohlížeč

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 aplikace a dávkování   analogy a deriváty   MeSH
• buněčný cyklus účinky léků   MeSH
• buňky - růstové procesy účinky léků   MeSH
• chemorezistence MeSH
• cisplatina aplikace a dávkování   MeSH
• DNA nádorová biosyntéza   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 antitumorózní kombinované chemoterapie farmakologie   MeSH
• vault ribonucleoprotein particles biosyntéza   MeSH
• western blotting MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• amantadin MeSH
• bis(acetato)(1-adamantylamine)amminedichloroplatinum(IV) MeSH Prohlížeč
• cisplatina MeSH
• DNA nádorová MeSH
• major vault protein MeSH Prohlížeč
• nádorové proteiny MeSH
• organoplatinové sloučeniny MeSH
• poly(ADP-ribosa)-polymerasy MeSH
• vault ribonucleoprotein particles 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
• karbamáty chemická syntéza   chemie   farmakologie   MeSH
• krysa rodu Rattus MeSH
• kyselina uhličitá chemická syntéza   chemie   farmakologie   MeSH
• permeabilita MeSH
• prasata MeSH
• vysokoúčinná kapalinová chromatografie MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH
• Názvy látek
• carbamic acid MeSH Prohlížeč
• estery MeSH
• karbamáty MeSH
• kyselina uhličitá MeSH
• transkarbam 12 MeSH Prohlížeč

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
• antitumorózní látky terapeutické užití   MeSH
• chemorezistence MeSH
• cisplatina škodlivé účinky   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
• transplantace heterologní MeSH
• viabilita buněk účinky léků   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH
• Názvy látek
• amantadin MeSH
• antitumorózní látky MeSH
• bis(acetato)(1-adamantylamine)amminedichloroplatinum(IV) MeSH Prohlížeč
• cisplatina MeSH
• ligandy MeSH
• organoplatinové sloučeniny MeSH
• satraplatin MeSH Prohlížeč

A novel anti-tumor platinum(IV) complex, coded as LA-12, with a bulky adamantylamine ligand displaying oral activity was prepared and its oral activity was evaluated. The murine ADJ/PC6 plasmacytoma and human A2780 ovarian carcinoma tumor model were used to evaluate the in vivo anti-tumor activity of a single dose and also of repeated doses with comparison to the activity of cisplatin and of the platinum(IV) complex satraplatin. The acute toxicity of LA-12 in mice is relatively low (maximum tolerated dose 1000 mg/kg), and the effective dose is comparable to that of cisplatin and higher than that of satraplatin. The therapeutic index derived from this is very high (250). In the human tumor model, two repeated dose schedule regimens were evaluated. LA-12 exerted a significantly higher anti-tumor activity than other substances, i.e. cisplatin and satraplatin, in repeated doses on the murine ADJ/PC6 plasmacytoma tumor model. The dailyx5 repeated dose regimen was selected for further evaluation.

• MeSH
• adenokarcinom farmakoterapie   MeSH
• amantadin aplikace a dávkování   analogy a deriváty   MeSH
• antitumorózní látky aplikace a dávkování   MeSH
• aplikace orální MeSH
• inbrední kmeny myší MeSH
• léky antitumorózní - screeningové testy metody   MeSH
• lidé MeSH
• maximální tolerovaná dávka MeSH
• modely nemocí na zvířatech MeSH
• myši inbrední BALB C MeSH
• myši MeSH
• nádorové buňky kultivované MeSH
• nádory vaječníků farmakoterapie   MeSH
• organoplatinové sloučeniny aplikace a dávkování   MeSH
• plazmocytom farmakoterapie   MeSH
• xenogenní modely - testy antitumorózní aktivity MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH
• Názvy látek
• amantadin MeSH
• antitumorózní látky MeSH
• bis(acetato)(1-adamantylamine)amminedichloroplatinum(IV) MeSH Prohlížeč
• organoplatinové sloučeniny MeSH
• satraplatin MeSH Prohlížeč

[(OC-6-43)-bis(acetato)(1-adamantylamine)amminedichloroplatinum(IV)], coded as LA-12, is an octahedral platinum(IV) complex containing a bulky hydrophobic ligand - adamantylamine. The use of bulky hydrophobic amines as non-leaving ligands, may increase uptake of the compound by the cancer cells. Therefore, the effects of LA-12 on sensitive (A2780) and cisplatin resistant (A2780cis) ovarian cancer cell lines were investigated and compared to those of cisplatin. IC(50) and IC(90) concentrations of LA-12 were 6- (A2780) or 18-fold (A2780cis) lower than those for cisplatin (MTT assay). Equitoxic concentrations (IC(50) or IC(90)) of both compounds caused a significant and similar time- and dose-dependent inhibition of cell proliferation and an increase in the number of floating cells which corresponded to the decrease of total cell viability. A different type and dynamics of cell cycle perturbation after cisplatin and LA-12 treatment were detected. Exposure to LA-12 resulted in transient accumulation of A2780 and A2780cis cells in S phase, while cisplatin caused G(2)/M arrest in sensitive and S phase arrest in resistant cells. A relatively low rate of apoptosis after exposure to IC(50) or IC(90) of both complexes was observed, markedly higher in resistant A2780cis cells. Western blot analysis indicated a concentration-dependent p53 level increase in both lines (higher after cisplatin treatment). PARP cleavage was observed only in A2780cis cells. In conclusion, LA-12 was found to be significantly more efficient than cisplatin, and it was able to overcome the acquired cisplatin resistance (showing resistance factor 2.84-fold lower than those for cisplatin). In spite of the low rate of apoptosis, LA-12 caused increase of p53 level and cell cycle perturbations in the ovarian cancer cell lines studied.

• MeSH
• amantadin analogy a deriváty   farmakologie   MeSH
• antitumorózní látky farmakologie   MeSH
• buněčný cyklus účinky léků   MeSH
• chemorezistence MeSH
• cisplatina farmakologie   MeSH
• fragmentace DNA účinky léků   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• nádorový supresorový protein p53 analýza   MeSH
• nádory vaječníků farmakoterapie   patologie   MeSH
• organoplatinové sloučeniny farmakologie   MeSH
• poly(ADP-ribosa)-polymerasy analýza   MeSH
• proliferace buněk účinky léků   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• amantadin MeSH
• antitumorózní látky MeSH
• bis(acetato)(1-adamantylamine)amminedichloroplatinum(IV) MeSH Prohlížeč
• cisplatina MeSH
• nádorový supresorový protein p53 MeSH
• organoplatinové sloučeniny MeSH
• poly(ADP-ribosa)-polymerasy MeSH

The pharmacokinetics of total and free plasma platinum (Pt) and Pt tissue distribution were investigated in rats after oral administration of (OC-6-43)-bis(acetato)(1-adamantylamine)amminedichloroplatinum(IV) (LA-12). Plasma and ultrafiltrate were sampled until 48 h and tissue samples were taken at 24 and 48 h after single doses of 38.6 or 540 mg LA-12/kg, and after once-a-day dosing of 4.3 or 38.6 mg kg(-1) LA-12 over 14 consecutive days. Total plasma Pt concentrations increased less than proportionally to the 14-fold increase in the single dose. The mean C(max) values of 1.5 and 6.3 mg L(-1) were observed at 0.5 and 1 h, respectively, and the mean AUC values achieved were 29 and 144 mg h L(-1). The highest tissue Pt concentrations were found in the liver and kidneys. Platinum was undetectable in the brain while in other tissues (muscle, skin, heart, lungs), the concentrations were lower (after single dose) or similar (after multiple doses) when compared to the plasma C(max) values. Plasma Pt concentrations after once-a-day dosing of 38.6 mg kg(-1) were two- to three-fold less than that after a single dose while Pt concentrations in various tissues rose two- to four-fold. Accumulation of Pt was even higher in the kidneys (seven-fold) and spleen (nine-fold). After once-a-day dosing, tissue Pt levels increased proportionally with the dose within the range from 4.3 to 38.6 mg kg(-1). At the same time, the increase in total plasma Pt concentrations was 40% less than proportional. Concentrations of Pt in the plasma ultrafiltrate decreased rapidly with the initial half-life of 1 h.

• MeSH
• amantadin aplikace a dávkování   analogy a deriváty   farmakokinetika   MeSH
• aplikace orální MeSH
• krysa rodu Rattus MeSH
• organoplatinové sloučeniny aplikace a dávkování   farmakokinetika   MeSH
• platina aplikace a dávkování   farmakokinetika   MeSH
• potkani Wistar MeSH
• tkáňová distribuce účinky léků   fyziologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH
• Názvy látek
• amantadin MeSH
• bis(acetato)(1-adamantylamine)amminedichloroplatinum(IV) MeSH Prohlížeč
• organoplatinové sloučeniny MeSH
• platina MeSH

The aim of this study was to compare anti-tumor potency of platinum(IV) complexes with increasing hydrophobicity of their ligands. Cytotoxic potential of the new platinum(IV) complex, coded as LA-12 [(OC-6-43)-bis(acetato)(1-adamantylamine)amminedichloroplatinum(IV)], was compared within the series of complexes of the general formula (OC-6-43)-bis(acetato)(alkylamine)amminedichloroplatinum(IV). Alkylamine ligands with increasing hydrophobicity were: isopropylamine, cyclohexylamine, 1-adamantylamine and 3,5-dimethyl-1-adamantylamine. Particular platinum(IV) complexes were coded as LA-4, LA-2 (known as JM-216), LA-12 and LA-15, respectively. Cytotoxicity was tested with the microplate tetrazolium (MTT) assay on the panel of cancer cell lines and the results were verified by microscopy. HPLC was used to measure hydrophobicity, stability of complexes in various buffers and velocity constants for their reactivity with glutathione. Platinum(IV) complexes with bulky hydrophobic ligands (LA-12 and LA-15) demonstrated about one order higher velocity constant for pseudo-first-order reaction with glutathione in comparison to cisplatin, LA-4 and LA-2, whose velocity constants were close to those measured for cisplatin and related platinum(II) complexes. Cytotoxicities of LA-12 and LA-15 towards cisplatin-resistant epithelial carcinoma A2780/cisR were superior to cisplatin, LA-4 and LA-2 in both 24- and 72-h continuous exposure MTT tests. Rapid induction of apoptosis in the treated cancer cell lines and no cisplatin cross-resistance were found for LA-12, which is a candidate for clinical testing.

• MeSH
• amantadin analogy a deriváty   chemie   farmakologie   MeSH
• antitumorózní látky chemie   farmakologie   MeSH
• chemorezistence MeSH
• cisplatina chemie   farmakologie   MeSH
• glutathion metabolismus   MeSH
• ligandy MeSH
• nádorové buněčné linie MeSH
• organoplatinové sloučeniny chemie   farmakologie   MeSH
• viabilita buněk účinky léků   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH
• Názvy látek
• amantadin MeSH
• antitumorózní látky MeSH
• bis(acetato)(1-adamantylamine)amminedichloroplatinum(IV) MeSH Prohlížeč
• cisplatina MeSH
• glutathion MeSH
• ligandy MeSH
• organoplatinové sloučeniny MeSH

Procedure of the synthesis is described for new platinum(IV) drug LA-12 [(OC-6-43)-bis(acetato)(1-adamantylamine)amminedichloroplatinum(IV)]. The X-ray diffraction analysis shows that the structure is created by molecules with octahedral arrangement of ligands around a platinum atom and contains one H(2)O molecule that is not a part of the coordination sphere of platinum. This new drug is more reactive with glutathione than cisplatin and is lacking cross-resistance with cisplatin as proven on the panel of cancer cell lines.

• MeSH
• amantadin analogy a deriváty   chemická syntéza   chemie   farmakologie   MeSH
• antitumorózní látky chemická syntéza   chemie   farmakologie   MeSH
• chemorezistence MeSH
• cisplatina farmakologie   MeSH
• krystalografie rentgenová MeSH
• léky antitumorózní - screeningové testy MeSH
• lidé MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• organoplatinové sloučeniny chemická syntéza   chemie   farmakologie   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• amantadin MeSH
• antitumorózní látky MeSH
• bis(acetato)(1-adamantylamine)amminedichloroplatinum(IV) MeSH Prohlížeč
• cisplatina MeSH
• organoplatinové sloučeniny MeSH