Oxime-based molecules are used for the treatment of patients to reactivate acetylcholinesterase (AChE) function after organophosphate intoxication. However, their efficacy is limited by low penetration through the blood-brain barrier and fast elimination. In this work, the cucurbit[7]uril (CB[7]) carrier was used for the encapsulation of the clinical agent asoxime to enhance brain bioavailability and the treatment window. We present a pharmacokinetic study of asoxime and the asoxime-CB[7] complex in an in vivo mouse model. Ultrahigh-performance liquid chromatography with electrospray ionization-mass spectrometry detection was developed to determine asoxime and CB[7] in biological fluids and tissues after thorough optimization of chromatographic conditions. The dihydroxypropane-silica stationary phase using hydrophilic interaction liquid chromatography conditions provided the best chromatographic performance. The final method was validated and applied for the pharmacokinetic study of mouse plasma, urine, bile, liver, kidney, and brain samples at different times after administration of asoxime and the asoxime-CB[7] complex. The results showed a greater than 3-fold increase in the area under the curve (AUC) in the brain for asoxime administered as a complex with CB[7] relative to that for the administration of asoxime alone. The effectiveness of the treatment strategy was evaluated using a reactivation study and a functional observatory battery. Protection of brain AChE activity is crucial for saving human lives or reducing the consequences of poisoning. The asoxime administered as a complex increased the brain activity by approximately 30% compared to that with atropine alone. CB[7] coadministration improved the AChE activity by 11%, which agrees with the higher asoxime AUC assessed in the pharmacokinetic study.
- Klíčová slova
- acetylcholinesterase, cucurbit[n]uril, liquid chromatography, mass spectrometry, oxime, reactivator,
- MeSH
- acetylcholinesterasa metabolismus MeSH
- cholinesterasové inhibitory aplikace a dávkování toxicita MeSH
- enzymatické testy MeSH
- hematoencefalická bariéra metabolismus MeSH
- hmotnostní spektrometrie MeSH
- hydrofobní a hydrofilní interakce MeSH
- imidazoly chemie MeSH
- lidé MeSH
- modely nemocí na zvířatech MeSH
- myši MeSH
- nosiče léků chemie MeSH
- otrava organofosfáty farmakoterapie MeSH
- oximy aplikace a dávkování farmakokinetika MeSH
- plocha pod křivkou MeSH
- přemostěné cyklické sloučeniny chemie MeSH
- pyridinové sloučeniny aplikace a dávkování farmakokinetika MeSH
- reaktivátory cholinesterasy aplikace a dávkování farmakokinetika MeSH
- sarin aplikace a dávkování toxicita MeSH
- vysokoúčinná kapalinová chromatografie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- acetylcholinesterasa MeSH
- asoxime chloride MeSH Prohlížeč
- cholinesterasové inhibitory MeSH
- cucurbit(7)uril MeSH Prohlížeč
- imidazoly MeSH
- nosiče léků MeSH
- oximy MeSH
- přemostěné cyklické sloučeniny MeSH
- pyridinové sloučeniny MeSH
- reaktivátory cholinesterasy MeSH
- sarin MeSH
Antidotes against organophosphates often possess physicochemical properties that mitigate their passage across the blood-brain barrier. Cucurbit[7]urils may be successfully used as a drug delivery system for bisquaternary oximes and improve central nervous system targeting. The main aim of these studies was to elucidate the relationship between cucurbit[7]uril, oxime K027, atropine, and paraoxon to define potential risks or advantages of this delivery system in a complex in vivo system. For this reason, in silico (molecular docking combined with umbrella sampling simulation) and in vivo (UHPLC-pharmacokinetics, toxicokinetics; acetylcholinesterase reactivation and functional observatory battery) methods were used. Based on our results, cucurbit[7]urils affect multiple factors in organophosphates poisoning and its therapy by (i) scavenging paraoxon and preventing free fraction of this toxin from entering the brain, (ii) enhancing the availability of atropine in the central nervous system and by (iii) increasing oxime passage into the brain. In conclusion, using cucurbit[7]urils with oximes might positively impact the overall treatment effectiveness and the benefits can outweigh the potential risks.
- Klíčová slova
- CB7, K027, acetylcholinesterase, antidote, cucurbit[7]uril, cucurbiturils, in vivo, mouse, paraoxon, pesticide,
- MeSH
- atropin chemie MeSH
- hematoencefalická bariéra MeSH
- imidazoly chemie MeSH
- myši MeSH
- oximy chemie MeSH
- paraoxon chemie toxicita MeSH
- počítačová simulace MeSH
- přemostěné cyklické sloučeniny chemie MeSH
- pyridinové sloučeniny chemie MeSH
- reaktivátory cholinesterasy chemie toxicita MeSH
- simulace molekulového dockingu MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- 1-(4-hydroxyiminomethylpyridinium)-3-(carbamoylpyridinium) propane dibromide MeSH Prohlížeč
- atropin MeSH
- cucurbit(7)uril MeSH Prohlížeč
- imidazoly MeSH
- oximy MeSH
- paraoxon MeSH
- přemostěné cyklické sloučeniny MeSH
- pyridinové sloučeniny MeSH
- reaktivátory cholinesterasy MeSH
A novel macrocycle, decamethylpressocucurbit[5]uril (Me10prCB[5]), was synthesized by acid-catalyzed condensation of propanediurea and paraformaldehyde. This macrocycle binds methane with higher affinity than cucurbit[5]uril and its permethylated derivative.
- MeSH
- imidazoly chemická syntéza chemie MeSH
- katalýza MeSH
- makrocyklické sloučeniny chemická syntéza chemie MeSH
- molekulární struktura MeSH
- přemostěné cyklické sloučeniny chemická syntéza chemie MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- cucurbit(5)uril MeSH Prohlížeč
- imidazoly MeSH
- makrocyklické sloučeniny MeSH
- přemostěné cyklické sloučeniny MeSH
- pressocucurbit(5)uril MeSH Prohlížeč
The synthesis of a novel library of purine derivatives bearing various bicyclic and polycylic substituents at the N-9 position is described. The series includes norbornanes, bicyclo[2.2.2]octanes, and bicyclo[3.2.1]octanes attached at the bridgehead position as well as bicyclo[3.1.1]heptanes, tetrahydro-1-naphthalenes, and adamantanes bonded either directly or via a linear chain to the 6-chloropurine nucleobase. A number of prepared derivatives exerted significant activity against the enterovirus. Despite attempts to correlate the activity against picornaviruses with their phosphatidylinositol 4-kinase KIIIβ inhibitory activity, it is clear that the inhibition of this host factor cannot explain the observed antiviral potency.
- Klíčová slova
- Antiviral, Coxsackievirus B3, Enteroviruses, Phosphatidylinositol 4-kinase (PI4K), Purines,
- MeSH
- antivirové látky chemická syntéza chemie farmakologie toxicita MeSH
- cytopatogenní efekt virový MeSH
- Enterovirus účinky léků fyziologie MeSH
- kultivované buňky MeSH
- molekulární struktura MeSH
- norbornany chemická syntéza chemie farmakologie toxicita MeSH
- přemostěné cyklické sloučeniny chemická syntéza chemie farmakologie toxicita MeSH
- puriny chemická syntéza chemie farmakologie toxicita MeSH
- replikace viru účinky léků MeSH
- viabilita buněk účinky léků MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- antivirové látky MeSH
- norbornany MeSH
- přemostěné cyklické sloučeniny MeSH
- puriny MeSH
By using quantum mechanical DFT calculations, the most probable structures of the cucurbit[7]urilH3O+ and cucur-bit[7]uril'(H3O+)2 cationic complex species were derived. In these two complexes having a plane symmetry, each of the considered H3O+ cations is bound by relatively strong hydrogen bonds to the corresponding carbonyl oxygens of the parent cucurbit[7]uril macrocycle.
- MeSH
- imidazoly chemie MeSH
- molekulární modely MeSH
- přemostěné cyklické sloučeniny chemie MeSH
- protony * MeSH
- teoretické modely * MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- cucurbit(7)uril MeSH Prohlížeč
- imidazoly MeSH
- přemostěné cyklické sloučeniny MeSH
- protony * MeSH
Cucurbit[6]uril (CB6) and bispyridinium ethylene form a stable inclusion complex. A rotaxane derived from this complex was prepared in which a CB6 wheel shuttles along an axle in an NMR time-resolved regime.
- MeSH
- ethyleny chemie MeSH
- imidazoly chemie MeSH
- magnetická rezonanční spektroskopie MeSH
- molekulární struktura MeSH
- přemostěné cyklické sloučeniny chemie MeSH
- pyridinové sloučeniny chemie MeSH
- rotaxany chemická syntéza chemie MeSH
- teplota MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- cucurbit(6)uril MeSH Prohlížeč
- ethyleny MeSH
- imidazoly MeSH
- přemostěné cyklické sloučeniny MeSH
- pyridinové sloučeniny MeSH
- rotaxany MeSH
We have prepared organic guest molecules in which two pyridinium rings are connected through an aromatic/aliphatic bridge bearing a carboxyl group. The supramolecular interactions between these guests and macrocyclic hosts cucurbit[7]uril (CB7) and cucurbit[8]uril (CB8) has been studied. We have demonstrated that the binding modes of the complexes depend on the type of central bridge present in the guest molecules and the size of the macrocycle. We have also showed that the binding mode between cucurbiturils and guests with aromatic bridges is pH independent. On the other hand, a guest containing an aliphatic bridge and CB7 formed a pseudorotaxane, which behaved as a pH-driven molecular switch.
- MeSH
- imidazoly chemie MeSH
- magnetická rezonanční spektroskopie MeSH
- makromolekulární látky chemická syntéza chemie MeSH
- molekulární modely MeSH
- molekulární struktura MeSH
- oxid uhličitý chemie MeSH
- přemostěné cyklické sloučeniny chemie MeSH
- rotaxany chemická syntéza chemie MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- carboxyl radical MeSH Prohlížeč
- cucurbit(7)uril MeSH Prohlížeč
- cucurbit(8)uril MeSH Prohlížeč
- imidazoly MeSH
- makromolekulární látky MeSH
- oxid uhličitý MeSH
- přemostěné cyklické sloučeniny MeSH
- rotaxany MeSH
In this study, we have investigated the supramolecular interaction between series of 1-alkyl-3-methylimidazolium guests with variable alkyl substituent lengths and cucurbit[6]uril (CB6) in the solution and the solid state. Correct interpretation of (1)H NMR spectra was a key issue for determining the binding modes of the complexes in solution. Unusual chemical shifts of some protons in the (1)H NMR spectra were explained by the polarization of the imidazolium aromatic ring upon the complexation with the host. The formation of 1:1 complex between 1-ethyl-3-methylimidazolium and CB6 is in disagreement with previously reported findings describing an inclusion of two guest molecules in the CB6 cavity.
- MeSH
- elektrony MeSH
- imidazoly chemie MeSH
- iontové kapaliny chemie MeSH
- magnetická rezonanční spektroskopie MeSH
- molekulární modely MeSH
- přemostěné cyklické sloučeniny chemie MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- cucurbit(6)uril MeSH Prohlížeč
- imidazoly MeSH
- iontové kapaliny MeSH
- přemostěné cyklické sloučeniny MeSH
