Casualties caused by nerve agents, potent acetylcholinesterase inhibitors, have attracted attention from media recently. Poisoning with these chemicals may be fatal if not correctly addressed. Therefore, research on novel antidotes is clearly warranted. Pyridinium oximes are the only clinically available compounds, but poor penetration into the blood-brain barrier hampers efficient enzyme reactivation at the central nervous system. In searching for structural factors that may be explored in SAR studies, we synthesized and evaluated neutral aryloximes as reactivators for acetylcholinesterase inhibited by NEMP, a VX surrogate. Although few tested compounds reached comparable reactivation results with clinical standards, they may be considered as leads for further optimization.
- MeSH
- acetylcholinesterasa chemie metabolismus MeSH
- Anguilliformes MeSH
- antidota chemická syntéza metabolismus MeSH
- cholinesterasové inhibitory chemie metabolismus MeSH
- organothiofosforové sloučeniny chemie metabolismus MeSH
- oximy chemie metabolismus MeSH
- pyrrolidiny chemie metabolismus MeSH
- reaktivátory cholinesterasy chemická syntéza metabolismus MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Inhibition of the biosynthesis of complex N-glycans in the Golgi apparatus influences progress of tumor growth and metastasis. Golgi α-mannosidase II (GMII) has become a therapeutic target for drugs with anticancer activities. One critical task for successful application of GMII drugs in medical treatments is to decrease their unwanted co-inhibition of lysosomal α-mannosidase (LMan), a weakness of all known potent GMII inhibitors. A series of novel N-substituted polyhydroxypyrrolidines was synthesized and tested with modeled GH38 α-mannosidases from Drosophila melanogaster (GMIIb and LManII). The most potent structures inhibited GMIIb (Ki =50-76 μm, as determined by enzyme assays) with a significant selectivity index of IC50 (LManII)/IC50 (GMIIb) >100. These compounds also showed inhibitory activities in in vitro assays with cancer cell lines (leukemia, IC50 =92-200 μm) and low cytotoxic activities in normal fibroblast cell lines (IC50 >200 μm). In addition, they did not show any significant inhibitory activity toward GH47 Aspergillus saitoiα1,2-mannosidase. An appropriate stereo configuration of hydroxymethyl and benzyl functional groups on the pyrrolidine ring of the inhibitor may lead to an inhibitor with the required selectivity for the active site of a target α-mannosidase.
- MeSH
- Aspergillus enzymologie MeSH
- buněčné linie MeSH
- Drosophila melanogaster enzymologie MeSH
- dusík chemie MeSH
- fungální proteiny antagonisté a inhibitory metabolismus MeSH
- Golgiho aparát enzymologie MeSH
- inhibiční koncentrace 50 MeSH
- katalytická doména MeSH
- lidé MeSH
- mannosidasy antagonisté a inhibitory metabolismus MeSH
- pyrrolidiny chemie metabolismus farmakologie MeSH
- simulace molekulového dockingu MeSH
- vazebná místa MeSH
- viabilita buněk účinky léků MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- MeSH
- adenosintrifosfatasy metabolismus MeSH
- ascitická tekutina patologie MeSH
- leukemie L1210 MeSH
- myši MeSH
- nádorové cirkulující buňky metabolismus MeSH
- permeabilita buněčné membrány MeSH
- pyrrolidiny analogy a deriváty metabolismus MeSH
- techniky in vitro MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- MeSH
- lidé MeSH
- pyrrolidiny metabolismus MeSH
- železo metabolismus MeSH
- Check Tag
- lidé MeSH
