title: Detoxification of tabun at physiological pH mediated by substituted β-cyclodextrin and glucose derivatives containing oxime groups.
abstract: The ability of 13 β-cyclodextrin and 2 glucose derivatives containing substituents with oxime groups as nucleophilic components to accelerate the degradation of tabun at physiological pH has been evaluated. To this end, a qualitative and a quantitative enzymatic assay as well as a highly sensitive enantioselective GC-MS assay were used. In addition, an assay was developed that provided information about the mode of action of the investigated compounds. The results show that attachment of pyridinium-derived substituents with an aldoxime group in 3- or 4-position to a β-cyclodextrin ring affords active compounds mediating tabun degradation. Activities differ depending on the structure, the number, and the position of the substituent on the ring. Highest activity was observed for a β-cyclodextrin containing a 4-formylpyridinium oxime residue in 6-position of one glucose subunit, which detoxifies tabun with a half-time of 10.2 min. Comparison of the activity of this compound with that of an analog in which the cyclodextrin ring was replaced by a glucose residue demonstrated that the cyclodextrin is not necessary for activity but certainly beneficial. Finally, the results provide evidence that the mode of action of the cyclodextrin involves covalent modification of its oxime group rendering the scavenger inactive after reaction with the first tabun molecule.
authors.affiliation: Institut für Pharmakologie und Toxikologie der Bundeswehr, Neuherbergstrasse 11, D-80937 München, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Brandhuber
authors.forename: Michael
authors.initials: M
authors.lastname: Zengerle
authors.forename: Luzian
authors.initials: L
authors.lastname: Porwol
authors.forename: Oliver
authors.initials: O
authors.lastname: Tenberken
authors.forename: Horst
authors.initials: H
authors.lastname: Thiermann
authors.forename: Franz
authors.initials: F
authors.lastname: Worek
authors.forename: Stefan
authors.initials: S
authors.lastname: Kubik
authors.forename: Georg
authors.initials: G
authors.lastname: Reiter
mesh_terms: D002619:Chemical Warfare Agents / Q000737:chemistry / Q000633:toxicity; D002800:Cholinesterase Inhibitors / Q000737:chemistry; D008401:Gas Chromatography-Mass Spectrometry; D005947:Glucose / Q000737:chemistry*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008658:Inactivation, Metabolic; D015394:Molecular Structure; D009768:Obidoxime Chloride / Q000737:chemistry*; D010755:Organophosphates / Q000737:chemistry* / Q000633:toxicity*; D010091:Oximes / Q000737:chemistry; D011726:Pyridinium Compounds / Q000737:chemistry; D047392:beta-Cyclodextrins / Q000737:chemistry*
chemical_list: D002619:Chemical Warfare Agents; D002800:Cholinesterase Inhibitors; D010755:Organophosphates; D010091:Oximes; D011726:Pyridinium Compounds; D047392:beta-Cyclodextrins; D009768:Obidoxime Chloride; D005947:Glucose; C023728:acetaldehyde oxime; C009374:tabun