title: New modified β-cyclodextrin derivatives as detoxifying agents of chemical warfare agents (I). Synthesis and preliminary screening: evaluation of the detoxification using a half-quantitative enzymatic assay.
abstract: Current treatments of organophosphorus nerve agents poisoning are imperfect, and more efficient medical countermeasures need to be developed. Chemical scavengers based on β-cyclodextrin displayed promising results, but further investigations have to be performed to evaluate the possibility of application of substituted cyclodextrins as potential detoxification agents. Herein, five new cyclodextrins scavengers were synthesized. New optimal conditions for regioselectively monosubstitution of β-cyclodextrin at O-2 position were then studied to access to key intermediates. After these optimizations, a new series of three permethylated derivatives was developed, and two compounds bearing an α-nucleophilic group via a three carbon atoms linker were prepared. The ability of these five scavengers to detoxify nerve agents (cyclosarin, soman, tabun and VX) was evaluated by a semi-quantitative biological assay. All the modified cyclodextrins significantly decreased the inhibitory effect of chemical warfare G agents on acetylcholinesterase activity. For this purpose, we showed that the specific interactions between the organophosphorus compound and the oligosaccharidic moiety of the scavenger played a pivotal role in the detoxification process.
authors.affiliation: Université de Rouen, UMR 6014 CNRS & FR 3038, IRCOF, 1 rue Tesnière, 76821 Mont-Saint-Aignan Cedex, France.
authors.forename: Raman Kumar
authors.initials: RK
authors.lastname: Kalakuntla
authors.forename: Timo
authors.initials: T
authors.lastname: Wille
authors.forename: Romain
authors.initials: R
authors.lastname: Le Provost
authors.forename: Sophie
authors.initials: S
authors.lastname: Letort
authors.forename: Georg
authors.initials: G
authors.lastname: Reiter
authors.forename: Susanne
authors.initials: S
authors.lastname: Müller
authors.forename: Horst
authors.initials: H
authors.lastname: Thiermann
authors.forename: Franz
authors.initials: F
authors.lastname: Worek
authors.forename: Géraldine
authors.initials: G
authors.lastname: Gouhier
authors.forename: Olivier
authors.initials: O
authors.lastname: Lafont
authors.forename: François
authors.initials: F
authors.lastname: Estour
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D002619:Chemical Warfare Agents / Q000493:pharmacokinetics*; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D009943:Organophosphorus Compounds / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics*; D021241:Spectrometry, Mass, Electrospray Ionization; D013237:Stereoisomerism; D047392:beta-Cyclodextrins / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D002619:Chemical Warfare Agents; D002800:Cholinesterase Inhibitors; D009943:Organophosphorus Compounds; D047392:beta-Cyclodextrins; D000110:Acetylcholinesterase