title: Functionalized cyclodextrins bearing an alpha nucleophile--a promising way to degrade nerve agents.
abstract: Organophosphorus nerve agents are irreversible inhibitors of acetylcholinesterase. Current treatment of nerve agent poisoning has limited efficacy and more efficient medical countermeasures need to be developed. A promising approach is to design chemical scavengers more stable during storage and less immunogenic than bioscavengers. Furthermore, they could be produced at lowest production costs. Cyclodextrins are attractive cyclic oligosaccharides that can be used to develop chemical scavengers of organophosphorus nerve agents. Their abilities to form inclusion and non-inclusion complexes with organic substrates are useful to trap chemical warfare agents. Selective introduction of an α-nucleophile residue on the secondary face of β-cyclodextrin allowed to obtain supramolecular derivatives active against organophosphorus compounds. The degradation activity of these monosubstituted cyclodextrins was determined against paraoxon and chemical warfare agents. These tests showed that the structure of the scavengers mainly influences the interaction between the organophosphorus substrate, or its reaction products, and the cyclodextrin moiety. All the tested G-type agents were efficiently degraded. According to the binding modes of cyclosarin, some oligosaccharidic scavengers led to an enantioselective degradation of this nerve agent. These promising derivatives open the way to further investigations of new structural modifications to reach more sophisticated and efficient scavengers for prophylactic and curative medical applications.
authors.affiliation: Université de Rouen, UMR 6014 CNRS & FR 3038, IRCOF, 1 rue Tesnière, 76821 Mont-Saint-Aignan Cedex, France. francois.estour@univ-rouen.fr
authors.forename: F
authors.initials: F
authors.lastname: Estour
authors.forename: S
authors.initials: S
authors.lastname: Letort
authors.forename: S
authors.initials: S
authors.lastname: Müller
authors.forename: R K
authors.initials: RK
authors.lastname: Kalakuntla
authors.forename: R
authors.initials: R
authors.lastname: Le Provost
authors.forename: T
authors.initials: T
authors.lastname: Wille
authors.forename: G
authors.initials: G
authors.lastname: Reiter
authors.forename: F
authors.initials: F
authors.lastname: Worek
authors.forename: O
authors.initials: O
authors.lastname: Lafont
authors.forename: G
authors.initials: G
authors.lastname: Gouhier
mesh_terms: D002619:Chemical Warfare Agents / Q000378:metabolism* / Q000506:poisoning; D002800:Cholinesterase Inhibitors / Q000378:metabolism / Q000506:poisoning; D003505:Cyclodextrins / Q000737:chemistry / Q000378:metabolism* / Q000627:therapeutic use*; D006801:Humans; D008658:Inactivation, Metabolic; D015394:Molecular Structure; D062025:Organophosphate Poisoning / Q000188:drug therapy* / Q000378:metabolism; D009943:Organophosphorus Compounds / Q000378:metabolism / Q000633:toxicity
chemical_list: D002619:Chemical Warfare Agents; D002800:Cholinesterase Inhibitors; D003505:Cyclodextrins; D009943:Organophosphorus Compounds; C053914:cyclohexyl methylphosphonofluoridate