title: Detoxification of alkyl methylphosphonofluoridates by an oxime-substituted β-cyclodextrin--an in vitro structure-activity study.
abstract: Detoxification rates of a series of alkyl methylphosphonofluoridates by an oxime-substituted β-cyclodextrin (β-CD) were assessed quantitatively by using an AChE inhibition assay. The cyclodextrin (CD) derivative was identified in previous work as a highly active cyclosarin scavenger. Here, a structure-activity relationship was established by investigating the effect of this CD on the detoxification of sarin derivatives differing in the structure of the alkoxy residue. The results show that detoxification rates correlate with the steric bulk and chain length of the alkoxy group in the organophosphonate (OP). OPs with larger, more bulky residues are detoxified more rapidly, with the exception of soman, which is bearing a pinacolyloxy side chain. In addition, the substituted CD was in every case more active than unsubstituted, native β-CD with up to a 400-fold difference. Comparing the kinetic results obtained with the known thermodynamic stabilities of related β-CD complexes indicate that detoxification rates generally increase when the alkoxy residue on the OP is exchanged by a residue, which forms a more stable complex with β-CD. This correlation lends support to the proposed mode of action of the substituted CD, involving initial complexation of the OP followed by reaction between the CD and the OP. The moderate to high efficacy on the detoxification of sarin derivatives suggests the potential applicability of this CD as a small molecule scavenger for G-type nerve agents.
authors.affiliation: Institut für Pharmakologie und Toxikologie der Bundeswehr, Neuherbergstraße 11, 80937 München, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Bierwisch
authors.forename: Michael
authors.initials: M
authors.lastname: Zengerle
authors.forename: Horst
authors.initials: H
authors.lastname: Thiermann
authors.forename: Stefan
authors.initials: S
authors.lastname: Kubik
authors.forename: Franz
authors.initials: F
authors.lastname: Worek
mesh_terms: D002800:Cholinesterase Inhibitors / Q000378:metabolism; D006801:Humans; D008658:Inactivation, Metabolic; D009943:Organophosphorus Compounds / Q000378:metabolism*; D010091:Oximes / Q000494:pharmacology*; D012524:Sarin / Q000031:analogs & derivatives / Q000378:metabolism; D013329:Structure-Activity Relationship; D047392:beta-Cyclodextrins / Q000494:pharmacology*
chemical_list: D002800:Cholinesterase Inhibitors; D009943:Organophosphorus Compounds; D010091:Oximes; D047392:beta-Cyclodextrins; D012524:Sarin; C053914:cyclohexyl methylphosphonofluoridate
keywords: Cyclodextrins; Detoxification; In vitro study; Organophosphorus compounds; Oximes