Detoxification of alkyl methylphosphonofluoridates by an oxime-substituted β-cyclodextrin—an in vitro structure-activity study

Anne Bierwisch, Michael Zengerle, Horst Thiermann, Stefan Kubik, Franz Worek
Toxicology Letters 2014 January 13, 224 (2): 209-14
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.

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