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.