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Elimination kinetics and molecular reaction mechanisms of cyclosarin (GF) by an oxime substituted β-cyclodextrin derivative in vitro

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Author: Kranawetvogl, A. · Müller, S. · Kubik, S. · Spruit, W.E.T. · Thiermann, H. · Worek, F. · Noort, D. · Reiter, G.
Type:article
Date:2015
Publisher: Elsevier Ireland Ltd
Source:Toxicology Letters, 1, 239, 41-52
Identifier: 528228
doi: doi:10.1016/j.toxlet.2015.08.007
Keywords: Chemistry · Covalent conjugate · Detoxification · Organophosphorus compound · Supramolecular scavenger · β-cyclodextrin · Observation, Weapon & Protection Systems · CBRN - CBRN Protection · TS - Technical Sciences

Abstract

Detoxification mechanisms of the chemical warfare agent cyclosarin (GF) in presence of 6-OxP-CD were investigated in detail in in vitro model systems. Most important finding was the preference of 6-Ox-P-CD to eliminate the more toxic (-)-GF. However, elimination of GF enantiomers was dependent on the 6-OxP-CD:GF ratios showing decreasing stereoselectivity and speed of the reaction with increasing GF concentrations. Formation of covalent mono, bis, tris and tetrakis conjugates ((CHMP)<inf>n</inf>-6-OxP-CD) and appearance of small molecular fragments (SMF) as possible decomposition products after consumption of 6-OxP-CD could be observed.. Interestingly, the non-toxic metabolite O-cyclohexyl methylphosphonic acid (CHMPA) and covalent mono and bis conjugates of 6-OxP-CD and GF were immediately formed, indicating that GF elimination proceeds along different pathways. These important new insights provide information about the mode of action of 6-Ox-P-CD including the role of the pyridinium aldoxime group on the cyclodextrin ring. They are the basis for further investigations in biological media, which could eventually lead to approval of 6-OxP-CD as a new antidote against nerve agent toxicity. © 2015 Elsevier Ireland Ltd.