Elimination kinetics and molecular reaction mechanisms of cyclosarin (GF) by an oxime substituted β-cyclodextrin derivative in vitro.
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)n-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.
Bundeswehr Institute of Pharmacology and Toxicology, Neuherbergstraße 11, 80937 Munich, Germany.
Andreas
A
Kranawetvogl
Bundeswehr Institute of Pharmacology and Toxicology, Neuherbergstraße 11, 80937 Munich, Germany.
Susanne
S
Müller
Fachbereich Chemie-Organische Chemie, Technische Universität Kaiserslautern, Erwin-Schrödinger-Straße, 67663 Kaiserslautern, Germany.
Stefan
S
Kubik
TNO Defence, Security and Safety, Department of CBRN Protection, P.O. Box 45, 2280 AA Rijswijk, The Netherlands.
Helma
H
Spruit
Bundeswehr Institute of Pharmacology and Toxicology, Neuherbergstraße 11, 80937 Munich, Germany.
Horst
H
Thiermann
Bundeswehr Institute of Pharmacology and Toxicology, Neuherbergstraße 11, 80937 Munich, Germany.
Franz
F
Worek
TNO Defence, Security and Safety, Department of CBRN Protection, P.O. Box 45, 2280 AA Rijswijk, The Netherlands.
Daan
D
Noort
Bundeswehr Institute of Pharmacology and Toxicology, Neuherbergstraße 11, 80937 Munich, Germany. Electronic address: georgreiter@bundeswehr.org.
Georg
G
Reiter
D000931:Antidotes / Q000494:pharmacology*; D009943:Organophosphorus Compounds / Q000378:metabolism / Q000493:pharmacokinetics*; D010091:Oximes / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D047392:beta-Cyclodextrins / Q000737:chemistry / Q000494:pharmacology*
D000931:Antidotes; D009943:Organophosphorus Compounds; D010091:Oximes; D047392:beta-Cyclodextrins; C073636:cyclohexyl methylphosphonic acid; C053914:cyclohexyl methylphosphonofluoridate
covalent conjugate; detoxification; organophosphorus compound; supramolecular scavenger; β-cyclodextrin