betadex and tabun

The ability of 13 β-cyclodextrin and 2 glucose derivatives containing substituents with oxime groups as nucleophilic components to accelerate the degradation of tabun at physiological pH has been evaluated. To this end, a qualitative and a quantitative enzymatic assay as well as a highly sensitive enantioselective GC-MS assay were used. In addition, an assay was developed that provided information about the mode of action of the investigated compounds. The results show that attachment of pyridinium-derived substituents with an aldoxime group in 3- or 4-position to a β-cyclodextrin ring affords active compounds mediating tabun degradation. Activities differ depending on the structure, the number, and the position of the substituent on the ring. Highest activity was observed for a β-cyclodextrin containing a 4-formylpyridinium oxime residue in 6-position of one glucose subunit, which detoxifies tabun with a half-time of 10.2 min. Comparison of the activity of this compound with that of an analog in which the cyclodextrin ring was replaced by a glucose residue demonstrated that the cyclodextrin is not necessary for activity but certainly beneficial. Finally, the results provide evidence that the mode of action of the cyclodextrin involves covalent modification of its oxime group rendering the scavenger inactive after reaction with the first tabun molecule.

Topics: beta-Cyclodextrins; Chemical Warfare Agents; Cholinesterase Inhibitors; Gas Chromatography-Mass Spectrometry; Glucose; Humans; Hydrogen-Ion Concentration; Inactivation, Metabolic; Molecular Structure; Obidoxime Chloride; Organophosphates; Oximes; Pyridinium Compounds

Chemical warfare agents (nerve agents) are still available and present a real threat to the population. Numerous in vitro and in vivo studies showed that various nerve agents, e.g. tabun and cyclosarin, are resistant towards standard therapy with atropine and oxime. Based on these facts we applied a modified biological assay for the easy, semi-quantitative testing of the detoxifying properties of the beta-cyclodextrin derivative CD-IBA. Cyclosarin, sarin, tabun and VX were incubated with CD-IBA for 1-50 min at 37 degrees C, then an aliquot was added to erythrocyte acetylcholinesterase (AChE) and the percentage of AChE inhibition was determined. The validity of the assay was confirmed by concomitant quantification of tabun by GC-MS. Different concentrations of cyclosarin were detoxified by CD-IBA in a concentration-dependent velocity. The ability to detoxify various nerve agents decreased in the order cyclosarin>sarin>tabun>>VX. Hereby, no detoxification of VX could be detected. Sarin was detoxified in a biphasic reaction with a fast reduction of inhibitory potential in the first phase and a slower detoxification in the second phase. CD-IBA detoxified tabun in a one phase decay and, compared to cyclosarin and sarin, a longer half-life was determined with tabun. The modified biological assay is appropriate for the initial semi-quantitative screening of candidate compounds for the detoxification of nerve agents. The beta-cyclodextrin derivative CD-IBA demonstrated its ability to detoxify different nerve agents.

Topics: Acetylcholinesterase; beta-Cyclodextrins; Biological Assay; Buffers; Chemical Warfare Agents; Cholinesterase Inhibitors; Erythrocyte Membrane; Humans; Hydrogen-Ion Concentration; Molecular Structure; Organophosphates; Organophosphorus Compounds; Organothiophosphorus Compounds; Reference Standards; Reproducibility of Results; Sarin; Time Factors

Cyclodextrins catalyzed the inactivation of sarin and soman but did not inactivate tabun and VX. Furthermore, sarin and soman showed greater affinity for beta-cyclodextrin than for alpha- or gamma-cyclodextrins. Thus beta-cyclodextrin appears to be an attractive starting material for the preparation of a catalyst able to inactivate sarin and soman more effectively. Such a catalyst might contribute to improving the therapy of poisoning caused by these two nerve agents.

Topics: alpha-Cyclodextrins; beta-Cyclodextrins; Cyclodextrins; Dextrins; gamma-Cyclodextrins; Kinetics; Organophosphates; Organophosphorus Compounds; Organothiophosphorus Compounds; Sarin; Soman; Starch

Of the following neurotoxic agents, pinacolyl methylphosphonofluoridate (soman), isopropyl methylphosphonofluoridate (sarin) and ethyl N,N-dimethylphosphoramidocyanidate (tabun), only soman was inactivated appreciably at pH 7.40 by beta-cyclodextrin. The interaction of soman, a mixture of four stereoisomers designated as C(+)P(-), C(-)P(-), C(+)P(+), and C(-)P(+), with cyclodextrins was revealed by methods based on the irreversible inhibition of acetylcholinesterase (AChE) that is phosphonylated chiefly by P(-)-isomers of racemic soman and continuous titration of fluoride ions released by soman using a fluoride-specific electrode. Soman and beta-cyclodextrin form a 1:1 complex. At pH 7.40 and 25 degrees C the dissociation constant Kd of this complex and the rate constant k2 of cleavage of soman by beta-cyclodextrin are (0.53 +/- 0.05) mM and (5.9 +/- 0.6) X 10(-2) min-1, respectively. The rate constant k2 max for the cleavage of soman by monoionized beta-cyclodextrin has a value of 2.8 X 10(3) min-1 and the second order rate constant k2 max/kd is 5.3 X 10(6) M-1 min-1. Consequently, soman is hydrolyzed about 2500 times faster by the monoanion of beta-cyclodextrin, than by the hydroxide ion. The cleavage of P(-)-soman by beta-cyclodextrin as estimated by AChE inhibition proceeds apparently at the same rate for the C(-)P(-)-and C(+)P(-)-isomers. However, the release of fluoride ions indicated a stereospecific rate of reaction, the P(-)-isomers reacting faster than the P(+)-isomers. At pH 7.40, the inactivation rate of soman by beta-cyclodextrin was as fast in human plasma in vitro as in Tris buffer. This interaction between soman and beta-cyclodextrin, and other data from the literature, suggests that the introduction of catalytic or noncatalytic groups on beta-cyclodextrin might possibly make it a better catalyst for soman inactivation through improvement in the catalytic or in the binding process.

Topics: Acetylcholinesterase; Animals; beta-Cyclodextrins; Binding Sites; Cholinesterase Inhibitors; Cyclodextrins; Dextrins; Drug Interactions; Electrophorus; Humans; Kinetics; Organophosphates; Organophosphorus Compounds; Sarin; Soman; Starch