Highly efficient cyclosarin degradation mediated by a β-cyclodextrin derivative containing an oxime-derived substituent

Abstract

SummaryThe potential of appropriately substituted cyclodextrins to act as scavengers for neurotoxic organophosphonates under physiological conditions was evaluated. To this end, a series of derivatives containing substituents with an aldoxime or a ketoxime moiety along the narrow opening of the β-cyclodextrin cavity was synthesized, and the ability of these compounds to reduce the inhibitory effect of the neurotoxic organophosphonate cyclosarin on its key target, acetylcholinesterase, was assessed in vitro. All compounds exhibited a larger effect than native β-cyclodextrin, and characteristic differences were noted. These differences in activity were correlated with the structural and electronic parameters of the substituents. In addition, the relatively strong effect of the cyclodextrin derivatives on cyclosarin degradation and, in particular, the observed enantioselectivity are good indications that noncovalent interactions between the cyclodextrin ring and the substrate, presumably involving the inclusion of the cyclohexyl moiety of cyclosarin into the cyclodextrin cavity, contribute to the mode of action. Among the nine compounds investigated, one exhibited remarkable activity, completely preventing acetylcholinesterase inhibition by the (−)-enantiomer of cyclosarin within seconds under the conditions of the assay. Thus, these investigations demonstrate that decoration of cyclodextrins with appropriate substituents represents a promising approach for the development of scavengers able to detoxify highly toxic nerve agents.

Catalytic bioscavengers in nerve agent poisoning: A promising approach?

“…This unsatisfying situation induced intensified research efforts for alternative therapeutic concepts. These include adjuncts to basic atropine and oxime therapy, receptor active compounds to improve neuromuscular transmission at respiratory muscles, small molecule scavengers and enzymes which can bind or hydrolyse nerve agents (Wetherell et al, 2007;Seeger et al, 2012;Timperley et al, 2012;Turner et al, 2011;Bierwisch et al, 2014;Worek et al, 2014c;Zengerle et al, 2011;Nachon et al, 2013).…”

Detoxification of VX and Other V‐Type Nerve Agents in Water at 37 °C and pH 7.4 by Substituted Sulfonatocalix[4]arenes

“…Tr is-HCl buffer was chosen as the medium because we typically also consider G-type nerve agents in the screening, whose spontaneous hydrolysis is too fast in phosphate buffer to allow reliable kinetic analyses. [13][14][15] Selected measurements were also performed in phosphate buffer to assess the influence of the buffer on the detoxification of the V-type nerve agents.I ti s worth noting that all of our detoxification studies involved the use of real nerve agents and not of less toxic simulants. Table 1s hows that the two calixarene-based hydroxamic acids 2a and 2b mediate VX detoxification with half-lives of about 5min in Tris-HCl buffer, which is approximately 3500 times faster than the spontaneous hydrolysis of VX under the same conditions.VXdetoxification induced by 2a is similarly fast in phosphate buffer.…”

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

“…aldoximes, ketoximes, hydroxamates, iodosobenzyl partial structures) were synthesized and their impact on GF detoxification was investigated (Brandhuber et al, 2012, Kalakuntla et al, 2013Müller et al, 2011, Zengerle et al, 2011. Up to now, the most effective OP scavenging β-cyclodextrin derivative bears an aldoxime bound to pyridinium in the six position of a glucose unit (6-(3-(hydroxyimino)methylpyridinium-1-yl)-β-cyclodextrin, 6-OxP-CD; (Bierwisch et al, 2014;Zengerle et al, 2011).…”

“…A relatively new therapeutic approach focuses on fast high-affine binding (stoichiometric elimination) and/or decomposition (catalytic or stoichiometric) of OPs as soon as they are available in the systemic circulation (Müller et al, 2011, Zengerle et al, 2011. Stoichiometric binding by proteins like butyrylcholinesterase (BChE) or catalytic degradation by phosphotriesterases (PTE, e.g.…”