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

Highly efficient cyclosarin degradation mediated by a β-cyclodextrin derivative containing an oxime-derived substituent Michael Zengerle1, Florian Brandhuber2, Christian Schneider1, Franz Worek2, Georg Reiter2 and Stefan Kubik*1 Full Research Paper Open Access Address: 1Fachbereich Chemie - Organische Chemie, Technische Universität Kaiserslautern, Erwin-Schrödinger-Straße, D-67663 Kaiserslautern, Germany, Fax: +49-631-205-3921 and 2Institut für Pharmakologie und Toxikologie der Bundeswehr, Neuherbergstraße 11, D-80937 München, Germany Beilstein J. Org. Chem. 2011, 7, 1543–1554. doi:10.3762/bjoc.7.182 Email: Stefan Kubik* - This article is part of the Thematic Series "Supramolecular chemistry II". Received: 28 September 2011 Accepted: 08 November 2011 Published: 22 November 2011 Guest Editor: C. A. Schalley * Corresponding author Keywords: acetylcholinesterase; cyclodextrins; cyclosarin; neurotoxic organophosphonates; oximes © 2011 Zengerle et al; licensee Beilstein-Institut. License and terms: see end of document. Abstract The 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. Introduction Cyclodextrins, cyclic oligosaccharides composed of α-1,4linked D-glucose units, represent one of the most important classes of host systems in supramolecular chemistry [1]. Their easy availability, their ability to include organic nonpolar molecules into the cavity made up by the cyclically arranged glucose units in aqueous solution, their predictable and controllable 1543 Beilstein J. Org. Chem. 2011, 7, 1543–1554. binding properties, and their relatively straightforward chemical modification have made cyclodextrins indispensable tools in applications such as sensing [2], nanotechnology [3,4], polymer chemistry [5-8], medicinal chemistry [9,10], food chemistry [11], and others. Importantly, the scope of cyclodextrins goes beyond molecular recognition since the recognition event can in some cases be coupled with the chemical transformation of a substrate. This property was already realized in 1959 when it was shown that native cyclodextrins accelerate the cleavage of some acetic acid esters [12]. Subsequent work then established cyclodextrins containing appropriate substituents or dimeric cyclodextrins as a potent class of enzyme mimics [13,14]. Interestingly, it was also demonstrated relatively early in the field of cyclodextrin chemistry that native cyclodextrins are able to accelerate the cleavage of phosphates and phosphonates [15-18], including the highly neurotoxic organophosphonates (OP) sarin and soman [19-21]. While α-cyclodextrin, the cyclodextrin containing six anhydroglucose units along the ring, was shown to be most effective for sarin [17,22], the larger β-cyclodextrin with the seven-membered ring was demonstrated to also mediate soman degradation [19,20]. Moreover, the cyclodextrins were shown to act enantioselectively, being more effective for the more toxic (R)-(−)-enantiomer of sarin, for example [17,22]. Surprisingly, this work has largely been overlooked despite the fact that it provided strong indications for the potential applicability of cyclodextrins for the detoxification of chemical warfare agents. Only very recently has the use of cyclodextrins to induce degradation of neurotoxic OPs been addressed again. These investigations showed that β-cyclodextrin derivatives with a substituent along the wider rim of the cavity, bearing a nucleophilic group in the form of an iodosylbenzoate [23-25] or an oxime [26], efficiently react with paraoxon, cyclosarin (GF), and tabun thus reducing the inhibitory effects of these OPs on the key target of OP toxicity, acetylcholinesterase (AChE). Moreover, the results indicate that the mode of action of these cyclodextrin derivatives involves the formation of an inclusion complex with the OP. The question thus arises as to whether suitable cyclodextrin derivatives could also be used in vivo as antidotes against OP poisonings. Such compounds should be able to act as scavengers by rapidly decomposing the OP into nontoxic byproducts before inhibition of AChE occurs. Catalytic action of the scavenger is desirable, reducing the necessary dose of the drug, but is not required if the toxicity is low. Since the amount of data currently available is too low to assess whether this approach has a realistic prospect of success, we initiated a research program aimed at the synthesis of a large number of structurally diverse cyclodextrin derivatives and the evaluation of their effect on OP degradation. In terms of structure, these compounds follow a common design principle, involving three distinct subunits each of which has a characteristic function (Figure 1): • A cyclodextrin ring, which forms the basis of each compound. Complex formation between this subunit and the substrate should bring the P-atom of the substrate into spatial proximity with the substituent on the ring, thus facilitating the attack by the reactive group on the substituent. The type of cyclodextrin in this subunit (α, β, γ) controls the substrate affinity. • The linking unit between the cyclodextrin ring and the reactive part of the substituent. This group should be chosen to allow straightforward synthetic access to the cyclodextrin derivatives, ideally allowing the synthesis to proceed in a modular fashion. • The reactive unit bearing a functional group that should be able to specifically cleave the P–X bond on the substrate. In the case of GF (Scheme 1), for example, the most labile P–F b (...truncated)