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

Abstract

Sulfonatocalix [4]arenes with an appended hydroxamic acid residue can detoxify VX and related V-type neurotoxico rganophosphonates with half-lives down to 3min in aqueous buffer at 37 8 8Cand pH 7.4. The detoxification activity is attributed to the millimolar affinity of the calixarene moiety for the positively charged organophosphonates in combination with the correct arrangement of the hydroxamic acid group. The reaction involves phosphonylation of the hydroxamic acid followed by aLossen rearrangement, thus rendering the mode of action stoichiometric rather than catalytic. Nevertheless, these calixarenes are currently the most efficient low-molecular-weight compounds for detoxifying persistent V-type nerve agents under mild conditions.T hey thus represent lead structures for novel antidotes that allow treatment of poisonings by these highly toxic chemicals.With ap ercutaneous LD 50 value of 10 mg/human, the organophosphonate (OP) O-ethyl S-[2-(diisopropylamino)ethyl] methylphosphonothioate (VX;F igure 1) is one of the most toxic and most persistent chemical warfare agents. [1] Analogues that likewise have the amino group in the side chain and the relatively stable phosphono-thioester bond are similarly harmful.Thetoxicity of nerve agents is mainly related to their high propensity to covalently modify aserine residue in the active site of the enzyme acetylcholinesterase (AChE).[2] In this form, AChE is unable to perform its function, namely to degrade the neurotransmitter acetylcholine,w hose accumulation leads to severe toxic effects on the central and peripheral nervous system and ultimately to death.Ap romising concept to treat poisonings by nerve agents involves the use of proteins,s oc alled bioscavengers,t hat detoxify OPs before clinical signs occur.[3] Bioscavengers have drawbacks,h owever, for example,l ow in vivo stability and immunogenicity,t hus rendering synthetic scavengers attractive alternatives.[4] With only af ew exceptions, [5] studies on synthetic scavengers have so far concentrated on cyclodextrin derivatives.[6] Their mode of action is expected to resemble that of proteins,w ith an initial complexation step that positions the phosphorus atom of the nerve agent close to asubstituent on the cyclodextrin ring to facilitate the reaction. Despite notable success in this context, [6] cyclodextrins that detoxify V-type nerve agents have so far remained elusive.A possible explanation could be that V-type nerve agents are poor substrates for cyclodextrins because of their protonated side chain amino groups and, hence,p olar nature at physiological pH values. [7] If this assumption is correct, hosts for ammonium ions in water should be more promising scaffolds for scavengers for V-type nerve agents.This idea is consistent with established design principles of supramolecular catalysts and reagents. [8] Ajami and Rebek proposed the use of resorcinarenederived cavitands as OP scavengers.[5c] They described the synthesis of functionalized derivatives that could be used as ab asis for such scav...

Comparison of Binding Affinities of Water-Soluble Calixarenes with the Organophosphorus Nerve Agent Soman (GD) and Commonly-Used Nerve Agent Simulants

“…While there is considerable literature on the inclusion properties of SCX4 and SCX6, many of the papers focus on complexes with a potential biological importance [ 27 , 33 , 34 , 35 , 36 ]. Calixarene binding to the OP VX has been reported [ 19 ] and, as we have demonstrated, the formation of host–guest inclusion complexes of the OP nerve agent GD and commonly used simulants with SCX4 and SCX6 is clearly feasible. In agreement with the literature, this appears to be driven by the hydrophobic inclusion of aliphatic groups [ 16 , 37 ].…”

“…Recently, Worek and co-workers have reported on the development of SCXs modified with hydroxamic acid, which is known to detoxify OP nerve agents [ 19 ]. The functionalized calixarenes show a clear enhancement in the half-life of the detoxification reactions of V-series agents and GD compared to the reactive components in the absence of the calixarene host.…”

Synthetic Receptors for the Recognition and Discrimination of Post‐Translationally Methylated Lysines

“…Already, synthetic methyllysine receptors have prompted the development of macrocycles for the detoxification of organophosphonates, which can be, and are, misused as chemical warfare agents. By way of example, Kubik and co‐workers reported on a series of trisulfonatocalixarenes for the catalytic hydrolysis of V‐type nerve agents and soman; this demonstrated once again the variability of calixarene hosts (Scheme ) …”

Turn-On Supramolecular Host-Guest Nanosystems as Theranostics for Cancer

“…In this section, we restrict our discussion to a narrower subclass that includes only CAs that are generated by reactions of formaldehyde with p-alkylphenols under basic conditions. Water-soluble CA derivatives, especially the sulfonatocalixarenes (SCAs), which contain sulfonate groups at the upper rim, have shown great potential as multifunctional synthetic receptors that can be utilized for drug solubilization, 29 detoxification of herbicides and nerve agents, 30,31 screening of bioorganic analytes inside live cells, 32 and membrane transport activation of peptide substrates. 33 To further improve the biocompatibility of CA derivatives and explore their compatibility with anionic biomolecules, attention has been given to cationic CAs.…”