Acceleration of the Hydrolysis of Organic Fluorophosphates and Fluorophosphonates with Hydroxamic Acids

Hackley, Brennie E.; Plapinger, Robert E.; Stolberg, Marvin A.; Wagner‐Jauregg, Theodor

doi:10.1021/ja01618a072

Cited by 114 publications

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“…[10,11] These calixarenes were decorated with asubstituent containing ahydroxamic acid, which is known to detoxify OPs. [12,13] Synthesis involved the coupling of monoamine 1 [11a] to carboxylic acids with ap rotected hydroxamic acid. Deprotection followed by chromatographic purification and ion exchange afforded the products as sodium salts.Scheme 1 shows the synthesis of 2a as an example (for synthetic details, see the Supporting Information).…”

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confidence: 99%

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

Schneider

Bierwisch²,

Koller³

et al. 2016

Angew Chem Int Ed

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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...

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confidence: 99%

“…Thep roducts observed indicate that the reaction includes aL ossen rearrangement, as also observed for the reaction of other organophosphates with hydroxamic acids. [12] Thei socyanates resulting from this rearrangement are either hydrolyzed or react with nucleophiles,inour experiments buffer molecules, to yield the corresponding adducts.…”

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confidence: 99%

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

Schneider

Bierwisch²,

Koller³

et al. 2016

Angew Chem Int Ed

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“…[50] We extended the library with oxime-related compounds also known to act as phosphorylated cholinesterase reactivators such as hydroxamic acids. [51] In this context it is interesting to note the early report of Sloan et al [52] who found a marked acceleration of paraoxon hydrolysis with various Nalkylhydroxamic acids in micellar conditions.…”

Section: Resultsmentioning

confidence: 94%

A HTS Assay for the Detection of Organophosphorus Nerve Agent Scavengers

Louise-Leriche

Păunescu

Saint‐Andre

et al. 2010

Chemistry A European J

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A new pro-fluorescent probe aimed at a HTS assay of scavengers is able to selectively and efficiently cleave the P-S bond of organophosphorus nerve agents and by this provides non-toxic phosphonic acid has been designed and synthesised. The previously described pro-fluorescent probes were based on a conventional activated P-Oaryl bond cleavage, whereas our approach uses a self-immolative linker strategy that allows the detection of phosphonothioase activity with respect to a non-activated P-Salkyl bond. Further, we have also developed and optimised a high-throughput screening assay for the selection of decontaminants (chemical or biochemical scavengers) that could efficiently hydrolyse highly toxic V-type nerve agents. A preliminary screening, realised on a small alpha-nucleophile library, allowed us to identify some preliminary "hits", among which pyridinealdoximes, alpha-oxo oximes, hydroxamic acids and, less active but more original, amidoximes were the most promising. Their selective phosphonothioase activity has been further confirmed by using PhX as the substrate, and thus they offer new perspectives for the synthesis of more potent V nerve agent scavengers.

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“…Hackley et al and other workers (7)(8)(9)(10)(11)(12)(13) have found that the reaction of sarin with hydroxamic acids involves a nucleophilic'attack by the hydroximate ion as the rate determining step. The tautomeric form of the ion was proposed to be the reactive species in order to explain the very high activity of these compounds.…”

Section: Past Work Organophosphorous Compounds Reactionsmentioning

confidence: 99%

Molecular Catalysis and Interactions in Aqueous Solutions

Higuchi¹

1964

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Acceleration of the Hydrolysis of Organic Fluorophosphates and Fluorophosphonates with Hydroxamic Acids

Cited by 114 publications

References 0 publications

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

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

A HTS Assay for the Detection of Organophosphorus Nerve Agent Scavengers

Molecular Catalysis and Interactions in Aqueous Solutions

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