Tabun scavengers based on hydroxamic acid containing cyclodextrins

Brandhuber, Florian; Zengerle, Michael; Porwol, Luzian; Bierwisch, Anne; Koller, Marianne; Reiter, Georg; Worek, Franz; Kubik, Stefan

doi:10.1039/c3cc41290c

Cited by 37 publications

(25 citation statements)

References 21 publications

(28 reference statements)

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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%

“…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.…”

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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%

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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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“…There are two key intermediates in the synthesis of azido derivatives of -CD substituted at position 2 A : 2 A -O-tosyl--CD [115,116] and 3 A -O-(naphthalene-2-sulfonyl)--CD. 2 A -O-Tosyl--CD can be directly substituted to give 2 Aazido-2 A -deoxy-manno--CD [119] or can be transformed into 2 A ,3 A -manno-epoxy--CD. 2 A -O-Tosyl--CD can be directly substituted to give 2 Aazido-2 A -deoxy-manno--CD [119] or can be transformed into 2 A ,3 A -manno-epoxy--CD.…”

Section: Synthesis Of Derivatives Substituted At Positionmentioning

confidence: 99%

Monosubstituted Cyclodextrins as Precursors for Further Use

Řezanka

2016

Eur J Org Chem

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Cyclodextrin derivatives find use in a broad field of applications (e.g., nanomaterials, biomedical applications, catalysis, separation techniques, sensors etc.), with monosubstitution allowing cyclodextrins to be attached to various types of surfaces or for a new feature to be introduced onto a cyclodextrin skeleton (recognition, catalysis, …). Although an enormous number of monosubstituted cyclodextrin derivatives have been synthesised, this review focuses only on the synthesis of several interesting monosubstituted derivatives (allyl, cinnamyl, propargyl, formylmethyl, carboxymethyl, azido and amino) suitable for further modifications. These derivatives allow the synthesis of an unlimited number of desired cyclodextrin derivatives. Using a cyclodextrin derivative already monosubstituted with a suitable functional group is much easier than the optimisation of monosubstitution for every new cyclodextrin derivative desired.

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“…Dabei konzentrierten wir uns auf Hydroxamsäuren, die OPs bekann-termaßen entgiften kçnnen. [12,13] Quantitative Informationen über die Entgiftungsaktivität der hergestellten Verbindungen wurden mittels eines in früheren Arbeiten etablierten enzymatischen In-vivo-Assays erhalten (Details siehe die Hintergrundinformationen). [14] In diesem Assay wird ein Nervenkampfstoff mit einem Überschuss einer Te stverbindung bei 37 8 8Ci nT RIS-HCl-Puffer (0.1m,p H7.40) inkubiert.…”

Section: Ein Vielversprechendes Konzept Zur Behandlung Vonunclassified

Entgiftung von VX und anderen V‐Stoffen in Wasser bei 37 °C und pH 7.4 durch substituierte Sulfonatocalix[4]arene

Schneider

Bierwisch²,

Koller³

et al. 2016

Angewandte Chemie

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Sulfonatocalix[4]arene mit einem geeigneten Hydroxamsäurerest kçnnen neurotoxische Organophosphonate der Klasse der V-Stoffe mit Halbwertszeiten bis hinunter zu 3min in wässriger Pufferlçsung bei 37 8 8Cund pH 7.4 entgiften. Diese Aktivitäti st auf die millimolare Affinitätd es Calixarenrings fürk ationische V-Stoffe in Kombination mit einer geeigneten Positionierung des Hydroxamsäurerests zurückzuführen. Bei der Reaktion wird zunächst die Hydroxamsäure phosphonyliert. Anschließend erfolgt eine Lossen-Umlagerung, sodass der Wirkmechanismus dieser Verbindungen insgesamt stçchiometrischer und nichtk atalytischer Natur ist. Dennochs tellen die entwickelten Calixarene momentan die effizientesten synthetischen Scavenger dar,d ie persistente V-Stoffe unter milden Bedingungen entgiften. Sie kçnnen als Leitverbindungen fürn eue Wirkstoffe aufgefasst werden, die eine Behandlung von Vergiftungen mit hochtoxischen Nervenkampfstoffen ermçglichen. Abbildung 1. Strukturen von Soman (GD) und den untersuchten V-Stoffen.

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Tabun scavengers based on hydroxamic acid containing cyclodextrins

Abstract: Arrangement of several hydroxamic acid-derived substituents along the cavity of a cyclodextrin ring leads to compounds that detoxify tabun in TRIS-HCl buffer at physiological pH and 37.0 °C with half-times as low as 3 min.

Cited by 37 publications

References 21 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

Monosubstituted Cyclodextrins as Precursors for Further Use

Entgiftung von VX und anderen V‐Stoffen in Wasser bei 37 °C und pH 7.4 durch substituierte Sulfonatocalix[4]arene

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