Design, synthesis and evaluation of new α-nucleophiles for the hydrolysis of organophosphorus nerve agents: application to the reactivation of phosphorylated acetylcholinesterase

Saint‐Andre, Geraldine; Kliachyna, Maria; Kodepelly, Sanjeevarao; Louise-Leriche, Ludivine; Gillon, Émilie; Renard, Pierre; Nachon, Florian; Baati, Rachid; Wagner, Alain

doi:10.1016/j.tet.2011.05.130

Cited by 70 publications

(38 citation statements)

References 81 publications

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“…Additional studies will be needed to identify the precise structural species and mechanistic nature of this functionally beneficial nucleophilic reaction. Enhanced nucleophilicity of ortho hydroxyl substituted benzene aldoximes, but with monophasic pH dependence and only limited in vitro reactivation potency has been observed elsewhere [25]. Additionally, hydroxyl groups positioned ortho to oxime reactivators enhance decomposition of phosphonyl-oximes, probably through intramolecular formation of an isoxazole ring [26, 27] and minimize eventual reinhibition of enzymes observed for some phosphonyl-oxime adducts [28].…”

Section: Discussionmentioning

confidence: 97%

Catalytic detoxification of nerve agent and pesticide organophosphates by butyrylcholinesterase assisted with non-pyridinium oximes

Radić

Dale

Kovarik

et al. 2013

Biochemical Journal

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SYNOPSIS We present here a comprehensive in vitro, ex vivo and in vivo study on hydrolytic detoxification of nerve agent and pesticide organophosphates (OPs) catalyzed by purified human butyrylcholinesterase (hBChE) in combination with novel non-pyridinium oxime reactivators. We identified 2-trimethylammonio-6-hydroxybenzaldehyde oxime (TAB2OH) as an efficient reactivator of OP-hBChE conjugates formed by the nerve agents, VX and cyclosarin, and the pesticide, paraoxon. It was also functional in reactivation of sarin and tabun inhibited hBChE. A three to five-fold enhancement of in vitro reactivation of VX, cyclosarin and paraoxon inhibited hBChE was observed, when compared to the commonly used N-methylpyridinium aldoxime reactivator, 2PAM. Kinetic analysis showed the enhancement resulted from improved molecular recognition of corresponding OP-hBChE conjugates by TAB2OH. The unique features of TAB2OH stem from an exocyclic quaternary nitrogen and a hydroxyl, both ortho to an oxime group on a benzene ring. pH dependences reveal participation of the hydroxyl (pKa=7.6) forming an additional ionizing nucleophile to potentiate the oxime (pKa=10) at physiological pH. The TAB2OH protective indices in therapy of sarin and paraoxon exposed mice were enhanced by 30% – 60% when they were treated with a combination of TAB2OH and sub-stoichiometric hBChE. These results establish that oxime-assisted catalysis is feasible for OP bioscavenging.

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Section: Discussionmentioning

confidence: 97%

Catalytic detoxification of nerve agent and pesticide organophosphates by butyrylcholinesterase assisted with non-pyridinium oximes

Radić

Dale

Kovarik

et al. 2013

Biochemical Journal

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“…(2011), 3-hydroxy-2-pyridinealdoxime was found to be a very promising neutral a-nucleophile with a high reactivation rate constant. 73 It is able to cleave the P-S bond of OP thereby yielding to the corresponding isoxazole analogue and non-toxic phosphonic adduct, thus through this preventing recapture phenomena. 74 The two uncharged oximes (35 and 36) as shown in Fig.…”

Section: Development Of Uncharged Oximesmentioning

confidence: 99%

Recent developments on oximes to improve the blood brain barrier penetration for the treatment of organophosphorus poisoning: a review

et al. 2020

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“…Nesse sentido, buscam-se alfa-nucleófilos mais eficientes em relação àqueles atualmente empregados. 28,29,38,39 A reatividade dos compostos é em geral avaliada por meio do estudo cinético e mecanístico das reações entre os nucleófilos e organofosforados representativos, bem como através da quantificação direta da reativação de enzimas específicas inibidas em laboratório. 40 O estudo de modelos em meios micro-heterogêneos é particularmente interessante, pois contribui para a mimetização do caráter hidrofóbico característico de sítios enzimáticos.…”

Section: Conclusões E Perspectivasunclassified

Recent Advances on the Decomposition of Neurotoxic Phosphorous Triesters

Wanderlind¹,

Medeiros²,

Souza³

et al. 2014

Revista Virtual De Química

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The anti-cholinesterase activity exhibited by several organophosphorus compounds brings interest to the development of new antidotes for poisoning cases with such chemicals. The advance of more efficient methods for destruction of stockpiles of chemical warfare agents is also currently important. In this sense, the aim of this work is to present a review of the recent progress in the investigation of the reactivity of phosphate triesters in several different systems, which can give insights into the development of novel strategies for application in chemical defense.

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Design, synthesis and evaluation of new α-nucleophiles for the hydrolysis of organophosphorus nerve agents: application to the reactivation of phosphorylated acetylcholinesterase

Cited by 70 publications

References 81 publications

Catalytic detoxification of nerve agent and pesticide organophosphates by butyrylcholinesterase assisted with non-pyridinium oximes

Catalytic detoxification of nerve agent and pesticide organophosphates by butyrylcholinesterase assisted with non-pyridinium oximes

Recent developments on oximes to improve the blood brain barrier penetration for the treatment of organophosphorus poisoning: a review

Recent Advances on the Decomposition of Neurotoxic Phosphorous Triesters

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