Nerve agent stereoisomers: analysis, isolation and toxicology

Benschop, H. P.; Jong, L.P.A. de

doi:10.1021/ar00154a003

Cited by 214 publications

(189 citation statements)

References 36 publications

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“…Furthermore, under similar experimental conditions, the titration studies demonstrate that for soman 1:2 stoichiometry is obtained for the wild type enzyme as well as for the mutants examined. Due to the chirality of the phosphorous in soman, this OP-inhibitor is known to exhibit a marked stereoselectivity in reactions with AChE from Table I Compilation of kinetic constants for ATC and TB hydrolysis by HuAChE and its mutants various sources [30], including recombinant HuAChE [14]. Thus, the HuAChE mutants studied appear to retain the stereoselectivity towards soman diastereomers.…”

Section: Effect Of Mutation On Hydrolysis Of Charged and Uncharged Sumentioning

confidence: 99%

Engineering resistance to ‘aging’ of phosphylated human acetylcholinesterase Role of hydrogen bond network in the active center

et al. 1993

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Recombinant human acetylcholinesterase (HuAChE) and selected mutants (E202Q, Y337A, F,450A) were studied with respect to catalytic activity towards charged and noncharged substrates, phosphylation with organophosphorus (OP) inhibitors and subsequent aging of the OP-conjugates. Amino acid E450, unlike residues E202 and Y337, is not within interaction distance from the active center. Yet, the bimolecular rates of catalysis and phosphylation are 30~100 fold lower for both FA50A and E202Q compared to Y337A or the wild type and in both mutants the resulting OP-conjugates show striking resistance to aging. It is proposed that a hydrogen bond network, that maintains the functional architecture of the active center, involving water molecules and residues E202 and E450, is responsible for the observed behaviour.

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Section: Effect Of Mutation On Hydrolysis Of Charged and Uncharged Sumentioning

confidence: 99%

Engineering resistance to ‘aging’ of phosphylated human acetylcholinesterase Role of hydrogen bond network in the active center

et al. 1993

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“…For nerve agents, the stereoisomer with the absolute configuration shown in Figure 9 is usually the most active AChE inhibitor, since the R'O group is greater than the R group. 113 This configuration corresponds to the S-isomers of sarin and VX, and to S-configuration around the phosphorus atom (P S ) for soman. 63,97,118 Table 3 shows the effect of the stereochemistry of nerve agents on their anticholinesterase activity and acute lethality, which is not very expressive.…”

Section: Opcs As Chemical Warfare Agentsmentioning

confidence: 97%

“…At the CNS the symptoms are usually headache, muscle tremors, giddiness, convulsions and respiratory arrest, being the latter the responsible for most fatalities caused by OPCs. 3,4,113 The signs and symptoms of intoxication by these agents (cholinergic syndrome) just appear when more than 50% of AChE is inhibited, and death occurs after inhibition of 90% of the enzyme. 71 Interestingly, the symptoms caused by different nerve agents are similar, with the differences being caused by the variation of inactivation or ageing rates, as well as differences in absorption, distribution and metabolism.…”

Section: Mechanism Of Action Of Opcsmentioning

confidence: 99%

Organophosphorus compounds as chemical warfare agents: a review

Delfino¹,

Ribeiro²,

Figueroa‐Villar³

2009

J. Braz. Chem. Soc.

231

178

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Os agentes de guerra química constituem uma das maiores ameaças do mundo moderno. Dentre estes, destacam-se os agentes neurotóxicos, em virtude de sua alta letalidade e periculosidade. Eles são compostos organofosforados que atuam pela inibição da enzima acetilcolinesterase, a qual é fundamental no processo de transmissão de impulsos nervosos. Existem várias formas de tratamento para a intoxicação por organofosforados, mas nenhuma delas é eficaz contra todos os agentes conhecidos ou contra todos os seus efeitos. Esta revisão tem como foco o uso de compostos organofosforados como agentes neurotóxicos de guerra química. Após uma breve introdução histórica, será feita uma discussão sobre as principais características estruturais e biológicas da acetilcolinesterase, seguida por uma revisão das propriedades dos compostos organofosforados e da sua aplicação como agentes de guerra química. Por fim, serão discutidas as formas de tratamento contra estes agentes, com ênfase nas oximas usadas para reativar a acetilcolinesterase inibida.Chemical warfare agents constitute one of the greatest threats in the modern world. Among them, the neurotoxic agents are of special interest due to their high lethality and danger. Neurotoxic agents are organophosphorus compounds that act by inhibiting the enzyme acetylcholinesterase, which is fundamental for the control of transmission of nervous impulses. There are several ways of treating intoxication by organophosphorus compounds, but none of them is efficient against all the known neurotoxic agents or against all of their effects. This review focus on the use of organophosphorus compounds as neurotoxic chemical warfare agents. After a brief historical introduction, it will be done a discussion about the structural and biological characteristics of acetylcholinesterase, followed by a review of the properties of organophosphorus compounds and their application as chemical warfare agents. Finally, the ways of treatment against intoxication with these agents will be discussed, with emphasis on the oximes used for reactivating the inhibited acetylcholinesterase.

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“…Estes estereoisômeros podem ou não diferirem entre eles na velocidade com que reagem com a AChE, não havendo uma regra pré-definida. 28 O rompimento da ligação P-F por ataque nucleofílico rege a química do soman e do sarin. Para tal rompimento ocorrer, não são necessárias condições enérgicas.…”

Section: Propriedades Físico-químicasunclassified