Notes: Preparation of O-(Isopropylmethylphosphono)-4-formyl-1-methylpyridinium Iodide Oxime

Hackley, Brennie E.; Owens, Omer O.

doi:10.1021/jo01090a022

Cited by 16 publications

(4 citation statements)

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“…The reactivation curves usually deviate from the pseudo first-order kinetics, and net reactivation stops when re-inhibition by POX equals reactivation. The POX hydrolysis kinetics is dependent on the position of the oxime function at the pyridinium ring (Ashani et al 2003;de Jong and Ceulen 1978;Hackley and Owens 1959), 4-oximes (e.g. obidoxime) forming much more stable POX than 2-oximes (e.g.…”

Section: Introductionmentioning

confidence: 99%

Effect of organophosphorus hydrolysing enzymes on obidoxime-induced reactivation of organophosphate-inhibited human acetylcholinesterase

Herkenhoff

Szinicz

Rastogi³

et al. 2004

Archives of Toxicology

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The reactivation of organophosphate (OP)-inhibited acetylcholinesterase (AChE) by oximes results inevitably in the formation of highly reactive phosphyloximes (POX), which may re-inhibit the enzyme. An impairment of net reactivation by stable POX was found with 4-pyridinium aldoximes, e.g. obidoxime, and a variety of OP compounds. In this study the effect of organophosphorus hydrolase (OPH), organophosphorus acid anhydrolase (OPAA) and diisopropylfluorophosphatase (DFPase) on obidoxime-induced reactivation of human acetylcholinesterase (AChE) inhibited by different OPs was investigated. Reactivation of paraoxon-, sarin-, soman- and VX-inhibited AChE by obidoxime was impaired by POX-induced re-inhibition whereas no deviation of pseudo first-order kinetics was observed with tabun, cyclosarin and VR. OPH prevented (paraoxon) or markedly reduced the POX-induced re-inhibition (VX, sarin, soman), whereas OPAA and DFPase were without effect. Additional experiments with sarin-inhibited AChE indicate that the POX hydrolysis by OPH was concentration-dependent. The activity of OP-inhibited AChE was not affected by OPH in the absence of obidoxime. In conclusion, OPH may be a valuable contribution to the therapeutic regimen against OP poisoning by accelerating the degradation of both the parent compound, OP, and the reaction product, POX.

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Section: Introductionmentioning

confidence: 99%

Effect of organophosphorus hydrolysing enzymes on obidoxime-induced reactivation of organophosphate-inhibited human acetylcholinesterase

Herkenhoff

Szinicz

Rastogi³

et al. 2004

Archives of Toxicology

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“…Hexanohydroxamic acid and benzohydroxamic acid were obtained from Mr. J. Epstein, Protection Research Branch, Edgewood Arsenal. The 4-PPAM was prepared by methylation, with methyl iodide, of the product of reaction of 4-PAM and isopropyl methylphosphonochloridate (Hackley and Owens, 1959). The sample was stored in a freezer under vacuum over P2O5.…”

Section: Methodsmentioning

confidence: 99%

Reaction of 4-Formyl-1-methylpyridinium Iodide Oxime with Isopropyl Methylphosphonofluoridate^*

Lamb¹,

Steinberg²,

Solomon³

et al. 1965

Biochemistry

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“…This POX salt precipitated thus enabling product purification. Following this two‐step strategy, pure products were obtained in moderate yields of about 30–57% 19–26…”

Section: Synthesis Spectroscopic Characteristics and Stability Of Phmentioning

confidence: 99%

“…Therefore, direct reaction of intact quarternary bicyclic oximes with OP was carried out, thus requiring subsequent chromatographic purification instead of crystallization (Figure 1). 14, 17, 18, 24, 25 Following this approach, for example, Waser et al produced mono‐ and di‐phosphonylated obidoxime from direct reaction with sarin27 and Becker reported on POX formation from obidoxime and V‐agents 16…”

Section: Synthesis Spectroscopic Characteristics and Stability Of Phmentioning

confidence: 99%

Chromatographic analysis of toxic phosphylated oximes (POX): a brief overview

Becker¹,

Worek²,

John³

2010

Drug Testing and Analysis

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Poisoning with organophosphorus compounds (OP), e.g. pesticides and nerve agents, causes inhibition of acetylcholinesterase (AChE) by phosphylation of the active site serine residue. Consequently, accumulation of stimulating acetylcholine in the synaptic cleft induces cholinergic crisis which ultimately may lead to death. For standard causal therapy, enzyme reactivators are administered representing oxime derivatives of quarternary pyridinium compounds, e.g. pralidoxime (2-PAM), obidoxime and HI 6. The mechanism of action includes removal of the phosphyl moiety by a nucleophilic attack of the oximate molecule substituting the enzyme and forming a phosphylated oxime (POX). POX is produced in stoichiometric amounts of reactivated enzyme and exhibits a significantly enhanced toxicity (inhibition rate constant) when compared to the parent OP. However, stability of POX under physiological conditions appears to be highly limited. Nevertheless, the presence of POX reveals a potential critical issue for both therapeutic efficacy in vivo and pharmacokinetic and pharmacodynamic (PK-PD) modelling based on cholinesterase activity data. Detailed characterization represents an important need for elaboration of the entire oxime pharmacology.Nevertheless, reports on POX toxicity and analysis are quite rare and may therefore be indicative of the challenge of POX analysis. This review provides a concise overview of chromatographic approaches applied to POX separation. Chromatography represents the key technology for POX purification and quantification in kinetic in vitro studies using buffers and biological fluids. Applications based on reversed-phase chromatography (RPC), ion pair chromatography (IPC) and an affinity approach as well as thin layer chromatography (TLC) are discussed and novel applications and data are presented.

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Notes: Preparation of O-(Isopropylmethylphosphono)-4-formyl-1-methylpyridinium Iodide Oxime

Cited by 16 publications

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Effect of organophosphorus hydrolysing enzymes on obidoxime-induced reactivation of organophosphate-inhibited human acetylcholinesterase

Effect of organophosphorus hydrolysing enzymes on obidoxime-induced reactivation of organophosphate-inhibited human acetylcholinesterase

Reaction of 4-Formyl-1-methylpyridinium Iodide Oxime with Isopropyl Methylphosphonofluoridate^*

Chromatographic analysis of toxic phosphylated oximes (POX): a brief overview

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Notes: Preparation of O-(Isopropylmethylphosphono)-4-formyl-1-methylpyridinium Iodide Oxime

Cited by 16 publications

References 0 publications

Effect of organophosphorus hydrolysing enzymes on obidoxime-induced reactivation of organophosphate-inhibited human acetylcholinesterase

Effect of organophosphorus hydrolysing enzymes on obidoxime-induced reactivation of organophosphate-inhibited human acetylcholinesterase

Reaction of 4-Formyl-1-methylpyridinium Iodide Oxime with Isopropyl Methylphosphonofluoridate*

Chromatographic analysis of toxic phosphylated oximes (POX): a brief overview

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Reaction of 4-Formyl-1-methylpyridinium Iodide Oxime with Isopropyl Methylphosphonofluoridate^*