関: DFP、diisopropylfluorophosphate、isoflurophate

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2019/08/04 23:06:37」(JST)

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Diisopropyl fluorophosphate is an oily, colorless liquid with the chemical formula C₆H₁₄FO₃P. It is used in medicine^[1] and as an organophosphorus insecticide^{[citation needed]}. It is stable, but undergoes hydrolysis when subjected to moisture, producing hydrofluoric acid.

Uses in medicine

Diisopropyl fluorophosphate is a parasympathomimetic drug irreversible anti-cholinesterase and has been used in ophthalmology as a miotic agent in treatment of chronic glaucoma, as a miotic in veterinary medicine, and as an experimental agent in neuroscience because of its acetylcholinesterase inhibitory properties and ability to induce delayed peripheral neuropathy.^[1]

Uses as toxin

Reaction of the DIFP with a serine protease

The marked toxicity of esters of monofluorophosphoric acid was discovered in 1932, when Willy Lange and his PhD student Gerda von Krueger prepared the methyl, ethyl, n-propyl, and n-butyl esters and incidentally experienced their toxic effects. Another homologue of this series of esters, Diisopropyl fluorophosphate, was developed by British scientist Bernard Charles Saunders. On his search for compounds to be used as chemical warfare agents, Saunders was inspired by the report by Lange and Krueger and decided to prepare the new homologue which he labeled PF-3. It was much less effective as a chemical weapon than the G series agents. It was often mixed with mustard gas, forming a more effective mixture with significantly lower melting point, resulting in an agent suitable for use in cold weather.

Crystal structure of Herpes Simplex Virus Protease/Inhibitor (DFP) complex. The active site serine (yellow) has undergone phosphonylation resulting in irreversible inhibition. Rendered from PDB 1AT3.

In military research, due to its physical and chemical similarities and comparatively low toxicity, it is used as a simulant of G-agents (GA, GB, GD, and GF). Diisopropyl fluorophosphate is used in civilian laboratories to mimic lethal nerve gas exposure or organophosphate toxicities.^[2]^[3]^[4] It has also been used to develop a rodent model of Gulf War Syndrome.^[5]

Diisopropyl fluorophosphate is a very potent neurotoxin. Its LD₅₀ in rats is 6 mg/kg (oral). It combines with the amino acid serine at the active site of the enzyme acetylcholinesterase,^[6] an enzyme that deactivates the neurotransmitter acetylcholine. Neurotransmitters are needed to continue the passage of nerve impulses from one neuron to another across the synapse. Once the impulse has been transmitted, acetylcholinesterase functions to deactivate the acetylcholine almost immediately by breaking it down. If the enzyme is inhibited, acetylcholine accumulates and nerve impulses cannot be stopped, causing prolonged muscle contraction. Paralysis occurs and death may result since the respiratory muscles are affected.

DFP also inhibits some proteases. It is a useful additive for protein or cell isolation procedure.

Production

Isoflurophate, the diisopropyl ester of fluorophosphoric acid, is made by reacting isopropyl alcohol with phosphorus trichloride, forming diisopropylphosphite, which is chlorinated and further reacted with sodium fluoride to replace the chlorine atom with fluorine, thus giving diisopropyl fluorophosphate.^[7]

Biochemistry

DIPF is a diagnostic test for the presence of the active site Ser in serine proteases. The toxin, along with other neurotoxins is inactivated by the enzyme paraoxonase, which is present in widely varying levels in humans.

Society and culture

It is marketed under many brand names including Difluorophate, Diflupyl, Diflurphate, Dyflos, Dyphlos, Fluropryl, Fluostigmine, Neoglaucit.^{[citation needed]}

References

^ ^a ^b "Isofluorphate definition". Drugs.com. Retrieved 6 September 2017.
^ Deshpande, Laxmikant S.; Carter, Dawn S.; Blair, Robert E.; DeLorenzo, Robert J. (2010-08-01). "Development of a prolonged calcium plateau in hippocampal neurons in rats surviving status epilepticus induced by the organophosphate diisopropylfluorophosphate". Toxicological Sciences. 116 (2): 623–631. doi:10.1093/toxsci/kfq157. ISSN 1096-0929. PMC 2905411. PMID 20498005.
^ Pessah, Isaac N.; Rogawski, Michael A.; Tancredi, Daniel J.; Wulff, Heike; Zolkowska, Dorota; Bruun, Donald A.; Hammock, Bruce D.; Lein, Pamela J. (2016-08-01). "Models to identify treatments for the acute and persistent effects of seizure-inducing chemical threat agents". Annals of the New York Academy of Sciences. 1378 (1): 124–136. doi:10.1111/nyas.13137. ISSN 1749-6632. PMC 5063690. PMID 27467073.
^ Kadriu, Bashkim; Guidotti, Alessandro; Costa, Erminio; Davis, John M.; Auta, James (2011-03-01). "Acute imidazenil treatment after the onset of DFP-induced seizure is more effective and longer lasting than midazolam at preventing seizure activity and brain neuropathology". Toxicological Sciences. 120 (1): 136–145. doi:10.1093/toxsci/kfq356. ISSN 1096-0929. PMID 21097996.
^ Phillips, Kristin F.; Deshpande, Laxmikant S. (2016-01-01). "Repeated low-dose organophosphate DFP exposure leads to the development of depression and cognitive impairment in a rat model of Gulf War Illness". Neurotoxicology. 52: 127–133. doi:10.1016/j.neuro.2015.11.014. ISSN 1872-9711. PMID 26619911.
^ Millard, C.B.; Kryger, G.; Ordentlich, A.; Greenblatt, H.M.; Harel, M.; Raves, M.L.; Segall, Y.; Barak, D.; Shafferman, A.; Silman, I.; Sussman, J.L (1999). "Crystal structures of phosphylated acetylcholinesterase: Nerve agent reaction products at atomic resolution". Biochemistry. 38 (22): 7032–9. doi:10.1021/bi982678l. PMID 10353814.
^ US patent 2409039, E.E. Hardy & G.M. Kosoloapoff, "Halogenated compounds and process for making same", issued 1946-10-08, assigned to Monsanto Chemical Company

Brenner, G. M. (2000). Pharmacology. Philadelphia, PA: W.B. Saunders Company. ISBN 0-7216-7757-6.
Meiers, P. (2006). "History of the fluorophosphates".

External links

The MEROPS online database for peptidases and their inhibitors: DFP

English Journal

High concentration of trichlorfon (1mM) disrupts axonal cytoskeleton and decreases the expression of plasticity-related proteins in SH-SY5Y cells.

Fernandes LS1, Emerick GL2, Ferreira RS1, Santos NA1, Santos AC3.
Toxicology in vitro : an international journal published in association with BIBRA.Toxicol In Vitro.2017 Mar;39:84-92. doi: 10.1016/j.tiv.2016.12.003. Epub 2016 Dec 7.
PMID 27939611

Effects of mipafox, paraoxon, chlorpyrifos and its metabolite chlorpyrifos-oxon on the expression of biomarker genes of differentiation in D3 mouse embryonic stem cells.

Sogorb MA1, Fuster E2, Del Río E2, Estévez J2, Vilanova E2.
Chemico-biological interactions.Chem Biol Interact.2016 Nov 25;259(Pt B):368-373. doi: 10.1016/j.cbi.2016.04.017. Epub 2016 Apr 23.
PMID 27117976

Combination of DFP and Taurine Counteracts the Aluminum-Induced Alterations in Oxidative Stress and ATPase in Cortex and Blood of Rats.

Feng T1, Liu P2, Zhang Z1, Hu J1, Kong Z1.
Biological trace element research.Biol Trace Elem Res.2016 Nov;174(1):142-149. Epub 2016 Apr 8.
PMID 27059757

「フルオロリン酸ジイソプロピル」

Diisopropyl fluorophosphate
Clinical data
Synonyms	isofluorophate, isofluorphate, DFP, DIFP, DIPF, diisopropyl phosphorofluoridate, EA-1152, PF-3, PF3, T-1703, TL 466
ATC code	S01EB07 (WHO) ;
Identifiers
	IUPAC name bis(propan-2-yl) fluorophosphonate;
CAS Number	55-91-4 ;
PubChem CID	5936;
DrugBank	DB00677 ;
ChemSpider	5723 ;
UNII	12UHW9R67N;
KEGG	D00043 ;
ChEBI	CHEBI:17941 ;
ChEMBL	ChEMBL1025 ;
CompTox Dashboard (EPA)	DTXSID1040667 ;
ECHA InfoCard	100.000.225
Chemical and physical data
Formula	C6H14FO3P
Molar mass	184.146 g/mol g·mol−1
3D model (JSmol)	Interactive image;
Melting point	−82 °C (−116 °F)
Boiling point	183 °C (361 °F) 1013 mbar
	SMILES FP(=O)(OC(C)C)OC(C)C;
	InChI InChI=1S/C6H14FO3P/c1-5(2)9-11(7,8)10-6(3)4/h5-6H,1-4H3 ; Key:MUCZHBLJLSDCSD-UHFFFAOYSA-N ;
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