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Diisopropyl fluorophosphate (DFP, DIFP, diisopropyl phosphorofluoridate) is an oily, colorless liquid with the chemical formula C₆H₁₄FO₃P. It is used in medicine^{[citation needed]} and as an organophosphorus insecticide^{[citation needed]}. It is stable, but undergoes hydrolysis when subjected to moisture, producing hydrofluoric acid. It is known also under names Difluorophate, Diflupyl, Diflurphate, Dyflos, Dyphlos, Fluropryl, Fluostigmine, isofluorophate, isofluorphate, Neoglaucit, PF-3, PF3, T-1703, TL 466, and others.

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^{[citation needed]}. It is known as fluostigmine and Dyflos in such uses.

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.^[1]^[2]^[3] It has also been used to develop a rodent model of Gulf War Syndrome.^[4]

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,^[5] 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.

Chemistry

Isoflurophate, the di-iso-propyl ester of fluorophosphoric acid, is made by reacting isopropyl alcohol with phosphorus trichloride, forming di-iso-propylphosphite, which is chlorinated and further reacted with sodium fluoride to replace the chlorine atom with fluorine, thus giving isofluorophate.

E.E. Hardy, G.M. Kosoloapoff, U.S. Patent 2,409,039 (1946).

References

^ 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: An Official Journal of the Society of Toxicology. 116 (2): 623–631. ISSN 1096-0929. PMC 2905411 . PMID 20498005. doi:10.1093/toxsci/kfq157.
^ 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. ISSN 1749-6632. PMC 5063690 . PMID 27467073. doi:10.1111/nyas.13137.
^ 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: An Official Journal of the Society of Toxicology. 120 (1): 136–145. ISSN 1096-0929. PMID 21097996. doi:10.1093/toxsci/kfq356.
^ 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. ISSN 1872-9711. PMID 26619911. doi:10.1016/j.neuro.2015.11.014.
^ 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. PMID 10353814. doi:10.1021/bi982678l.

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

Protein binding of isofluorophate in vivo after coexposure to multiple chemicals.

Vogel JS1, Keating GA 2nd, Buchholz BA.
Environmental health perspectives.Environ Health Perspect.2002 Dec;110 Suppl 6:1031-6.
Full toxicologic profiles of chemical mixtures, including dose-response extrapolations to realistic exposures, is a prohibitive analytical problem, even for a restricted class of chemicals. We present an approach to probing in vivo interactions of pesticide mixtures at relevant low doses using a mon
PMID 12634135

Age-related differences in the recovery rate of brain cholinesterases, choline acetyltransferase and muscarinic acetylcholine receptor sites after a subacute intoxication of rats with the anticholinesterase agent, isofluorophate.

Michałek H1, Fortuna S, Volpe MT, Pintor A.
Acta neurobiologiae experimentalis.Acta Neurobiol Exp (Wars).1990;50(4-5):237-49.
The recovery rate of brain cholinesterase activity (ChE) and muscarinic acetylcholine receptor sites (MAChRs) following a reduction due to a repeated treatment (2 weeks) with the antiChE agent, isofluorophate (diisopropyl fluorophosphate, DFP) was studied in young (3 months) and aged (24 months) mal
PMID 2130646

Molecular forms of rat brain acetylcholinesterase in DFP intoxication and subsequent recovery.

Michalek H, Meneguz A, Bisso GM.
Neurobehavioral toxicology and teratology.Neurobehav Toxicol Teratol.1981 Fall;3(3):303-12.
The effects of acute administration of diisopropyl fluorophosphate, Isofluorophate (DFP) 1.1 mg/kg SC on soluble brain acetylcholinesterase were studied in male Sprague-Dawley rats sacrificed at time intervals ranging from 3 hr to 25 days. Three main molecular forms of AChE were separated by polyacr
PMID 7290286

Related Pictures

Reaction of the DIFP with a serine image https://classconnection.s3.amazonaws Medicinal Chemistry Exam 1 Let Me Buy university of wollongong, a.markosweb.com 藥品外觀辨識

★リンクテーブル★

リンク元	「フルオロリン酸ジイソプロピル」

「フルオロリン酸ジイソプロピル」

Diisopropyl fluorophosphate
Clinical data
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 ;
ECHA InfoCard	100.000.225
Chemical and physical data
Formula	C6H14FO3P
Molar mass	184.146 g/mol
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 ;
(verify)

　　[★]

英: diisopropyl phosphofluoridate
同: イソフルオロフェート isofluorophate、フルオスチグミン fluostigmine、ジイソプロピルフルオロリン酸 diisopropyl fluorophosphate DFP

[1] 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: An Official Journal of the Society of Toxicology. 116 (2): 623–631. ISSN 1096-0929. PMC 2905411 . PMID 20498005. doi:10.1093/toxsci/kfq157.

[2] 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. ISSN 1749-6632. PMC 5063690 . PMID 27467073. doi:10.1111/nyas.13137.

[3] 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: An Official Journal of the Society of Toxicology. 120 (1): 136–145. ISSN 1096-0929. PMID 21097996. doi:10.1093/toxsci/kfq356.

[4] 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. ISSN 1872-9711. PMID 26619911. doi:10.1016/j.neuro.2015.11.014.

[5] 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. PMID 10353814. doi:10.1021/bi982678l.

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isofluorophate