Diisopropyl fluorophosphate: Difference between revisions

{{Short description|Chemical compound}}

| Watchedfields = changed

| verifiedrevid = 458440771

| IUPAC_name = bis(propan-2-yl) fluorophosphonate

| tradename =

|synonyms= Isofluorophate, Isofluorphate, DFP, DIFP, DIPF, Diisopropyl phosphorofluoridate, EA-1152, PF-3, T-1703, TL-466

| C=6 | H=14 | F=1 | O=3 | P=1

'''Diisopropyl fluorophosphate''' ('''DFP''') or '''Isoflurophate''' is an oily, colorless liquid with the chemical formula C₆H₁₄FO₃P. It is used in medicine<ref name=drugsIsofluorphate>{{cite web|title=Isofluorphate definition|url=https://www.drugs.com/dict/isofluorphate.html|publisher=Drugs.com|access-date=6 September 2017|archive-url=https://web.archive.org/web/20170906134840/https://www.drugs.com/dict/isofluorphate.html|archive-date=6 September 2017|url-status=dead}}</ref> and as an [[organophosphorus compounds|organophosphorus]] [[insecticide]].<ref>{{Cite web |title=Isoflurophate |url=https://ncithesaurus.nci.nih.gov/ncitbrowser/ConceptReport.jsp?dictionary=NCI_Thesaurus&ns=ncit&code=C65979 |access-date=2022-10-30 |website=National Cancer Institute}}</ref> It is stable, but undergoes hydrolysis when subjected to moisture.

==Uses in medicine==

Diisopropyl fluorophosphate is a [[parasympathomimetic drug]] [[acetylcholinesterase inhibitor|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]] [[enzyme inhibitor|inhibitory]] properties and ability to induce [[organophosphate-induced delayed neuropathy|delayed peripheral neuropathy]].<ref name=drugsIsofluorphate/>

==Uses as toxin==

[[Image:DIFP serine inactivation.svg|thumb|400px|left|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. [[Image:Crystal structure of Herpes Simplex Virus Protease-Inhibitor (DFP) complex.jpg|thumb|right|250px|alt=Protease-Inhibitor Complex.|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 [http://www.rcsb.org/pdb/explore/explore.do?structureId=1AT3 1AT3].]] In military research, due to its physical and chemical similarities and comparatively low toxicity, it is used as a simulant of [[G-agent]]s ([[tabun (nerve agent)|GA]], [[sarin|GB]], [[soman|GD]], and [[cyclosarin|GF]]). Diisopropyl fluorophosphate is used in civilian laboratories to mimic lethal nerve gas exposure or organophosphate toxicities.<ref>{{cite journal | vauthors = Deshpande LS, Carter DS, Blair RE, DeLorenzo RJ | title = Development of a prolonged calcium plateau in hippocampal neurons in rats surviving status epilepticus induced by the organophosphate diisopropylfluorophosphate | journal = Toxicological Sciences | volume = 116 | issue = 2 | pages = 623–31 | date = August 2010 | pmid = 20498005 | pmc = 2905411 | doi = 10.1093/toxsci/kfq157 }}</ref><ref>{{cite journal | vauthors = Pessah IN, Rogawski MA, Tancredi DJ, Wulff H, Zolkowska D, Bruun DA, Hammock BD, Lein PJ | display-authors = 6 | title = Models to identify treatments for the acute and persistent effects of seizure-inducing chemical threat agents | journal = Annals of the New York Academy of Sciences | volume = 1378 | issue = 1 | pages = 124–136 | date = August 2016 | pmid = 27467073 | pmc = 5063690 | doi = 10.1111/nyas.13137 }}</ref><ref>{{cite journal | vauthors = Kadriu B, Guidotti A, Costa E, Davis JM, Auta J | title = 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 | journal = Toxicological Sciences | volume = 120 | issue = 1 | pages = 136–45 | date = March 2011 | pmid = 21097996 | doi = 10.1093/toxsci/kfq356 | doi-access = free }}</ref> It has also been used to develop a rodent model of [[Gulf War Syndrome]].<ref>{{cite journal | vauthors = Phillips KF, Deshpande LS | title = Repeated low-dose organophosphate DFP exposure leads to the development of depression and cognitive impairment in a rat model of Gulf War Illness | journal = Neurotoxicology | volume = 52 | pages = 127–33 | date = January 2016 | pmid = 26619911 | doi = 10.1016/j.neuro.2015.11.014 | url = https://zenodo.org/record/894926 | doi-access = free }}</ref>

Diisopropyl fluorophosphate is a very potent [[neurotoxin]]. Its {{LD50}} in rats is 6&nbsp;mg/kg (oral). It combines with the [[amino acid]] [[serine]] at the active site of the enzyme [[acetylcholinesterase]],<ref>{{cite journal | vauthors = Millard CB, Kryger G, Ordentlich A, Greenblatt HM, Harel M, Raves ML, Segall Y, Barak D, Shafferman A, Silman I, Sussman JL | display-authors = 6 | title = Crystal structures of aged phosphonylated acetylcholinesterase: nerve agent reaction products at the atomic level | journal = Biochemistry | volume = 38 | issue = 22 | pages = 7032–9 | date = June 1999 | pmid = 10353814 | doi = 10.1021/bi982678l }}</ref> an enzyme that deactivates the [[neurotransmitter]] [[acetylcholine]]. Neurotransmitters are needed to continue the passage of [[nerve impulse]]s 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 [[diaphragm (anatomy)|respiratory muscles]] are affected.

DFP also inhibits some [[protease]]s. It is a useful additive for protein or cell isolation procedure.

Diisopropyl fluorophosphate (DFP) was a nerve gas developed by the German during the [[Second World War]]. DFP irreversibly binds with the enzymes containing serine at the active site, e g. Serine proteases, acetylcholine esterase.

==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.<ref>{{cite patent | inventor1-first=Edgar E|inventor1-last=Hardy|inventor2-first=Gennady M|inventor2-last= Kosoloapoff| country = US | assign = [[Monsanto Chemical Company]] | gdate = 1946-10-08 | number = 2409039 | title = Halogenated compounds and process for making same | status = patent}}</ref>

:[[File:DIFP synthesis.svg|600px]]

==Biochemistry==

DFP is a diagnostic test for the presence of the active site Ser in serine proteases, as well as a serine protease inhibitor. [[PMSF]] and [[AEBSF]] are alternative, less toxic, but presumably also less reactive, reagents for these same applications. DFP and other analogous organophosphate neurotoxins are 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|date=September 2017}}

*[[MAFP]] (methoxy arachidonoylfluorophosphonate), a mechanistically related inhibitor

*[[Neopentylene fluorophosphate]], a cyclic analogue

*[[Sarin]] (isopropyl methylphosphonofluoridate), a related phosphofluoridate

*[[PMSF]] (4-(2-aminoethyl)benzenesulfonyl fluoride), an analogous sulfonyl fluoride sulfonating reagent

*[[AEBSF]] (phenylmethylsulfonyl fluoride), an analogous sulfonyl fluoride sulfonating reagent

{{reflist|32em}}

== Further reading ==

{{refbegin}}

* {{cite book| vauthors = Brenner GM |year=2000|title= Pharmacology|location= Philadelphia, PA|publisher= W.B. Saunders Company. |isbn =0-7216-7757-6}}

* {{cite web| vauthors = Meiers P |year=2006|url=http://www.fluoride-history.de/p-mfp.htm|title= History of the fluorophosphates}}

{{refend}}

== External links ==

*The [[MEROPS]] online database for peptidases and their inhibitors: [http://merops.sanger.ac.uk/cgi-bin/smi_summary?mid=J00067 DFP]

{{Chemical agents}}

{{Acetylcholine metabolism and transport modulators}}

[[Category:Isopropyl esters]]

[[Category:Ophthalmology drugs]]

[[Category:Organophosphate insecticides]]

[[Category:Phosphorofluoridates]]