Diisopropyl fluorophosphate (DFP) or Isoflurophate is an oily, colorless liquid with the chemical formula C₆H₁₄FO₃P. It is used in medicine and as an

organophosphorus Organophosphorus chemistry is the scientific study of the synthesis and properties of organophosphorus compounds, which are organic compounds containing phosphorus. They are used primarily in pest control as an alternative to chlorinated hydrocarb ...

insecticide Insecticides are pesticides used to kill insects. They include ovicides and larvicides used against insect eggs and larvae, respectively. The major use of insecticides is in agriculture, but they are also used in home and garden settings, i ...

. It is stable, but undergoes hydrolysis when subjected to moisture.

Uses in medicine

Diisopropyl fluorophosphate is a

parasympathomimetic drug A parasympathomimetic drug, sometimes called a cholinomimetic drug or cholinergic receptor stimulating agent, is a substance that stimulates the parasympathetic nervous system (PSNS). These chemicals are also called cholinergic drugs becaus ...

irreversible anti-cholinesterase and has been used in

ophthalmology Ophthalmology (, ) is the branch of medicine that deals with the diagnosis, treatment, and surgery of eye diseases and disorders. An ophthalmologist is a physician who undergoes subspecialty training in medical and surgical eye care. Following a ...

as a

miotic Miosis, or myosis (), is excessive pupillary response, constriction of the pupil.Farlex medical diction ...

agent in treatment of chronic

glaucoma Glaucoma is a group of eye diseases that can lead to damage of the optic nerve. The optic nerve transmits visual information from the eye to the brain. Glaucoma may cause vision loss if left untreated. It has been called the "silent thief of ...

, as a miotic in veterinary medicine, and as an experimental agent in neuroscience because of its

acetylcholinesterase Acetylcholinesterase (HUGO Gene Nomenclature Committee, HGNC symbol ACHE; EC 3.1.1.7; systematic name acetylcholine acetylhydrolase), also known as AChE, AChase or acetylhydrolase, is the primary cholinesterase in the body. It is an enzyme th ...

inhibitory An inhibitory postsynaptic potential (IPSP) is a kind of synaptic potential that makes a Chemical synapse, postsynaptic neuron less likely to generate an action potential.Purves et al. Neuroscience. 4th ed. Sunderland (MA): Sinauer Associates, Inc ...

properties and ability to induce delayed peripheral neuropathy.

Uses as toxin

The marked toxicity of esters of monofluorophosphoric acid was discovered in 1932, when

Willy Lange Willy or Willie is a masculine, male given name, often a diminutive form of William or Wilhelm, and occasionally a nickname. It may refer to: People Given name or nickname * Willie Allen (basketball) (born 1949), American basketball player and d ...

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 Mustard gas or sulfur mustard are names commonly used for the organosulfur compound, organosulfur chemical compound bis(2-chloroethyl) sulfide, which has the chemical structure S(CH2CH2Cl)2, as well as other Chemical species, species. In the wi ...

, forming a more effective mixture with significantly lower melting point, resulting in an agent suitable for use in cold weather. In military research, due to its physical and chemical similarities and comparatively low toxicity, it is used as a simulant of

G-agent Nerve agents, sometimes also called nerve gases, are a class of organic chemicals that disrupt the mechanisms by which nerves transfer messages to organs. The disruption is caused by the blocking of acetylcholinesterase (AChE), an enzyme that ...

s ( GA, GB, GD, and GF). Diisopropyl fluorophosphate is used in civilian laboratories to mimic lethal nerve gas exposure or organophosphate toxicities. It has also been used to develop a rodent model of Gulf War Syndrome. Diisopropyl fluorophosphate is a very potent

neurotoxin Neurotoxins are toxins that are destructive to nervous tissue, nerve tissue (causing neurotoxicity). Neurotoxins are an extensive class of exogenous chemical neurological insult (medical), insultsSpencer 2000 that can adversely affect function ...

. Its in rats is 6 mg/kg (oral). It combines with the

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...

serine Serine (symbol Ser or S) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α- amino group (which is in the protonated − form under biological conditions), a carboxyl group (which is in the deprotonated − ...

at the active site of the enzyme

, an enzyme that deactivates the

neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a Chemical synapse, synapse. The cell receiving the signal, or target cell, may be another neuron, but could also be a gland or muscle cell. Neurotra ...

acetylcholine Acetylcholine (ACh) is an organic compound that functions in the brain and body of many types of animals (including humans) as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Par ...

. Neurotransmitters are needed to continue the passage of

nerve impulse An action potential (also known as a nerve impulse or "spike" when in a neuron) is a series of quick changes in voltage across a cell membrane. An action potential occurs when the membrane potential of a specific Cell (biology), cell rapidly ri ...

s from one

neuron A neuron (American English), neurone (British English), or nerve cell, is an membrane potential#Cell excitability, excitable cell (biology), cell that fires electric signals called action potentials across a neural network (biology), neural net ...

to another across the

synapse In the nervous system, a synapse is a structure that allows a neuron (or nerve cell) to pass an electrical or chemical signal to another neuron or a target effector cell. Synapses can be classified as either chemical or electrical, depending o ...

. 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 Paralysis (: paralyses; also known as plegia) is a loss of Motor skill, motor function in one or more Skeletal muscle, muscles. Paralysis can also be accompanied by a loss of feeling (sensory loss) in the affected area if there is sensory d ...

occurs and

death Death is the end of life; the irreversible cessation of all biological functions that sustain a living organism. Death eventually and inevitably occurs in all organisms. The remains of a former organism normally begin to decompose sh ...

may result since the

respiratory muscles The muscles of respiration are the muscles that contribute to inhalation and exhalation, by aiding in the expansion and contraction of the thoracic cavity. The diaphragm and, to a lesser extent, the intercostal muscles drive respiration during ...

are affected. DFP also inhibits some

protease A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalysis, catalyzes proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the formation of new protein products ...

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 World War II or the Second World War (1 September 1939 – 2 September 1945) was a World war, global conflict between two coalitions: the Allies of World War II, Allies and the Axis powers. World War II by country, Nearly all of the wo ...

. 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 Isopropyl alcohol (IUPAC name propan-2-ol and also called isopropanol or 2-propanol) is a colorless, flammable, organic compound with a pungent alcoholic odor. Isopropyl alcohol, an organic polar molecule, is miscible in water, ethanol, an ...

with

phosphorus trichloride Phosphorus trichloride is an inorganic compound with the chemical formula PCl3. A colorless liquid when pure, it is an important industrial chemical, being used for the manufacture of phosphites and other organophosphorus compounds. It is toxic ...

, forming diisopropylphosphite, which is chlorinated and further reacted with

sodium fluoride Sodium fluoride (NaF) is an inorganic compound with the formula . It is a colorless or white solid that is readily soluble in water. It is used in trace amounts in the fluoridation of drinking water to prevent tooth decay, and in toothpastes ...

to replace the chlorine atom with fluorine, thus giving diisopropyl fluorophosphate. : DIFP synthesis

Another synthesis that is only of academic interest entails the reaction between two equivalents of isopropyl alcohol and phosphoryl dichloride fluoride.

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 In biochemistry, phenylmethylsulfonyl fluoride (PMSF) is a serine protease inhibitor (serine hydrolase inactivator) commonly used in the preparation of cell lysates. PMSF does not inactivate all serine proteases. The effective concentration of P ...

and

AEBSF AEBSF or 4-(2-aminoethyl)benzenesulfonyl fluoride hydrochloride is a water-soluble, irreversible serine protease inhibitor with a molecular weight of 239.5 Da. It inhibits proteases like chymotrypsin, kallikrein, plasmin, thrombin, and trypsin. ...

are less toxic alternatives that work well for most serine proteases. However, only DFP potently inhibits a subclass of serine proteases collectively known as neutrophil serine proteases (namely, neutrophil elastase, cathepsin G, and proteinase 3). DFP and other analogous organophosphate neurotoxins are inactivated by the enzyme

paraoxonase Paraoxonases are a protein family, family of mammalian enzymes with aryldialkylphosphatase activity. There are three paraoxonase isozymes, which were originally discovered for their involvement in the hydrolysis of organophosphates. Research ...

, 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.

References

External links

*The

MEROPS MEROPS is an online database for peptidases (also known as proteases, proteinases and proteolytic enzymes) and their inhibitors. The classification scheme for peptidases was published by Rawlings & Barrett in 1993, and that for protein inhibito ...

online database for peptidases and their inhibitors
DFP
{{DEFAULTSORT:Diisopropyl Fluorophosphate Acetylcholinesterase inhibitors Isopropyl esters Neurotoxins Ophthalmology drugs Organophosphate insecticides Phosphorofluoridates