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Soman (or GD, EA 1210, Zoman, PFMP, A-255, systematic name: ''O''-pinacolyl methylphosphonofluoridate) is an extremely toxic chemical substance. It is a
nerve 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 ...
, interfering with normal functioning of the mammalian
nervous system In biology, the nervous system is the highly complex part of an animal that coordinates its actions and sensory information by transmitting signals to and from different parts of its body. The nervous system detects environmental changes th ...
by inhibiting the enzyme
cholinesterase The enzyme cholinesterase (EC 3.1.1.8, choline esterase; systematic name acylcholine acylhydrolase) catalyses the hydrolysis of choline-based esters: : an acylcholine + H2O = choline + a carboxylate Several of these serve as neurotransmitters ...
. It is an inhibitor of both
acetylcholinesterase Acetylcholinesterase (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 Enzymes () are proteins that a ...
and
butyrylcholinesterase Butyrylcholinesterase ( HGNC symbol BCHE; EC 3.1.1.8), also known as BChE, BuChE, BuChase, pseudocholinesterase, or plasma (cholin)esterase, is a nonspecific cholinesterase enzyme that hydrolyses many different choline-based esters. In humans, it ...
. As a
chemical weapon A chemical weapon (CW) is a specialized munition that uses chemicals formulated to inflict death or harm on humans. According to the Organisation for the Prohibition of Chemical Weapons (OPCW), this can be any chemical compound intended as a ...
, it is classified as a
weapon of mass destruction A weapon of mass destruction (WMD) is a chemical, biological, radiological, nuclear, or any other weapon that can kill and bring significant harm to numerous individuals or cause great damage to artificial structures (e.g., buildings), natu ...
by the
United Nations The United Nations (UN) is an intergovernmental organization whose stated purposes are to maintain international peace and international security, security, develop friendly relations among nations, achieve international cooperation, and be ...
according to UN Resolution 687. Its
production Production may refer to: Economics and business * Production (economics) * Production, the act of manufacturing goods * Production, in the outline of industrial organization, the act of making products (goods and services) * Production as a stati ...
is strictly controlled, and stockpiling is outlawed by the Chemical Weapons Convention of 1993 where it is classified as a Schedule 1 substance. Soman was the third of the so-called ''G-series'' nerve agents to be discovered along with GA (tabun), GB (sarin), and GF (cyclosarin). When pure, soman is a volatile, corrosive, and colorless liquid with a faint odor like that of mothballs or rotten fruit. More commonly, it is a yellow to brown color and has a strong odor described as similar to camphor. The LCt50 for soman is 70 mg·min/m3 in humans. GD can be thickened for use as a chemical spray using an acryloid copolymer. It can also be deployed as a binary chemical weapon; its precursor chemicals are
methylphosphonyl difluoride Methylphosphonyl difluoride (DF), also known as EA-1251 or difluoro, is a chemical weapon precursor. Its chemical formula is CH3POF2. It is a Schedule 1 substance under the Chemical Weapons Convention. It is used for production of sarin and so ...
and a mixture of
pinacolyl alcohol Pinacolyl alcohol is a common name for 3,3-dimethylbutan-2-ol, also known as pine alcohol. It is one of the isomeric hexanols and a secondary alcohol. Pinacolyl alcohol appears on the List of Schedule 2 substances (CWC) as a precursor for the ne ...
and an
amine In chemistry, amines (, ) are compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are formally derivatives of ammonia (), wherein one or more hydrogen atoms have been replaced by a substituen ...
.


History

After World War I, during which
mustard gas Mustard gas or sulfur mustard is a chemical compound belonging to a family of cytotoxic and blister agents known as mustard agents. The name ''mustard gas'' is technically incorrect: the substance, when dispersed, is often not actually a gas, b ...
and phosgene were used as chemical warfare agents, the 1925
Geneva Protocol The Protocol for the Prohibition of the Use in War of Asphyxiating, Poisonous or other Gases, and of Bacteriological Methods of Warfare, usually called the Geneva Protocol, is a treaty prohibiting the use of chemical and biological weapons in ...
was signed in an attempt to ban chemical warfare. Nevertheless, research into chemical warfare agents and the use of them continued. In 1936 a new, more dangerous chemical agent was discovered when
Gerhard Schrader Gerhard Schrader (25 February 1903 – 10 April 1990) was a German chemist specializing in the discovery of new insecticides, hoping to make progress in the fight against hunger in the world. Schrader is best known for his accidental discovery of ...
of
IG Farben Interessengemeinschaft Farbenindustrie AG (), commonly known as IG Farben (German for 'IG Dyestuffs'), was a German chemical and pharmaceutical conglomerate (company), conglomerate. Formed in 1925 from a merger of six chemical companies—BASF, ...
in Germany isolated tabun (named GA for German Agent A by the United States), the first nerve agent, while developing new
insecticide Insecticides are substances used to kill insects. They include ovicides and larvicides used against insect eggs and larvae, respectively. Insecticides are used in agriculture, medicine, industry and by consumers. Insecticides are claimed to b ...
s. This discovery was followed by the isolation of
sarin Sarin (NATO designation GB G-series, "B"">Nerve_agent#G-series.html" ;"title="hort for Nerve agent#G-series">G-series, "B" is an extremely toxic synthetic organophosphorus compound.Richard Kuhn Richard Johann Kuhn (; 3 December 1900 – 1 August 1967) was an Austrian-German biochemist who was awarded the Nobel Prize in Chemistry in 1938 "for his work on carotenoids and vitamins". Biography Early life Kuhn was born in Vienna, Austr ...
together with
Konrad Henkel Konrad Henkel (25 October 1915 - 24 April 1999) was a German chemist and industrialist, and long-time head of the Henkel, Henkel Group. Life Konrad Henkel was born in 1915, the grandson of Friedrich Karl Henkel, Fritz Henkel (1848-1930), founde ...
discovered soman during research into the pharmacology of tabun and sarin at the Kaiser Wilhelm Institute for Medical Research at
Heidelberg Heidelberg (; Palatine German language, Palatine German: ''Heidlberg'') is a city in the States of Germany, German state of Baden-Württemberg, situated on the river Neckar in south-west Germany. As of the 2016 census, its population was 159,914 ...
. This research was commissioned by the German Army. Soman was produced in small quantities at a pilot plant at the IG Farben factory in
Ludwigshafen Ludwigshafen, officially Ludwigshafen am Rhein (; meaning " Ludwig's Port upon Rhine"), is a city in the German state of Rhineland-Palatinate, on the river Rhine, opposite Mannheim. With Mannheim, Heidelberg, and the surrounding region, it form ...
. It was never used in World War II. Producing or stockpiling soman was banned by the 1993 Chemical Weapons Convention. When the convention entered force, the parties declared worldwide stockpiles of 9,057 tonnes of soman. As of December 2015, 84% of the stockpiles had been destroyed. The crystal structure of soman complexed with
acetylcholinesterase Acetylcholinesterase (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 Enzymes () are proteins that a ...
was determined by Millard et al. in 1999 by X-ray crystallography
1som
Other solved acetylcholinesterase structures with soman bound to them includ
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an
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Structure and reactivity

Soman (C(±)P(±)-soman) has four
stereoisomers In stereochemistry, stereoisomerism, or spatial isomerism, is a form of isomerism in which molecules have the same molecular formula and sequence of bonded atoms (constitution), but differ in the three-dimensional orientations of their atoms in ...
, each with a different toxicity, though largely similar. The stereoisomers are C(+)P(+)-soman, C(+)P(−)-soman C(−)P(−)-soman and C(−)P(+)-soman. Soman has a phosphonyl group with a fluoride and a (large) hydrocarbon covalently bound to it. The structure is thus similar to that of sarin, which has only a smaller hydrocarbon group attached (isopropyl). Because of the similarity between the chemical structures, the reactivity of the two compounds is almost the same. Soman and sarin will both react using the phospho oxygen group, which can bind to amino acids like serine.


Synthesis

The manufacture of soman is very similar to the manufacture of sarin. The difference is that the
isopropanol 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. As an isopropyl group linked to a hydroxyl group (chemical formula ) it is the simple ...
from the sarin processes is replaced with
pinacolyl alcohol Pinacolyl alcohol is a common name for 3,3-dimethylbutan-2-ol, also known as pine alcohol. It is one of the isomeric hexanols and a secondary alcohol. Pinacolyl alcohol appears on the List of Schedule 2 substances (CWC) as a precursor for the ne ...
: Soman is synthesized by reacting
pinacolyl alcohol Pinacolyl alcohol is a common name for 3,3-dimethylbutan-2-ol, also known as pine alcohol. It is one of the isomeric hexanols and a secondary alcohol. Pinacolyl alcohol appears on the List of Schedule 2 substances (CWC) as a precursor for the ne ...
with
methylphosphonyl difluoride Methylphosphonyl difluoride (DF), also known as EA-1251 or difluoro, is a chemical weapon precursor. Its chemical formula is CH3POF2. It is a Schedule 1 substance under the Chemical Weapons Convention. It is used for production of sarin and so ...
. The result of this reaction is the forming of soman which is described as “colorless liquid with a somewhat fruity odor.” The low vapor pressure of soman will also produce the volatile gas form of soman. Also, the acid
hydrogen fluoride Hydrogen fluoride (fluorane) is an inorganic compound with the chemical formula . This colorless gas or liquid is the principal industrial source of fluorine, often as an aqueous solution called hydrofluoric acid. It is an important feedstock i ...
will form due to the elimination of fluoride and a proton. This acid is indirectly dangerous to humans. Skin contact with hydrogen fluoride will cause an immediate reaction with water which produces
hydrofluoric acid Hydrofluoric acid is a Solution (chemistry), solution of hydrogen fluoride (HF) in water. Solutions of HF are colourless, acidic and highly Corrosive substance, corrosive. It is used to make most fluorine-containing compounds; examples include th ...
.


Mechanisms of action

Soman is an organophosphorus nerve agent with a mechanism of action similar to Tabun. Nerve agents inhibit
acetylcholine esterase Acetylcholinesterase (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 that catalyzes the breakdown of acet ...
(AChE) by forming an adduct with the enzyme via a serine residue on that enzyme. These adducts may be decomposed hydrolytically or, for example, by the action of some oximes and thereby regenerate the enzyme. A second reaction type, one in which the enzyme–organophosphate (OP) complex undergoes a subsequent reaction, is usually described as "aging". Once the enzyme–OP complex has aged it is no longer regenerated by the common, oxime reactivators. The rate of this process is dependent on the OP. Soman is an OP that stimulates the rate of aging most rapidly decreasing the half-life to just a few minutes. AChE is an enzyme involved with neurotransmission. Because of the severe decrease of the half-life of this enzyme, neurotransmission is abolished in a matter of minutes.


Metabolism

Once taken up in the human body, soman not only inhibits AChE, but it is also a substrate for other esterases. Reaction of soman with these esterases allows for the detoxication of the compound. No metabolic toxification reactions are known for soman. Soman can be hydrolyzed by a so-called A-esterase, more specific a diisopropylfluorophosphatase. This esterase, also called somanase, reacts with the anhydride bond between phosphorus and fluorine and accounts for the hydrolysis of the fluoride. Somanase also hydrolyses the methyl group of soman resulting in the formation of pinacolyl methylphosphonic acid (PMPA), which is a less potent AChE inhibitor. Soman can also bind to other
esterase An esterase is a hydrolase enzyme that splits esters into an acid and an alcohol in a chemical reaction with water called hydrolysis. A wide range of different esterases exist that differ in their substrate specificity, their protein structure ...
s, e.g.,
AChE Ache or Aches may refer to: Ethnography * Aché, an indigenous people of eastern Paraguay * Aché language, the language of the Aché people * Ache language (China) * Aṣẹ (Cuban spelling: ''aché''), a concept in Orisha belief People * Ach ...
,
cholinesterase The enzyme cholinesterase (EC 3.1.1.8, choline esterase; systematic name acylcholine acylhydrolase) catalyses the hydrolysis of choline-based esters: : an acylcholine + H2O = choline + a carboxylate Several of these serve as neurotransmitters ...
(ChE) and
carboxylesterase The enzyme carboxylesterase (or carboxylic-ester hydrolase, EC 3.1.1.1; systematic name carboxylic-ester hydrolase) catalyzes reactions of the following form: :a carboxylic ester + H2O \rightleftharpoons an alcohol + a carboxylate Most enzymes fr ...
s (CarbE). In this binding, soman loses its fluoride. After binding to AChE or ChE soman also loses its phosphoryl group, leading to the formation of
methylphosphonic acid Methylphosphonic acid is an organophosphorus compound with the chemical formula CH3P(O)(OH)2. The phosphorus center is tetrahedral and is bonded to a methyl group, two OH groups and an oxygen. Methylphosphonic acid is a white, non-volatile solid t ...
(MPA). Binding to CarbE reduce the total concentration of soman in the blood, thus resulting in a lower toxicity. Furthermore, CarbE are involved in the detoxication by hydrolysing soman to PMPA. So CarbE account for the detoxication of soman in two ways. The importance of the detoxication of soman after exposure was illustrated in experiments of Fonnum and Sterri (1981). They reported that only 5% of
LD50 In toxicology, the median lethal dose, LD50 (abbreviation for "lethal dose, 50%"), LC50 (lethal concentration, 50%) or LCt50 is a toxic unit that measures the lethal dose of a toxin, radiation, or pathogen. The value of LD50 for a substance is the ...
inhibited AChE in rats, resulting in acute toxic effects. This shows that metabolic reactions accounted for the detoxification of the remaining 95% of the dose.


Signs and symptoms

As soman is closely related to compounds such as sarin, indications for a soman poisoning are relatively similar. One of the first observable signs of a soman poisoning is
miosis Miosis, or myosis (), is excessive constriction of the pupil.Farlex medical dictionary
citing: ...
. Some, but not all of the later indications are vomiting, extreme muscle pain and peripheral nervous system problems. Those symptoms show as soon as 10 minutes after exposure and may last for many days. In addition to the direct toxic effects on the nervous system, people exposed to soman may experience long-term effects, most of which are psychological. Subjects who were exposed to a small dose of soman suffered severe toxic effects; once treated, the subjects often developed depression, had antisocial thoughts, were withdrawn and subdued, slept restlessly and had bad dreams. These symptoms lasted six months after exposure but disappeared without lasting damage.


Toxicity and efficacy

The LC50 of soman in air is estimated to be 70 mg min per m3. Compared with the LC50 value of a rat, the human lethal concentration is much lower (954.3 mg min/m3 versus 70 mg min/m3). For compounds such as soman, which may also be used as a weapon, often a fraction of the LC50 dose is where the first effects appear.
Miosis Miosis, or myosis (), is excessive constriction of the pupil.Farlex medical dictionary
citing: ...
is one of the first symptoms of soman intoxication and can be seen in doses of less than 1% of the LC50.


Effects on animals

Experiments have been done in which rats were exposed to soman to test if behavioral effects could be seen at low doses without generating overt symptoms. Exposure of the rats to soman in a dose of less than 3 percent of the LD50 caused alterations of the behavior. The active avoidance of the exposed rats was less than the avoidance of non-exposed rats (two-way shuttlebox experiment). Also the motor coordination (hurdle-stepping task), open field behavior and active as well as passive avoidance behavior were affected. One can conclude that rats that are exposed to soman performed with less success in tasks that require motor activity as well as the function of higher structures of the central nervous system (CNS) on the same time. In this, soman has a predominantly central effect. The knowledge of the effects of low doses of soman and other choline esterase inhibitors on rats could possibly be used to explain the relatively high incidence of airplane accidents due to errors of agricultural pilots. If this knowledge could be applied to humans, one could explain this high incidence with depressed choline esterase activity due to exposure to pesticides. It is not known whether the extrapolation from rats to humans can be made.


References


External links

* United States Senate, 103d Congress, 2d Session. (May 25, 1994)
Material Safety Data Sheet -- Lethal Nerve Agents Somain (GD and Thickened GD)
. Retrieved Nov. 6, 2004.
AChE inhibitors and substrates
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Proteopedia Proteopedia is a wiki, 3D encyclopedia of proteins and other molecules. The site contains a page for every entry in the Protein Data Bank (>130,000 pages), as well as pages that are more descriptive of protein structures in general such as acetylc ...

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Proteopedia Proteopedia is a wiki, 3D encyclopedia of proteins and other molecules. The site contains a page for every entry in the Protein Data Bank (>130,000 pages), as well as pages that are more descriptive of protein structures in general such as acetylc ...

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Proteopedia Proteopedia is a wiki, 3D encyclopedia of proteins and other molecules. The site contains a page for every entry in the Protein Data Bank (>130,000 pages), as well as pages that are more descriptive of protein structures in general such as acetylc ...

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Proteopedia Proteopedia is a wiki, 3D encyclopedia of proteins and other molecules. The site contains a page for every entry in the Protein Data Bank (>130,000 pages), as well as pages that are more descriptive of protein structures in general such as acetylc ...

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Proteopedia Proteopedia is a wiki, 3D encyclopedia of proteins and other molecules. The site contains a page for every entry in the Protein Data Bank (>130,000 pages), as well as pages that are more descriptive of protein structures in general such as acetylc ...
* https://somantoxicologia.wixsite.com/meusite {{Acetylcholine metabolism and transport modulators Acetylcholinesterase inhibitors G-series nerve agents Methylphosphonofluoridates German inventions of the Nazi period Cold War weapons of the Soviet Union Soviet chemical weapons program Pinacolyl esters German chemical weapons program