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It:Saxitoxin

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Saxitoxin is the parent compound of a family of chemically related neurotoxins. It is mainly produced by marine dinoflagellates, which are then ingested by bivalve molluscs (shellfish) during filter feeding. It is the ingestion of these infected molluscs by humans that results in the condition known as paralytic shellfish poisoning (PSP), a severe illness which can result in death. Saxitoxin binds to the sodium channels of neurones within the nervous system, rendering them inactive, and hence causing muscle paralysis which may eventually lead to death.

Saxitoxin
Saxitoxin
General
Systematic name (1R)-2c,15c-dihydroxy-7t-methyl-(1t,13t)-6-

oxa-bicyclo[11.3.0]hexadeca-3t,11t-dien-

5-onebrefeldin A

Molecular formula C10H17N7O4
SMILES N=C1N[C@@H](COC(N)=O)[C@H]3[C@]2

(N=C(N)N3)N1CCC2(O)O

Molar mass 299.29
CAS number 35523-89-8
Type of Substance heterocyclic
Properties
Solubility Freely soluble in water and methanol.

Limited solubility in ethanol and acetic acid.

Insoluble in lipid solvents

Basicity (pKa in water) 8.24
Hazards
Main hazards T+ (Very Toxic)
Risk statement Very Toxic in contact with skin and

if swallowed.Very Toxic by inhalation

and if swallowed

Safety Wear suitable protective clothing and

eye/face protection

RIDADR UN 3172 6.1/PG 1
Related compounds
Related compounds See table below


Synthesis

The first laboratory preparation of saxitoxin was carried out by Kishi at Harvard University in 1977. This synthesis relied on the condensation of a vinylogous carbamate with benzyloxyacetaldehyde and silicon tetraisopropoxide to produce an intermediate thiourea-ester which was converted to a thiourea-urea using standard methods. Cyclisation to provide the saxitoxin skeleton was accomplished readily by treatment with acid, the reaction proceeding via the intermediacy of an iminium ion. Functional group exchanges were then executed to achieve the first complete synthesis of racemic saxitoxin. Synthesis

The second laboratory synthesis of saxitoxin was carried out by Jacobi and his collaborators whilst at Wesleyan University, Connecticut. The key step of Jacobi's synthesis of saxitoxin relied on formation of a benzylhydrazide intermediate, which was subjected to methyl glyoxylate hemimethyl acetal and a Lewis acid, in order to construct a highly reactive azomethine imine, which subsequently underwent an intramolecular 1,3-dipolar cycloaddition reaction, leading to an advanced tetracyclic intermediate. This was readily elaborated to accomplish a formal synthesis of the racemic natural product.

Synthesis of Saxitoxin

Saxitoxin: A Chemical Weapon

Saxitoxin has obvious dangers to public health via the contamination of foodstocks. But saxitoxin may also be used in chemical warfare. Saxitoxin is around 1000 times more toxic than a typical synthetic nerve gas such as sarin, and in the 1950s, the CIA began experimenting with it, reportedly using it in suicide capsules provided to its agents. In 1970, it is reported that President Nixon ordered the CIA to destroy its entire stock of saxitoxin as part of the US commitment in accordance with the United Nations agreement on biological weapons. Saxitoxin, along with a similar chemical called ricin, currently appear on Schedule 1 of the Chemical Weapons Convention (CWC) and are the only substances on this schedule to have some industrial use (besides nitrogen mustards), as these toxins are generally isolated from natural sources as opposed to the synthesis. The use of these two toxins is exhaustively monitored nationally and the CWC shall ensure that the toxins are adequately reported for arms control purposes, due to their harmful nature. However, in 1975 William Colby, Director of the CIA , revealed to Congress that they still possessed over 10 grammes of saxitoxin in Washington, and this supply was then distributed to scientists and medical researchers to prevent further use in chemical warfare. Saxitoxin has thus been used for the labelling, characterisation and isolation of various sodium channel components (due to its otherwise toxic effects on these) and this has opened up new avenues for the study of various nervous disorders.

Paralytic Shellfish Poisoning (PSP)

After ingestion, absorption of toxins by the gastrointestinal tract is extremely fast. Symptoms typically begin to show around 10 minutes to an hour after initial exposure, but can be delayed a few hours depending on the dose received and the individual's natural defence. Symptoms begin with numbness or tingling of the lips, tongue, and fingertips, followed by numbness of the neck and extremities and general muscular incoordination. Nausea and vomiting may occur. Respiratory distress and flaccid muscular paralysis are the terminal stages and generally occur around 2-12 hours after initial intoxication. Death can result, due to respiratory paralysis. Clearance of the toxin is rapid and those surviving past 12-24 hours post exposure will usually recover. There are no known cases of inhalation exposure to saxitoxin by humans, but data from animal experiments suggest the entire syndrome is compressed and death may occur in minutes.


Effects of Saxitoxin

Bivalve molluscs, the ingestion of which causes paralytic shellfish poisoning (PSP) in humans, show marked inter-species variation in their ability to accumulate paralytic shellfish toxins (PSTs) which has a neural basis. PSTs cause death in humans by blocking sodium channels in neurons. PSTs lead to death of toxin-sensitive molluscs, but it has been seen that some molluscs have gained a resistance to these PSTs. For example, softshell clams (Mya arenaria) from areas exposed to red tides have a higher resistance to PSTs, and accumulate these toxins at much greater rates than toxin-sensitive clams from unexposed areas. This apparent resistance is caused by the natural mutation of a single amino acid residue, thus causing a thousand-fold decrease in affinity at the saxitoxin-binding site in the sodium channel of resistant, but not sensitive, clams. Thus PSTs might act as potent natural selection agents, leading to greater toxin resistance in clam populations and increased risk of PSP in humans.

Saxitoxin is also used in nervous system experiments and has been used in mixtures to improve the function of several anaesthetics.

Related Compounds

R1 R2 R3 R4
Saxitoxin H H H OCONH2
Gonyautoxin II H OSO3- H OCONH2
Gonyautoxin III H H OSO3- OCONH2
Neosaxitoxin OH H H OCONH2
Gonyautoxin I OH OSO3- H OCONH2
Gonyautoxin IV OH H OSO3- OCONH2

Sax


References

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