View source for It:Saxitoxin

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 [http://en.wikipedia.org/wiki/Paralytic_shellfish_poisoning 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.

{| class="toccolours" border="1" style="float: right; clear: right; margin: 0 0 1em 1em; border-collapse: collapse;"
! {{chembox header}}  colspan="3" |Saxitoxin 
|-
| align="center" colspan="3" bgcolor="#ffffff" | [[Image:saxitoxin.gif|Saxitoxin]] 
|-
! {{chembox header}} colspan="3" | General
|- 
| colspan="1" |[http://en.wikipedia.org/wiki/IUPAC_nomenclature Systematic name]
| colspan="2"|(1R)-2c,15c-dihydroxy-7t-methyl-(1t,13t)-6-

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

5-onebrefeldin A
|-
| colspan="1" |[http://en.wikipedia.org/wiki/Chemical_formula Molecular formula]
| colspan="2" |C<sub>10</sub>H<sub>17</sub>N<sub>7</sub>O<sub>4</sub>
|-
| colspan="1" |[http://en.wikipedia.org/wiki/Simplified_molecular_input_line_entry_specification SMILES]
| colspan="2" |N=C1N[C@@H](COC(N)=O)[C@H]3[C@]2
(N=C(N)N3)N1CCC2(O)O
|-
| colspan="1" |[http://en.wikipedia.org/wiki/Molar_mass Molar mass]
| colspan="2" |299.29
|-
| colspan="1" |[http://en.wikipedia.org/wiki/CAS_registry_number CAS number]
| colspan="2" |35523-89-8
|-
| colspan="1" |Type of Substance
| colspan="2" |heterocyclic
|-

! {{chembox header}} colspan="3"| Properties
|-
| [http://en.wikipedia.org/wiki/Solubility Solubility]
| colspan="2" |Freely soluble in water and methanol.
Limited solubility in ethanol and acetic acid. 

Insoluble in lipid solvents
|-
| [http://en.wikipedia.org/wiki/Acid_dissociation_constant Basicity] (p''K''a in water) <!-- omit if not a base. If several values, be clear -->
| colspan="2" |8.24
|-
! {{chembox header}} colspan="3" | Hazards <!--  Summary only- MSDS entry provides more complete information -->
|-
| Main [http://en.wikipedia.org/wiki/Worker_safety_and_health hazard]s
| colspan="2" |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
| colspan="2" |UN 3172 6.1/PG 1
|-
! {{chembox header}} colspan="3" | Related compounds
|-
| Related compounds 
| colspan="2" |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. 
[[Image:Saxsyn1.gif|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.

[[Image:Saxitoxinsynthesis.gif|Synthesis of Saxitoxin]]

== Saxitoxin: A Chemical Weapon ==
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ATOM      1  N           0       0.477   0.862   3.016  0.00  0.00           N+0
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ATOM      4  C           0       0.632   1.192  -0.578  0.00  0.00           C+0
ATOM      5  H           0       0.895   2.032  -1.221  0.00  0.00           H+0
ATOM      6  C           0       1.718   0.120  -0.696  0.00  0.00           C+0
ATOM      7  O           0       3.015   0.714  -0.428  0.00  0.00           O+0
ATOM      8  C           0       4.126  -0.045  -0.475  0.00  0.00           C+0
ATOM      9  N           0       5.331   0.506  -0.227  0.00  0.00           N+0
ATOM     10  O           0       4.043  -1.228  -0.742  0.00  0.00           O+0
ATOM     11  C           0      -0.687   0.607  -1.048  0.00  0.00           C+0
ATOM     12  H           0      -0.539   0.032  -1.962  0.00  0.00           H+0
ATOM     13  C           0      -1.391  -0.241  -0.001  0.00  0.00           C+0
ATOM     14  N           0      -2.772   0.254   0.009  0.00  0.00           N+0
ATOM     15  C           0      -2.837   1.348  -0.688  0.00  0.00           C+0
ATOM     16  N           0      -3.994   2.077  -0.830  0.00  0.00           N+0
ATOM     17  N           0      -1.644   1.711  -1.284  0.00  0.00           N+0
ATOM     18  N           0      -0.797  -0.158   1.335  0.00  0.00           N+0
ATOM     19  C           0      -1.280  -1.330   2.081  0.00  0.00           C+0
ATOM     20  C           0      -1.634  -2.406   1.032  0.00  0.00           C+0
ATOM     21  C           0      -1.373  -1.739  -0.357  0.00  0.00           C+0
ATOM     22  O           0      -2.400  -2.087  -1.288  0.00  0.00           O+0
ATOM     23  O           0      -0.086  -2.103  -0.860  0.00  0.00           O+0
ATOM     24  H           0       1.114   1.540   3.290  0.00  0.00           H+0
ATOM     25  H           0       0.863   2.552   1.041  0.00  0.00           H+0
ATOM     26  H           0       1.525  -0.673   0.027  0.00  0.00           H+0
ATOM     27  H           0       1.710  -0.296  -1.703  0.00  0.00           H+0
ATOM     28  H           0       5.397   1.450  -0.014  0.00  0.00           H+0
ATOM     29  H           0       6.131  -0.041  -0.261  0.00  0.00           H+0
ATOM     30  H           0      -4.811   1.780  -0.400  0.00  0.00           H+0
ATOM     31  H           0      -3.993   2.889  -1.361  0.00  0.00           H+0
ATOM     32  H           0      -1.469   2.541  -1.755  0.00  0.00           H+0
ATOM     33  H           0      -0.497  -1.699   2.744  0.00  0.00           H+0
ATOM     34  H           0      -2.166  -1.066   2.659  0.00  0.00           H+0
ATOM     35  H           0      -1.004  -3.286   1.165  0.00  0.00           H+0
ATOM     36  H           0      -2.687  -2.678   1.110  0.00  0.00           H+0
ATOM     37  H           0      -2.371  -3.048  -1.390  0.00  0.00           H+0
ATOM     38  H           0      -0.089  -3.064  -0.969  0.00  0.00           H+0
CONECT    1    2   24    0    0                                         NONE  43
CONECT    2    1   18    3    0                                         NONE  44
CONECT    3    2    4   25    0                                         NONE  45
CONECT    4    3    5    6   11                                         NONE  46
CONECT    6    4    7   26   27                                         NONE  47
CONECT    7    6    8    0    0                                         NONE  48
CONECT    8    7    9   10    0                                         NONE  49
CONECT    9    8   28   29    0                                         NONE  50
CONECT   10    8    0    0    0                                         NONE  51
CONECT   11    4   12   17   13                                         NONE  52
CONECT   13   11   21   14   18                                         NONE  53
CONECT   14   13   15    0    0                                         NONE  54
CONECT   15   14   16   17    0                                         NONE  55
CONECT   16   15   30   31    0                                         NONE  56
CONECT   17   15   11   32    0                                         NONE  57
CONECT   18   13    2   19    0                                         NONE  58
CONECT   19   18   20   33   34                                         NONE  59
CONECT   20   19   21   35   36                                         NONE  60
CONECT   21   20   13   22   23                                         NONE  61
CONECT   22   21   37    0    0                                         NONE  62
CONECT   23   21   38    0    0                                         NONE  63
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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 [http://en.wikipedia.org/wiki/Ricin ricin], currently appear on Schedule 1 of the [http://en.wikipedia.org/wiki/Chemical_Weapons_Convention 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 [http://en.wikipedia.org/wiki/Sodium_channel 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 ==

{|Name 
| R1    
| R2    
| R3    
| R4    
|-
| Saxitoxin
| H
| H
| H
| OCONH<sub>2</sub>
|-
| Gonyautoxin II
| H
| OSO<sub>3</sub>- 
| H
| OCONH<sub>2</sub>
|-
| Gonyautoxin III
| H
| H
| OSO<sub>3</sub>-  
| OCONH<sub>2</sub>
|-
| Neosaxitoxin
| OH
| H
| H
| OCONH<sub>2</sub>
|-
| Gonyautoxin I
| OH
| OSO<sub>3</sub>- 
| H
| OCONH<sub>2</sub>
|-
| Gonyautoxin IV
| OH
| H
| OSO<sub>3</sub>- 
| OCONH<sub>2</sub>
|-
|}
[[Image:Saxi.gif|Sax]]


== References ==
*1. https://www.chm.bris.ac.uk/motm/stx/saxi.htm
*2. https://www.cbwinfo.com/Biological/Toxins/Saxitoxin.html 
*3. https://www.globalsecurity.org/wmd/intro/bio_saxitoxin.htm
*4. https://www.iscid.org/encyclopedia/Saxitoxin
*5. https://www.cbwinfo.com/Biological/Toxins/SaxMarkush.html 
*6. https://www.sigmaaldrich.com