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Revision as of 15:50, 30 November 2010 editBeetstra (talk | contribs)Edit filter managers, Administrators172,031 edits Script assisted update of identifiers from ChemSpider, CommonChemistry and FDA for the Chem/Drugbox validation project - Updated: InChI1->InChI StdInChI StdInChIKey.← Previous edit		Latest revision as of 02:57, 9 January 2024 edit undoWikiCleanerBot (talk | contribs)Bots926,203 editsm v2.05b - Bot T20 CW#61 - Fix errors for CW project (Reference before punctuation)Tag: WPCleaner
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			{{other uses|CYL (disambiguation){{!}}CYL}}
	{{redirect|CYL|the Polish footballer|Wawrzyniec Cyl}}
			{{redirect|CYN|the prefix "cyn-"|List of commonly used taxonomic affixes}}
	{{chembox		{{chembox
			| Verifiedfields = changed
⚫	| ImageFile = Cylindrospermopsin structure2.png|thumb|300px
			| Watchedfields = changed
			| verifiedrevid = 445353616
		⚫	| ImageFile = Cylindrospermopsin vector all paths.svg
	| ImageSize =		| ImageSize =
	| IUPACName = <small>2,4(1H,3H)-Pyrimidinedione, 6-methyl]-</small>		| IUPACName = <small>2,4(1H,3H)-Pyrimidinedione, 6-methyl]-</small>
	| OtherNames = Cylindrospermopsine		| OtherNames = Cylindrospermopsine{{citation needed|date=November 2017}}
	| Section1 = {{Chembox Identifiers		| Section1 = {{Chembox Identifiers
	| InChI = 1/C15H21N5O7S/c1-6-10-5-16-14-17-8(13(22)9-4-12(21)19-15(23)18-9)2-7(20(10)14)3-11(6)27-28(24,25)26/h4,6-8,10-11,13,22H,2-3,5H2,1H3,(H,16,17)(H,24,25,26)(H2,18,19,21,23)/p+1/t6-,7+,8-,10?,11+,13+/m1/s1		| InChI = 1/C15H21N5O7S/c1-6-10-5-16-14-17-8(13(22)9-4-12(21)19-15(23)18-9)2-7(20(10)14)3-11(6)27-28(24,25)26/h4,6-8,10-11,13,22H,2-3,5H2,1H3,(H,16,17)(H,24,25,26)(H2,18,19,21,23)/p+1/t6-,7+,8-,10?,11+,13+/m1/s1
	| InChIKey = LHJPHMKIGRLKDR-FGVRTCLEBA		| InChIKey = LHJPHMKIGRLKDR-FGVRTCLEBA
	| SMILES = O=C1/C=C(\N=C(\O)N1)(O)2C4C(OS(O)(=O)=O)(C)C3C\=C(\N2)N34		| SMILES = O=C1/C=C(\N=C(\O)N1)(O)2C4C(OS(O)(=O)=O)(C)C3C\=C(\N2)N34
			| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
	| StdInChI = 1S/C15H21N5O7S/c1-6-10-5-16-14-17-8(13(22)9-4-12(21)19-15(23)18-9)2-7(20(10)14)3-11(6)27-28(24,25)26/h4,6-8,10-11,13,22H,2-3,5H2,1H3,(H,16,17)(H,24,25,26)(H2,18,19,21,23)/p+1/t6-,7+,8-,10?,11+,13+/m1/s1		| StdInChI = 1S/C15H21N5O7S/c1-6-10-5-16-14-17-8(13(22)9-4-12(21)19-15(23)18-9)2-7(20(10)14)3-11(6)27-28(24,25)26/h4,6-8,10-11,13,22H,2-3,5H2,1H3,(H,16,17)(H,24,25,26)(H2,18,19,21,23)/p+1/t6-,7+,8-,10?,11+,13+/m1/s1
			| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
	| StdInChIKey = LHJPHMKIGRLKDR-NPSYHWQSSA-O		| StdInChIKey = LHJPHMKIGRLKDR-NPSYHWQSSA-O
			| CASNo_Ref = {{cascite|correct|??}}
	| CASNo = 143545-90-8		| CASNo = 143545-90-8
			| CASNo1 =265652-18-4
⚫	| ChemSpiderID=21106433
			| CASNo1_Comment = 7-epi
			| ChEBI_Ref = {{ebicite|changed|EBI}}
			| ChEBI = 26502525
			| ChEBI1 = 88049
			| ChEBI1_Comment = 7-epi
			| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
		⚫	| ChemSpiderID=21106433
			| PubChem = 42628600
			| PubChem1 = 115005
			| PubChem1_Comment = 7-epi
			| UNII = 2JIZ556BA3
			| ChEMBL = 1722002
			| KEGG = C19999
	}}		}}
	| Section2 = {{Chembox Properties		| Section2 = {{Chembox Properties
	| Formula = C<sub>15</sub>H<sub>21</sub> N<sub>5</sub>O<sub>7</sub>S		| Formula = C<sub>15</sub>H<sub>21</sub>N<sub>5</sub>O<sub>7</sub>S
	| MolarMass = 415.43		| MolarMass = 415.43
	| Appearance = White solid		| Appearance = White solid
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	}}		}}
	| Section7 = {{Chembox Hazards		| Section7 = {{Chembox Hazards
	| ExternalMSDS =		| ExternalSDS =
	| NFPA-H =		| NFPA-H =
	| NFPA-F =		| NFPA-F =
	| NFPA-R =		| NFPA-R =
	| NFPA-O =		| NFPA-S =
	| FlashPt =		| FlashPt =
			| GHSPictograms = {{GHS06}}{{GHS08}}
			| GHSSignalWord = Danger
			| HPhrases = {{H-phrases|300|341|370}}
			| PPhrases = {{P-phrases|201|202|260|264|270|281|301+310|307+311|308+313|321|330|405|501}}
	}}		}}
	}}		}}
	'''Cylindrospermopsin''' (abbreviated to '''CYN''', or '''CYL''') is a ] produced by a variety of ] ].<ref>{{cite journal |author=Fastner J, Heinze R, Humpage AR, Mischke U, Eaglesham GK, Chorus I |title=Cylindrospermopsin occurrence in two German lakes and preliminary assessment of toxicity and toxin production of Cylindrospermopsis raciborskii (Cyanobacteria) isolates |journal=Toxicon |volume=42 |issue=3 |pages=313–21 |year=2003 |month=September |pmid=14559084 |doi=10.1016/S0041-0101(03)00150-8}}</ref> CYN is a ] ] ] containing ] and ] groups. It is also ]ic, making it highly water ]. CYN is ] to ] and ] tissue and is thought to inhibit ] and to ]ly modify ] and/or ]. It is not known whether cylindrospermopsin is a ], but it appears to have no ] initiating activity in mice.<ref>{{cite journal |author=Falconer IR, Humpage AR |title=Preliminary evidence for in vivo tumour initiation by oral administration of extracts of the blue-green alga cylindrospermopsis raciborskii containing the toxin cylindrospermopsin |journal=Environmental Toxicology |volume=16 |issue=2 |pages=192–5 |year=2001 |pmid=11339720 |doi=10.1002/tox.1024}}</ref>		'''Cylindrospermopsin''' (abbreviated to '''CYN''', or '''CYL''') is a ] produced by a variety of ] ].<ref>{{cite journal |vauthors=Fastner J, Heinze R, Humpage AR, Mischke U, Eaglesham GK, Chorus I |title=Cylindrospermopsin occurrence in two German lakes and preliminary assessment of toxicity and toxin production of Cylindrospermopsis raciborskii (Cyanobacteria) isolates |journal=Toxicon |volume=42 |issue=3 |pages=313–21 |date=September 2003 |pmid=14559084 |doi=10.1016/S0041-0101(03)00150-8}}</ref> CYN is a ] ] ] containing ] and ] groups. It is also ]ic, making it highly water ]. CYN is ] to ] and ] tissue and is thought to inhibit ] and to ]ly modify ] and/or ]. It is not known whether cylindrospermopsin is a ], but it appears to have no ] initiating activity in mice.<ref>{{cite journal |vauthors=Falconer IR, Humpage AR |title=Preliminary evidence for in vivo tumour initiation by oral administration of extracts of the blue-green alga cylindrospermopsis raciborskii containing the toxin cylindrospermopsin |journal=Environmental Toxicology |volume=16 |issue=2 |pages=192–5 |year=2001 |pmid=11339720 |doi=10.1002/tox.1024|bibcode=2001EnTox..16..192F |s2cid=36541311 }}</ref>
	CYN was first discovered after an outbreak of a mystery disease on ], ], ]. The outbreak was traced back to a ] of ''Cylindrospermopsis raciborskii'' in the local drinking water supply, and the toxin was subsequently identified. Analysis of the toxin led to a proposed ] in 1992, which was revised after ] was achieved in 2000. Several analogues of CYN, both toxic and non-toxic, have been isolated or synthesised.		CYN was first discovered after an outbreak of a mystery disease on ], ], ]. The outbreak was traced back to a ] of '']'' in the local drinking water supply, and the toxin was subsequently identified. Analysis of the toxin led to a proposed ] in 1992, which was revised after ] was achieved in 2000. Several analogues of CYN, both toxic and non-toxic, have been isolated or synthesised.
	''C. raciborskii'' has been observed mainly in ] areas, however has also recently been discovered in temperate regions of ], ], ] and ], and ].		''C. raciborskii'' has been observed mainly in ] areas, however has also recently been discovered in temperate regions of ], ], ], ] and ].<ref name="Poniedziałek B, Rzymski P, Kokociński M 2012">{{cite journal |vauthors=Poniedziałek B, Rzymski P, Kokociński M |title=Cylindrospermopsin: Water-linked potential threat to human health in Europe|journal=Environmental Toxicology and Pharmacology |year=2012 |pmid=22986102|doi=10.1016/j.etap.2012.08.005 |volume=34 |issue=3 |pages=651–60}}</ref> However, CYN-producing strain of C. raciborskii has not been identified in Europe, several other cyanobacteria species occurring across the continent are able to synthesize it.<ref name="Poniedziałek B, Rzymski P, Kokociński M 2012"/>
	==Discovery==		==Discovery==
	In 1979, 138 inhabitants of ], ], ], were admitted to hospital, suffering various ] of ]. All of these were children; in addition, 10 adults were affected but not hospitalised. Initial symptoms, including ] pain and ], resembled those of ]; later symptoms included ] and bloody ]. ] analysis revealed high levels of ], ] and ] in many patients, along with ] and ] in lesser numbers. The urine analysis, along with ] ] and ] screening, could not provide a statistical link to the symptoms. All patients recovered within 4 to 26 days, and at the time there was no apparent cause for the outbreak. Initial thoughts on the cause included poor water quality and diet, however none were conclusive, and the illness was coined the “Palm Island Mystery Disease”.<ref name=Byth1980>{{cite journal |author=Byth S |title=Palm Island mystery disease |journal=The Medical Journal of Australia |volume=2 |issue=1 |pages=40, 42 |year=1980 |month=July |pmid=7432268}}</ref>		In 1979, 138 inhabitants of ], ], ], were admitted to hospital, suffering various ] of ]. All of these were children; in addition, 10 adults were affected but not hospitalised. Initial symptoms, including ] pain and ], resembled those of ]; later symptoms included ] and bloody ]. ] analysis revealed high levels of ], ] and ] in many patients, along with ] and ] in lesser numbers. The urine analysis, along with ] ] and ] screening, could not provide a statistical link to the symptoms. All patients recovered within 4 to 26 days, and at the time there was no apparent cause for the outbreak. Initial thoughts on the cause included poor water quality and diet, however none were conclusive, and the illness was coined the “Palm Island Mystery Disease”.<ref name=Byth1980>{{cite journal |author=Byth S |title=Palm Island mystery disease |journal=The Medical Journal of Australia |volume=2 |issue=1 |pages=40–42 |date=July 1980 |pmid=7432268|doi=10.5694/j.1326-5377.1980.tb131814.x |s2cid=273293 }}</ref>
	At the time, it was noticed that this outbreak coincided with a severe ]l bloom in the local drinking water supply, and soon after the focus turned to the dam in question. An ] study of this “mystery disease” later confirmed that the ] was implicated, as those that became ill had used water from the dam. It became apparent that a recent treatment of the ] with ] caused lysis of the algal cells, releasing a ] into the water.<ref name=Bourke1983>{{cite journal		At the time, it was noticed that this outbreak coincided with a severe ]l bloom in the local drinking water supply, and soon after the focus turned to the dam in question. An ] study of this “mystery disease” later confirmed that the ] was implicated, as those that became ill had used water from the dam. It became apparent that a recent treatment of the ] with ] caused lysis of the algal cells, releasing a ] into the water.<ref name=Bourke1983>{{cite journal
	| author = Bourke, A.T.C.		| author = Bourke, A.T.C. |author2=Hawes, R.B. |author3=Neilson, A. |author4=Stallman, N.D.
	| coauthors = Hawes, R.B.; Neilson, A.; Stallman, N.D.
	| year = 1983		| year = 1983
	| title = An outbreak of hepato-enteritis (the Palm Island mystery disease) possibly caused by algal intoxication		| title = An outbreak of hepato-enteritis (the Palm Island mystery disease) possibly caused by algal intoxication
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	| doi = 10.1016/0041-0101(83)90151-4		| doi = 10.1016/0041-0101(83)90151-4
	}}</ref>		}}</ref>
	A study of the dam revealed that periodic blooms of algae were caused predominantly by three strains of ]: two of the genus '']'', and ''Cylindrospermopsis raciborskii'', previously unknown in Australian waters.<ref name=Griffiths2003>{{cite journal |author=Griffiths DJ, Saker ML |title=The Palm Island mystery disease 20 years on: a review of research on the cyanotoxin cylindrospermopsin |journal=Environmental Toxicology |volume=18 |issue=2 |pages=78–93 |year=2003 |month=April |pmid=12635096 |doi=10.1002/tox.10103}}</ref> A mouse bioassay of the three demonstrated that although the two ''Anabaena'' strains were non-toxic, ''C. raciborskii'' was highly toxic.<ref name=Hawkins1985>{{cite journal |author=Hawkins PR, Runnegar MT, Jackson AR, Falconer IR |title=Severe hepatotoxicity caused by the tropical cyanobacterium (blue-green alga) Cylindrospermopsis raciborskii (Woloszynska) Seenaya and Subba Raju isolated from a domestic water supply reservoir |journal=Applied and Environmental Microbiology |volume=50 |issue=5 |pages=1292–5 |year=1985 |month=November |pmid=3937492 |pmc=238741 |url=http://aem.asm.org/cgi/pmidlookup?view=long&pmid=3937492}}</ref> Later isolation of the compound responsible led to the identification of the toxin cylindrospermopsin.<ref name=Ohtani1992>{{cite journal		A study of the dam revealed that periodic blooms of algae were caused predominantly by three strains of ]: two of the genus '']'', and ''Cylindrospermopsis raciborskii'', previously unknown in Australian waters.<ref name=Griffiths2003>{{cite journal |vauthors=Griffiths DJ, Saker ML |title=The Palm Island mystery disease 20 years on: a review of research on the cyanotoxin cylindrospermopsin |journal=Environmental Toxicology |volume=18 |issue=2 |pages=78–93 |date=April 2003 |pmid=12635096 |doi=10.1002/tox.10103|bibcode=2003EnTox..18...78G |s2cid=25219655 }}</ref> A mouse bioassay of the three demonstrated that although the two ''Anabaena'' strains were non-toxic, ''C. raciborskii'' was highly toxic.<ref name=Hawkins1985>{{cite journal |vauthors=Hawkins PR, Runnegar MT, Jackson AR, Falconer IR |title=Severe hepatotoxicity caused by the tropical cyanobacterium (blue-green alga) Cylindrospermopsis raciborskii (Woloszynska) Seenaya and Subba Raju isolated from a domestic water supply reservoir |journal=Applied and Environmental Microbiology |volume=50 |issue=5 |pages=1292–5 |date=November 1985 |pmid=3937492 |pmc=238741 |doi=10.1128/AEM.50.5.1292-1295.1985 |bibcode=1985ApEnM..50.1292H }}</ref> Later isolation of the compound responsible led to the identification of the toxin cylindrospermopsin.<ref name=Ohtani1992>{{cite journal
	| author = Ohtani, I.		| author = Ohtani, I. |author2=Moore, R.E. |author3=Runnegar, M.T.C.
	| coauthors = Moore, R.E.; Runnegar, M.T.C.
	| year = 1992		| year = 1992
	| title = Cylindrospermopsin: a potent hepatotoxin from the blue-green alga Cylindrospermopsis raciborskii		| title = Cylindrospermopsin: a potent hepatotoxin from the blue-green alga Cylindrospermopsis raciborskii
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	| issue = 20		| issue = 20
	| pages = 7941–7942		| pages = 7941–7942
	| accessdate = 2008-04-29
	| doi = 10.1021/ja00046a067		| doi = 10.1021/ja00046a067
	}}</ref>		}}</ref>
	A later report alternatively proposed that the excess copper in the water was the cause of the disease. The excessive dosing was following the use of least-cost contractors to control the algae, who were unqualified in the field.<ref name="MJA 2004">{{cite journal |author=Prociv P |title=Algal toxins or copper poisoning--revisiting the Palm Island "epidemic" |journal=The Medical Journal of Australia |volume=181 |issue=6 |pages=344 |year=2004 |month=September |pmid=15377259 |url=http://www.mja.com.au/public/issues/181_06_200904/letters_200904_fm-6.html}}</ref>		A later report alternatively proposed that the excess copper in the water was the cause of the disease. The excessive dosing was following the use of least-cost contractors to control the algae, who were unqualified in the field.<ref name="MJA 2004">{{cite journal |author=Prociv P |title=Algal toxins or copper poisoning--revisiting the Palm Island "epidemic" |journal=The Medical Journal of Australia |volume=181 |issue=6 |pages=344 |date=September 2004 |pmid=15377259 |url=http://www.mja.com.au/public/issues/181_06_200904/letters_200904_fm-6.html|doi=10.5694/j.1326-5377.2004.tb06316.x |s2cid=22054004 }}</ref>
	==Chemistry==		==Chemistry==
	===Structure determination===		===Structure determination===
	] group. This ] was later identified as 7-epicylindrospermopsin.]]		] group. This ] was later identified as 7-epicyclindrospermopsin.]]
	Isolation of the toxin using algae cultured from the original Palm Island strain was achieved by gel filtration of an ] extract, followed by ]. Structure elucidation was achieved via ] (MS) and ] (NMR) experiments, and a structure (later proven slightly incorrect) was proposed (Figure&nbsp;1).<ref name=Ohtani1992 />		Isolation of the toxin using cyanobacteria cultured from the original Palm Island strain was achieved by gel filtration of an ] extract, followed by reverse-phase ]. Structure elucidation was achieved via ] (MS) and ] (NMR) experiments, and a structure (later proven slightly incorrect) was proposed (Figure&nbsp;1).<ref name=Ohtani1992 />
	This almost-correct ] possesses a ] ] group (rings A, B & C), along with a ] ring (D). The ]ic nature of the molecule makes this highly water-soluble, as the presence of ] areas within the molecule creates a ] effect, suiting the ] ]. Sensitivity of key signals in the NMR ] to small changes in ] suggested that the uracil ring exists in a ]/] ]ic relationship, where a ] transfer results in two distinct structures (Figure 2). It was originally proposed that a ] between the uracil and guanidine groups in the enol tautomer would make this the dominant form.<ref name=Ohtani1992 />		This almost-correct ] possesses a ] ] group (rings A, B & C), along with a ] ring (D). The ]ic nature of the molecule makes this highly water-soluble, as the presence of ] areas within the molecule creates a ] effect, suiting the ] ]. Sensitivity of key signals in the NMR ] to small changes in ] suggested that the uracil ring exists in a ]/] ]ic relationship, where a ] transfer results in two distinct structures (Figure 2). It was originally proposed that a ] between the uracil and guanidine groups in the enol tautomer would make this the dominant form.<ref name=Ohtani1992 />
	] and ] forms, showing the ] between the ] nitrogen and the guanidino hydrogen.]]		] and ] forms, showing the ] between the ] nitrogen and the guanidino hydrogen.]]
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	===Analogues===		===Analogues===
	]		]
	A second ] of ''C. raciborskii'' was identified from extracts of the algae after the observation of a frequently occurring peak accompanying that of CYN during ] and MS experiments. Analysis by MS and NMR methods concluded that this new compound was missing the ] adjacent to the uracil ring, and was named deoxycylindrospermopsin (Figure 3).<ref name=Norris2001>{{cite journal |author=Norris RL, Eaglesham GK, Shaw GR, ''et al.'' |title=Extraction and purification of the zwitterions cylindrospermopsin and deoxycylindrospermopsin from Cylindrospermopsis raciborskii |journal=Environmental Toxicology |volume=16 |issue=5 |pages=391–6 |year=2001 |month=October |pmid=11594025 |doi=10.1002/tox.1048}}</ref>		A second ] of ''C. raciborskii'' was identified from extracts of the cyanobacteria after the observation of a frequently occurring peak accompanying that of CYN during ] and MS experiments. Analysis by MS and NMR methods concluded that this new compound was missing the ] adjacent to the uracil ring, and was named deoxycylindrospermopsin (Figure 3).<ref name=Norris2001>{{cite journal |vauthors=Norris RL, Eaglesham GK, Shaw GR |title=Extraction and purification of the zwitterions cylindrospermopsin and deoxycylindrospermopsin from Cylindrospermopsis raciborskii |journal=Environmental Toxicology |volume=16 |issue=5 |pages=391–6 |date=October 2001 |pmid=11594025 |doi=10.1002/tox.1048|bibcode=2001EnTox..16..391N |s2cid=31387760 |display-authors=etal}}</ref>
	In 1999, an ] of CYN, named 7-epicylindrospermopsin (epiCYN), was also identified as a minor metabolite from ''Aphanizomenon ovalisporum''. This occurred whilst isolating CYN from cyanobacteria taken from ] in ].<ref name=Banker2000>{{cite journal |author=Banker R, Teltsch B, Sukenik A, Carmeli S |title=7-Epicylindrospermopsin, a toxic minor metabolite of the cyanobacterium Aphanizomenon ovalisporum from lake Kinneret, Israel |journal=Journal of Natural Products |volume=63 |issue=3 |pages=387–9 |year=2000 |month=March |pmid=10757726 |doi=10.1021/np990498m}}</ref> The proposed structure of this molecule differed from CYN only in the orientation of the ] group adjacent to the uracil ring (Figure 4).		In 1999, an ] of CYN, named 7-epicyclindrospermopsin (epiCYN), was also identified as a minor metabolite from ''Aphanizomenon ovalisporum''. This occurred whilst isolating CYN from cyanobacteria taken from ] in ].<ref name=Banker2000>{{cite journal |vauthors=Banker R, Teltsch B, Sukenik A, Carmeli S |title=7-Epicylindrospermopsin, a toxic minor metabolite of the cyanobacterium Aphanizomenon ovalisporum from lake Kinneret, Israel |journal=Journal of Natural Products |volume=63 |issue=3 |pages=387–9 |date=March 2000 |pmid=10757726 |doi=10.1021/np990498m}}</ref> The proposed structure of this molecule differed from CYN only in the orientation of the ] group adjacent to the uracil ring (Figure 4).
	]		]
	===Total synthesis===		===Total synthesis===
	] approaches to CYN started with the ] ring (A), and progressed to ] of rings B and C.<ref name=Heintzelman1996>{{cite journal | author = Heintzelman, G.R. | coauthors = Weinreb, S.M.; Parvez, M. | year = 1996 | title = Imino Diels-Alder-Based Construction of a Piperidine A-Ring Unit for Total Synthesis of the Marine Hepatotoxin Cylindrospermopsin | journal = Chemical Abstracts | volume = 125 | issue = 5 | doi = 10.1021/jo960035a | pages = 4594 }}</ref> The first ] of CYN was reported in 2000 through a 20-step process.<ref name=Xie2000>{{cite journal		] approaches to CYN started with the ] ring (A), and progressed to ] of rings B and C.<ref name=Heintzelman1996>{{cite journal | author = Heintzelman, G.R. |author2=Weinreb, S.M. |author3=Parvez, M. | year = 1996 | title = Imino Diels-Alder-Based Construction of a Piperidine A-Ring Unit for Total Synthesis of the Marine Hepatotoxin Cylindrospermopsin | journal = The Journal of Organic Chemistry| volume = 125 | issue = 5 | doi = 10.1021/jo960035a |pmid=11667385 | pages = 4594–4599 }}</ref> The first ] of CYN was reported in 2000 through a 20-step process.<ref name=Xie2000>{{cite journal
	| author = Xie, C.Y.		| author = Xie, C.Y. |author2=Runnegar, M.T.C. |author3=Snider, B.B.
	| coauthors = Runnegar, M.T.C.; Snider, B.B.
	| year = 2000		| year = 2000
	| title = Total synthesis of (+/-)-cylindrospermopsin		| title = Total synthesis of (+/-)-cylindrospermopsin
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	| issue = 21		| issue = 21
	| pages = 5017–5024		| pages = 5017–5024
	| accessdate = 2008-04-29
	| doi = 10.1021/ja000647j		| doi = 10.1021/ja000647j
	}}</ref>		}}</ref>
	Improvements to synthetic methods led to a revision of the ] of CYN in 2001. A synthetic process controlling each of the six ] centres of epiCYN established that the original assignments of both CYN and epiCYN were in fact a reversal of the correct structures.<ref name=Heintzelman2001>{{cite journal		Improvements to synthetic methods led to a revision of the ] of CYN in 2001. A synthetic process controlling each of the six ] centres of epiCYN established that the original assignments of both CYN and epiCYN were in fact a reversal of the correct structures.<ref name=Heintzelman2001>{{cite journal
	| author = Heintzelman, G.R.		| author = Heintzelman, G.R. |author2=Fang, W.K. |author3=Keen, S.P. |author4=Wallace, G.A. |author5=Weinreb, S.M.
	| coauthors = Fang, W.K.; Keen, S.P.; Wallace, G.A.; Weinreb, S.M.
	| year = 2001		| year = 2001
	| title = Stereoselective total synthesis of the cyanobacterial hepatotoxin 7-epicylindrospermopsin: revision of the stereochemistry of cylindrospermopsin		| title = Stereoselective total synthesis of the cyanobacterial hepatotoxin 7-epicylindrospermopsin: revision of the stereochemistry of cylindrospermopsin
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	| pages = 8851–3		| pages = 8851–3
	| doi = 10.1021/ja011291u		| doi = 10.1021/ja011291u
			| pmid=11535093
	}}</ref> An alternative approach by White and Hansen supported these absolute configurations (Figure 5).<ref name=White2005>{{cite journal		}}</ref> An alternative approach by White and Hansen supported these absolute configurations (Figure 5).<ref name=White2005>{{cite journal
	| author = White, J.D.		| author = White, J.D.
	| coauthors = Hansen, J.D.		|author2=Hansen, J.D.
	| year = 2005		| year = 2005
	| title = Total synthesis of (-)-7-epicylindrospermopsin, a toxic metabolite of the freshwater cyanobacterium Aphanizomenon ovalisporum, and assignment of its absolute configuration		| title = Total synthesis of (−)-7-epicylindrospermopsin, a toxic metabolite of the freshwater cyanobacterium Aphanizomenon ovalisporum, and assignment of its absolute configuration
	| journal = ]		| journal = ]
	| pmid = 15760174		| pmid = 15760174
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	===Stability===		===Stability===
	One of the key factors associated with the ] of CYN is its ]. Although the toxin has been found to ] rapidly in an algal extract when exposed to ], it is resistant to degradation by changes in ] and ], and shows no degradation in either the pure solid form or in pure water. As a result, in ] and unmoving water the toxin can persist for long periods, and although boiling water will kill the algae, it may not remove the toxin.<ref name=Chiswell1999>{{cite journal		One of the key factors associated with the ] of CYN is its ]. Although the toxin has been found to ] rapidly in an algal extract when exposed to ], it is resistant to degradation by changes in ] and ], and shows no degradation in either the pure solid form or in pure water. As a result, in ] and unmoving water the toxin can persist for long periods, and although boiling water will kill the cyanobacteria, it may not remove the toxin.<ref name=Chiswell1999>{{cite journal
	| author = Chiswell, R.K.		| author = Chiswell, R.K.
	| coauthors = Shaw, G.R.; Eaglesham, G.; Smith, M.J.; Norris, R.L.; Seawright, A.A.; Moore, M.R.		|author2=Shaw, G.R. |author3=Eaglesham, G. |author4=Smith, M.J. |author5=Norris, R.L. |author6=Seawright, A.A. |author7= Moore, M.R.
	| year = 1999		| year = 1999
	| title = Stability of cylindrospermopsin, the toxin from the cyanobacterium, Cylindrospermopsis raciborskii: Effect of pH, temperature, and sunlight on decomposition		| title = Stability of cylindrospermopsin, the toxin from the cyanobacterium, Cylindrospermopsis raciborskii: Effect of pH, temperature, and sunlight on decomposition
Line 133:		Line 152:
	| pages = 155–161		| pages = 155–161
	| doi = 10.1002/(SICI)1522-7278(199902)14:1<155::AID-TOX20>3.0.CO;2-Z		| doi = 10.1002/(SICI)1522-7278(199902)14:1<155::AID-TOX20>3.0.CO;2-Z
	}}</ref>		|s2cid=83656273 }}</ref>
	==Toxicology==		==Toxicology==
	===Toxic effects===		===Toxic effects===
	Hawkins ''et al.''. demonstrated the toxic effects of CYN by mouse bioassay, using an extract of the original Palm Island strain. ] poisoned mice displayed ], ] and gasping ]. Autopsy results revealed haemorrhages in the ], ], ], ] and ]. ] revealed dose-related ] of ], ] accumulation, and ] ] formation in ] of the liver and lungs, along with varying ] necrosis in areas of the kidneys.<ref name=Hawkins1985 />		Hawkins ''et al.''. demonstrated the toxic effects of CYN by mouse bioassay, using an extract of the original Palm Island strain. ] poisoned mice displayed ], ] and gasping ]. Autopsy results revealed haemorrhages in the ], ], ], ] and ]. ] revealed dose-related ] of ], ] accumulation, and ] ] formation in ] of the liver and lungs, along with varying ] necrosis in areas of the kidneys.<ref name=Hawkins1985 />
	A more recent mouse bioassay of the effects of cylindrospermopsin revealed an increase in liver weight, with both lethal and non-lethal doses; in addition the livers appeared dark-coloured. Extensive necrosis of hepatocytes was visible in mice administered a lethal dose, and some localised damage was also observed in mice administered a non-lethal dose.<ref name=Saker1999 />		A more recent mouse bioassay of the effects of cylindrospermopsin revealed an increase in liver weight, with both lethal and non-lethal doses; in addition the livers appeared dark-coloured. Extensive necrosis of hepatocytes was visible in mice administered a lethal dose, and some localised damage was also observed in mice administered a non-lethal dose.<ref name=Saker1999 />
	===Toxicity===		===Toxicity===
	An initial estimate of the toxicity of CYN in 1985 was that an {{LD50}} at 24 hours was 64±5&nbsp;mg of freeze-dried culture/kg of mouse body weight on ] ].<ref name=Hawkins1985 /> A further experiment in 1997 measured the LD<sub>50</sub> as 52&nbsp;mg/kg at 24 hours and 32&nbsp;mg/kg at 7 days, however the data suggested that another toxic compound was present in the isolate of ] cells used;<ref name=Hawkins1997>{{cite journal |author=Hawkins PR, Chandrasena NR, Jones GJ, Humpage AR, Falconer IR |title=Isolation and toxicity of Cylindrospermopsis raciborskii from an ornamental lake |journal=Toxicon |volume=35 |issue=3 |pages=341–6 |year=1997 |month=March |pmid=9080590 |doi=10.1016/S0041-0101(96)00185-7}}</ref> predictions made by Ohtani ''et al.''<ref name=Ohtani1992 /> about the 24 hour toxicity were considerably higher, and it was proposed that another metabolite was present to account for the relatively low 24 hour toxicity level measured.<ref name=Hawkins1997 />		An initial estimate of the toxicity of CYN in 1985 was that an {{LD50}} at 24 hours was 64±5&nbsp;mg of freeze-dried culture/kg of mouse body weight on ] ].<ref name=Hawkins1985 /> A further experiment in 1997 measured the LD<sub>50</sub> as 52&nbsp;mg/kg at 24 hours and 32&nbsp;mg/kg at 7 days, however the data suggested that another toxic compound was present in the isolate of ] cells used;<ref name=Hawkins1997>{{cite journal |vauthors=Hawkins PR, Chandrasena NR, Jones GJ, Humpage AR, Falconer IR |title=Isolation and toxicity of Cylindrospermopsis raciborskii from an ornamental lake |journal=Toxicon |volume=35 |issue=3 |pages=341–6 |date=March 1997 |pmid=9080590 |doi=10.1016/S0041-0101(96)00185-7}}</ref> predictions made by Ohtani ''et al.''<ref name=Ohtani1992 /> about the 24‑hour toxicity were considerably higher, and it was proposed that another metabolite was present to account for the relatively low 24‑hour toxicity level measured.<ref name=Hawkins1997 />
	Because the most likely human route of uptake of CYN is ingestion, ] toxicity experiments were conducted on mice. The oral LD<sub>50</sub> was found to be 4.4-6.9&nbsp;mg CYN/kg, and in addition to some ] of the ] ] ], ] were consistent with that of intraperitoneal dosing. Stomach contents included ] material, which indicated that these LD<sub>50</sub> figures might be overestimated.<ref name=Seawright1999>{{cite journal		Because the most likely human route of uptake of CYN is ingestion, ] toxicity experiments were conducted on mice. The oral LD<sub>50</sub> was found to be 4.4-6.9&nbsp;mg CYN/kg, and in addition to some ] of the ] ], ] were consistent with that of intraperitoneal dosing. Stomach contents included ] material, which indicated that these LD<sub>50</sub> figures might be overestimated.<ref name=Seawright1999>{{cite journal
	| author = Seawright, A.A.		| author = Seawright, A.A.
	| coauthors = Nolan, C.C.; Shaw, G.R.; Chiswell, R.K.; Norris, R.L.; Moore, M.R.; Smith, M.J.		|author2=Nolan, C.C. |author3=Shaw, G.R. |author4=Chiswell, R.K. |author5=Norris, R.L. |author6=Moore, M.R. |author7= Smith, M.J.
	| year = 1999		| year = 1999
	| title = The oral toxicity for mice of the tropical cyanobacterium Cylindrospermopsis raciborskii (Woloszynska).(1999)		| title = The oral toxicity for mice of the tropical cyanobacterium Cylindrospermopsis raciborskii (Woloszynska).(1999)
	| journal = Environ. Toxicol		| journal = Environ. Toxicol.
	| volume = 14		| volume = 14
	| pages = 135–142		| pages = 135–142
	| doi = 10.1002/(SICI)1522-7278(199902)14:1<135::AID-TOX17>3.0.CO;2-L		| doi = 10.1002/(SICI)1522-7278(199902)14:1<135::AID-TOX17>3.0.CO;2-L
	}}</ref>		|s2cid=85166382 }}</ref>
			Another means of exposure to CYN is related to alterations in the gut microbiome by artificial sweetners. A study including ] conducted at Cedars-Sinai in Los Angeles by Ruchi Mathur, MD detected CYN in the duodenum at levels four times above baseline in Aspartame users, along with alterations in bacterial species.<ref name="Froscio2001" />
⚫	===Modes of action===
		⚫	===Mechanism of action===
⚫	] changes associated with CYN poisoning were reported to be in four distinct stages: ] of ], ] of ]s, lipid accumulation within cells, and finally ]. Examination of mice livers removed at autopsy showed that on intraperitoneal injection of CYN, after 16 hours ribosomes from the ] (rER) had detached, and at 24 hours, marked proliferation of the ] systems of the ] and ] had occurred. At 48 hours, small lipid droplets had accumulated in the cell bodies, and at 100 hours, hepatocytes in the hepatic ] were destroyed beyond function.<ref name=Terao1994>{{cite journal |author=Terao K, Ohmori S, Igarashi K, ''et al.'' |title=Electron microscopic studies on experimental poisoning in mice induced by cylindrospermopsin isolated from blue-green alga Umezakia natans |journal=Toxicon |volume=32 |issue=7 |pages=833–43 |year=1994 |month=July |pmid=7940590 |doi=10.1016/0041-0101(94)90008-6}}</ref>
		⚫	] changes associated with CYN poisoning were reported to be in four distinct stages: ] of ], ] of ]s, lipid accumulation within cells, and finally ]. Examination of mice livers removed at autopsy showed that on intraperitoneal injection of CYN, after 16 hours ribosomes from the ] (rER) had detached, and at 24 hours, marked proliferation of the ] systems of the ] and ] had occurred. At 48 hours, small lipid droplets had accumulated in the cell bodies, and at 100 hours, hepatocytes in the hepatic ] were destroyed beyond function.<ref name=Terao1994>{{cite journal |vauthors=Terao K, Ohmori S, Igarashi K |title=Electron microscopic studies on experimental poisoning in mice induced by cylindrospermopsin isolated from blue-green alga Umezakia natans |journal=Toxicon |volume=32 |issue=7 |pages=833–43 |date=July 1994 |pmid=7940590 |doi=10.1016/0041-0101(94)90008-6|display-authors=etal}}</ref>
⚫	The process of protein synthesis inhibition has been shown to be irreversible, however is not conclusively the method of ] of the compound. Froscio ''et al.''. proposed that CYN has at least two separate modes of action: the previously reported protein synthesis inhibition, and an as-yet unclear method of causing cell death. It has been shown that cells can survive for long periods (up to 20 hours) with 90% inhibition of protein synthesis, and still maintain viability.<ref name=Froscio2003>{{cite journal |author=Froscio SM, Humpage AR, Burcham PC, Falconer IR |title=Cylindrospermopsin-induced protein synthesis inhibition and its dissociation from acute toxicity in mouse hepatocytes |journal=Environmental Toxicology |volume=18 |issue=4 |pages=243–51 |year=2003 |month=August |pmid=12900943 |doi=10.1002/tox.10121}}</ref> Since CYN is cytotoxic within 16-18 hours<ref name=Runnegar1994>{{cite journal |author=Runnegar MT, Kong SM, Zhong YZ, Ge JL, Lu SC |title=The role of glutathione in the toxicity of a novel cyanobacterial alkaloid cylindrospermopsin in cultured rat hepatocytes |journal=Biochemical and Biophysical Research Communications |volume=201 |issue=1 |pages=235–41 |year=1994 |month=May |pmid=8198579 |doi=10.1006/bbrc.1994.1694}}</ref> it has been suggested that other mechanisms are the cause of cell death.
		⚫	The process of protein synthesis inhibition has been shown to be irreversible, however is not conclusively the method of ] of the compound. Froscio ''et al.''. proposed that CYN has at least two separate modes of action: the previously reported protein synthesis inhibition, and an as-yet unclear method of causing cell death. It has been shown that cells can survive for long periods (up to 20 hours) with 90% inhibition of protein synthesis, and still maintain viability.<ref name=Froscio2003>{{cite journal |vauthors=Froscio SM, Humpage AR, Burcham PC, Falconer IR |title=Cylindrospermopsin-induced protein synthesis inhibition and its dissociation from acute toxicity in mouse hepatocytes |journal=Environmental Toxicology |volume=18 |issue=4 |pages=243–51 |date=August 2003 |pmid=12900943 |doi=10.1002/tox.10121|bibcode=2003EnTox..18..243F |s2cid=36369852 }}</ref> Since CYN is cytotoxic within 16–18 hours<ref name=Runnegar1994>{{cite journal |vauthors=Runnegar MT, Kong SM, Zhong YZ, Ge JL, Lu SC |title=The role of glutathione in the toxicity of a novel cyanobacterial alkaloid cylindrospermopsin in cultured rat hepatocytes |journal=Biochemical and Biophysical Research Communications |volume=201 |issue=1 |pages=235–41 |date=May 1994 |pmid=8198579 |doi=10.1006/bbrc.1994.1694}}</ref> it has been suggested that other mechanisms are the cause of cell death.
	] has been implicated in the toxicity of CYN, as blocking the action of P450 reduces the toxicity of CYN.<ref name=Runnegar1995>{{cite journal |author=Runnegar MT, Kong SM, Zhong YZ, Lu SC |title=Inhibition of reduced glutathione synthesis by cyanobacterial alkaloid cylindrospermopsin in cultured rat hepatocytes |journal=Biochemical Pharmacology |volume=49 |issue=2 |pages=219–25 |year=1995 |month=January |pmid=7840799 |doi=10.1016/S0006-2952(94)00466-8}}</ref> It has been proposed that an activated P450-derived ] (or metabolites) of CYN is the main cause of toxicity.<ref name=Froscio2003 /> Shaw ''et al.''. demonstrated that the toxin could be metabolised '']'', resulting in bound metabolites in the liver tissue, and that damage was more prevalent in rat hepatocytes than other cell types.<ref name=Shaw2000>{{cite journal |author=Shaw GR, Seawright AA, Moore MR, Lam PK |title=Cylindrospermopsin, a cyanobacterial alkaloid: evaluation of its toxicologic activity |journal=Therapeutic Drug Monitoring |volume=22 |issue=1 |pages=89–92 |year=2000 |month=February |pmid=10688267 |doi=10.1097/00007691-200002000-00019}}</ref>
	Due to the structure of CYN, which includes ], ] and ] groups, it has been suggested that CYN acts on ] or ]. Shaw ''et al.''. reported ] binding of CYN or its metabolites to DNA in mice,<ref name=Shaw2000 /> and DNA strand breakage has also been observed.<ref name=Shen2002>{{cite journal |author=Shen X, Lam PK, Shaw GR, Wickramasinghe W |title=Genotoxicity investigation of a cyanobacterial toxin, cylindrospermopsin |journal=Toxicon |volume=40 |issue=10 |pages=1499–501 |year=2002 |month=October |pmid=12368121 |doi=10.1016/S0041-0101(02)00151-4}}</ref> Humpage ''et al.'' also supported this, and in addition postulated that CYN (or a metabolite) acts on either the ] or ] during ], inducing loss of whole ].<ref name=Humpage2000>{{cite journal |author=Humpage AR, Fenech M, Thomas P, Falconer IR |title=Micronucleus induction and chromosome loss in transformed human white cells indicate clastogenic and aneugenic action of the cyanobacterial toxin, cylindrospermopsin |journal=Mutation Research |volume=472 |issue=1-2 |pages=155–61 |year=2000 |month=December |pmid=11113708 |doi=10.1016/S1383-5718(00)00144-3}}</ref>		] has been implicated in the toxicity of CYN, as blocking the action of P450 reduces the toxicity of CYN.<ref name=Runnegar1995>{{cite journal |vauthors=Runnegar MT, Kong SM, Zhong YZ, Lu SC |title=Inhibition of reduced glutathione synthesis by cyanobacterial alkaloid cylindrospermopsin in cultured rat hepatocytes |journal=] |volume=49 |issue=2 |pages=219–25 |date=January 1995 |pmid=7840799 |doi=10.1016/S0006-2952(94)00466-8}}</ref> It has been proposed that an activated P450-derived ] (or metabolites) of CYN is the main cause of toxicity.<ref name=Froscio2003 /> Shaw ''et al.''. demonstrated that the toxin could be metabolised '']'', resulting in bound metabolites in the liver tissue, and that damage was more prevalent in rat hepatocytes than other cell types.<ref name=Shaw2000>{{cite journal |vauthors=Shaw GR, Seawright AA, Moore MR, Lam PK |title=Cylindrospermopsin, a cyanobacterial alkaloid: evaluation of its toxicologic activity |journal=Therapeutic Drug Monitoring |volume=22 |issue=1 |pages=89–92 |date=February 2000 |pmid=10688267 |doi=10.1097/00007691-200002000-00019}}</ref>
			Due to the structure of CYN, which includes ], ] and ] groups, it has been suggested that CYN acts on ] or ]. Shaw ''et al.''. reported ] binding of CYN or its metabolites to DNA in mice,<ref name=Shaw2000 /> and DNA strand breakage has also been observed.<ref name=Shen2002>{{cite journal |vauthors=Shen X, Lam PK, Shaw GR, Wickramasinghe W |title=Genotoxicity investigation of a cyanobacterial toxin, cylindrospermopsin |journal=Toxicon |volume=40 |issue=10 |pages=1499–501 |date=October 2002 |pmid=12368121 |doi=10.1016/S0041-0101(02)00151-4}}</ref> Humpage ''et al.'' also supported this, and in addition postulated that CYN (or a metabolite) acts on either the ] or ] during ], inducing loss of whole ].<ref name=Humpage2000>{{cite journal |vauthors=Humpage AR, Fenech M, Thomas P, Falconer IR |title=Micronucleus induction and chromosome loss in transformed human white cells indicate clastogenic and aneugenic action of the cyanobacterial toxin, cylindrospermopsin |journal=Mutation Research |volume=472 |issue=1–2 |pages=155–61 |date=December 2000 |pmid=11113708 |doi=10.1016/S1383-5718(00)00144-3}}</ref>
⚫	The ] group of CYN has been identified as a ] of the toxin. In two experiments, the ] ] atom on the uracil ring was replaced with a ] atom to form 5-chlorocylindrospermopsin, and the uracil group was truncated to a ], to form cylindrospermic acid (Figure 6). Both products were assessed as being ], even at 50 times the LD<sub>50</sub> of CYN.<ref name=Banker2001>{{cite journal |author=Banker R, Carmeli S, Werman M, Teltsch B, Porat R, Sukenik A |title=Uracil moiety is required for toxicity of the cyanobacterial hepatotoxin cylindrospermopsin |journal=Journal of Toxicology and Environmental Health. Part a |volume=62 |issue=4 |pages=281–8 |year=2001 |month=February |pmid=11245397 |doi=10.1080/009841001459432}}</ref> In the previous determination of the structure of deoxycylindrospermopsin, a toxicity assessment of the compound was carried out. Mice injected intraperitoneally with four times the 5-day median lethal dose of CYN showed no toxic effects. As this compound was shown to be relatively abundant, it was concluded that this ] was comparatively non-toxic.<ref name=Norris2001 /> Given that both CYN and epiCYN are toxic,<ref name=Banker2000 /> the ] group on the uracil bridge can be considered necessary for toxicity. As yet, the relative toxicities of CYN and epiCYN have not been compared.
		⚫	The ] group of CYN has been identified as a ] of the toxin. In two experiments, the ] ] atom on the uracil ring was replaced with a ] atom to form 5-chlorocylindrospermopsin, and the uracil group was truncated to a ], to form cylindrospermic acid (Figure 6). Both products were assessed as being ], even at 50 times the LD<sub>50</sub> of CYN.<ref name=Banker2001>{{cite journal |vauthors=Banker R, Carmeli S, Werman M, Teltsch B, Porat R, Sukenik A |title=Uracil moiety is required for toxicity of the cyanobacterial hepatotoxin cylindrospermopsin |journal=Journal of Toxicology and Environmental Health, Part A |volume=62 |issue=4 |pages=281–8 |date=February 2001 |pmid=11245397 |doi=10.1080/009841001459432|bibcode=2001JTEHA..62..281B |s2cid=32363711 }}</ref> In the previous determination of the structure of deoxycylindrospermopsin, a toxicity assessment of the compound was carried out. Mice injected intraperitoneally with four times the 5-day median lethal dose of CYN showed no toxic effects. As this compound was shown to be relatively abundant, it was concluded that this ] was comparatively non-toxic.<ref name=Norris2001 /> Given that both CYN and epiCYN are toxic,<ref name=Banker2000 /> the ] group on the uracil bridge can be considered necessary for toxicity. As yet, the relative toxicities of CYN and epiCYN have not been compared.
	] group as a ].]]		] group as a ].]]
			==Biosynthesis==
			The cylindrospermopsin biosynthetic gene cluster (BGC) was described from '']'' AWT205 in 2008.<ref name="Mihali2010">{{cite journal | last1=Mihali | first1=Troco Kaan | last2=Kellmann | first2=Ralf | last3=Muenchhoff | first3=Julia | last4=Barrow | first4=Kevin D. | last5=Neilan | first5=Brett A. | title=Characterization of the Gene Cluster Responsible for Cylindrospermopsin Biosynthesis | journal=Applied and Environmental Microbiology | publisher=American Society for Microbiology | volume=74 | issue=3 | date=2007-12-07 | issn=0099-2240 | doi=10.1128/aem.01988-07 | pages=716–722| pmid=18065631 | pmc=2227734 }}</ref>
	==Related toxic blooms and their impact==		==Related toxic blooms and their impact==
	], ], ].]]		], ], ].]]
	Since the Palm Island outbreak, several other species of cyanobacteria have been identified as producing CYN: ''Anabaena bergii'', ''Anabaena lapponica '',<ref name=Spoof2006>{{cite journal |author=Spoof L, Berg KA, Rapala J, ''et al.'' |title=First observation of cylindrospermopsin in Anabaena lapponica isolated from the boreal environment (Finland) |journal=Environmental Toxicology |volume=21 |issue=6 |pages=552–60 |year=2006 |month=December |pmid=17091499 |doi=10.1002/tox.20216}}</ref> ''Aphanizomenon ovalisporum'',<ref name=Banker1997>{{cite journal		Since the Palm Island outbreak, several other species of cyanobacteria have been identified as producing CYN: ''Anabaena bergii'', ''Anabaena lapponica '',<ref name=Spoof2006>{{cite journal |vauthors=Spoof L, Berg KA, Rapala J |title=First observation of cylindrospermopsin in Anabaena lapponica isolated from the boreal environment (Finland) |journal=Environmental Toxicology |volume=21 |issue=6 |pages=552–60 |date=December 2006 |pmid=17091499 |doi=10.1002/tox.20216|bibcode=2006EnTox..21..552S |s2cid=24456267 |display-authors=etal}}</ref> ''Aphanizomenon ovalisporum'',<ref name=Banker1997>{{cite journal
	| author = Banker, R.		| author = Banker, R.
	| coauthors = Carmeli, S.; Hadas, O.; Teltsch, B.; Porat, R.; Sukenik, A.		|author2=Carmeli, S. |author3=Hadas, O. |author4=Teltsch, B. |author5=Porat, R. |author6= Sukenik, A.
	| year = 1997		| year = 1997
	| title = Identification Of Cylindrospermopsin In Aphanizomenon Ovalisporum (cyanophyceae) Isolated From Lake Kinneret, Israel 1		| title = Identification Of Cylindrospermopsin In Aphanizomenon Ovalisporum (cyanophyceae) Isolated From Lake Kinneret, Israel 1
Line 182:		Line 207:
	| pages = 613–616		| pages = 613–616
	| doi = 10.1111/j.0022-3646.1997.00613.x		| doi = 10.1111/j.0022-3646.1997.00613.x
	}}</ref> ''Umezakia natans'',<ref name=Harada1994>{{cite journal |author=Harada KI, Ohtani I, Iwamoto K, ''et al.'' |title=Isolation of cylindrospermopsin from a cyanobacterium Umezakia natans and its screening method |journal=Toxicon |volume=32 |issue=1 |pages=73–84 |year=1994 |month=January |pmid=9237339 |doi=10.1016/0041-0101(94)90023-X}}</ref> ''Raphidiopsis curvata''.<ref name=Li2001>{{cite journal		|bibcode=1997JPcgy..33..613B |s2cid=84522324 }}</ref> ''Umezakia natans'',<ref name=Harada1994>{{cite journal |vauthors=Harada KI, Ohtani I, Iwamoto K |title=Isolation of cylindrospermopsin from a cyanobacterium Umezakia natans and its screening method |journal=Toxicon |volume=32 |issue=1 |pages=73–84 |date=January 1994 |pmid=9237339 |doi=10.1016/0041-0101(94)90023-X|display-authors=etal}}</ref> ''Raphidiopsis curvata''.<ref name=Li2001>{{cite journal
	| author = Li, R.		| author = Li, R.
	| coauthors = Carmichael, W.W.; Brittain, S.; Eaglesham, G.K.; Shaw, G.R.; Liu, Y.; Watanabe, M.M.		|author2=Carmichael, W.W. |author3=Brittain, S. |author4=Eaglesham, G.K. |author5=Shaw, G.R. |author6=Liu, Y. |author7= Watanabe, M.M.
	| year = 2001		| year = 2001
	| title = First Report Of The Cyanotoxins Cylindrospermopsin And Deoxycylindrospermopsin From Raphidiopsis Curvata (cyanobacteria)		| title = First Report Of The Cyanotoxins Cylindrospermopsin And Deoxycylindrospermopsin From Raphidiopsis Curvata (cyanobacteria)
Line 192:		Line 217:
	| pages = 1121–1126		| pages = 1121–1126
	| doi = 10.1046/j.1529-8817.2001.01075.x		| doi = 10.1046/j.1529-8817.2001.01075.x
	}}</ref> and ''Aphanizomenon issatschenkoi''.<ref>{{cite journal | author= Wood, S. A., J. P. Rasmussen, P. T. Holland, R. Campbell, and A. L. M. Crowe| title=First Report of the Cyanotoxin Anatoxin-A from Aphanizomenon issatschenkoi (cyanobacteria)| journal=Journal of Phycology | year= 2007| volume=43| pages=356–365| doi =10.1111/j.1529-8817.2007.00318.x }}</ref> In Australia, three main toxic cyanobacteria exist: '']'', ''Microcystis'' species and ''C. raciborskii''. Of these the latter, which produces CYN, has attracted considerable attention, not only due to the Palm Island outbreak, but also as the species is spreading to more ] areas. Previously, the algae was classed as only ], however it has recently been discovered in temperate regions of Australia, ], ] and ],<ref name=Griffiths2003>{{cite journal |author=Griffiths DJ, Saker ML |title=The Palm Island mystery disease 20 years on: a review of research on the cyanotoxin cylindrospermopsin |journal=Environmental Toxicology |volume=18 |issue=2 |pages=78–93 |year=2003 |month=April |pmid=12635096 |doi=10.1002/tox.10103}}</ref> and also ].<ref name=Stirling2001>{{cite journal |author=Stirling DJ, Quilliam MA |title=First report of the cyanobacterial toxin cylindrospermopsin in New Zealand |journal=Toxicon |volume=39 |issue=8 |pages=1219–22 |year=2001 |month=August |pmid=11306133 |doi=10.1016/S0041-0101(00)00266-X}}</ref>		|bibcode=2001JPcgy..37.1121L |s2cid=84743346 }}</ref> and ''Aphanizomenon issatschenkoi''.<ref>{{cite journal |author1=Wood, S. A. |author2=J. P. Rasmussen |author3=P. T. Holland |author4=R. Campbell |author5=A. L. M. Crowe |name-list-style=amp | title=First Report of the Cyanotoxin Anatoxin-A from Aphanizomenon issatschenkoi (cyanobacteria)| journal=Journal of Phycology | year= 2007| volume=43| pages=356–365| doi =10.1111/j.1529-8817.2007.00318.x | issue= 2 |s2cid=84284928 }}</ref> In Australia, three main toxic cyanobacteria exist: '']'', ''Microcystis'' species and ''C. raciborskii''. Of these the latter, which produces CYN, has attracted considerable attention, not only due to the Palm Island outbreak, but also as the species is spreading to more ] areas. Previously, the algae was classed as only ], however it has recently been discovered in temperate regions of Australia, ],<ref name="Poniedziałek B, Rzymski P, Kokociński M 2012"/> ] and ],<ref name="Griffiths2003"/> and also ].<ref name=Stirling2001>{{cite journal |vauthors=Stirling DJ, Quilliam MA |title=First report of the cyanobacterial toxin cylindrospermopsin in New Zealand |journal=Toxicon |volume=39 |issue=8 |pages=1219–22 |date=August 2001 |pmid=11306133 |doi=10.1016/S0041-0101(00)00266-X}}</ref>
	In August 1997, three ] and ten ] died from cylindrospermopsin ] on a farm in northwest Queensland. A nearby dam containing an algal bloom was tested, and ''C. raciborskii'' was identified. Analysis by ]/] revealed the presence of CYN in a sample of the ]. An ] of one of the calves reported a swollen ] and ], along with ]s of the ] and ]. ] examination of the ] tissue was consistent with that reported in CYN-affected mice.<ref name=Saker1999>{{cite journal		In August 1997, three ] and ten ] died from cylindrospermopsin ] on a farm in northwest Queensland. A nearby dam containing an algal bloom was tested, and ''C. raciborskii'' was identified. Analysis by ]/] revealed the presence of CYN in a sample of the ]. An ] of one of the calves reported a swollen ] and ], along with ]s of the ] and ]. ] examination of the ] tissue was consistent with that reported in CYN-affected mice.<ref name=Saker1999>{{cite journal
	| author = Saker, M.L.		| author = Saker, M.L. |author2=Thomas, A.D. |author3=Norton, J.H.
	| coauthors = Thomas, A.D.; Norton, J.H.
	| year = 1999		| year = 1999
	| title = Cattle mortality attributed to the toxic cyanobacterium Cylindrospermopsis raciborskii in an outback region of North Queensland		| title = Cattle mortality attributed to the toxic cyanobacterium Cylindrospermopsis raciborskii in an outback region of North Queensland
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	}}</ref> This was the first report of ''C. raciborskii'' causing ] in animals in Australia.		}}</ref> This was the first report of ''C. raciborskii'' causing ] in animals in Australia.
	The effect of a bloom of ''C. raciborskii'' on an ] pond in ], Australia was assessed in 1997. The pond contained ] ], along with a population of ] ] to control the excess food. Analysis revealed that the water contained both ] and ] CYN, and that the crayfish had accumulated this primarily in the liver but also in the ] tissue. Examination of the gut contents revealed cyanobacterial ], indicating that the crayfish had ] intracellular toxin. An experiment using an extract of the bloom showed that it was also possible to uptake extracellular toxin directly into the tissues. Such ], particularly in the aquaculture industry, was of concern, especially when humans were the end users of the product.<ref name=Saker1999>{{cite journal |author=Saker ML, Eaglesham GK |title=The accumulation of cylindrospermopsin from the cyanobacterium Cylindrospermopsis raciborskii in tissues of the Redclaw crayfish Cherax quadricarinatus |journal=Toxicon |volume=37 |issue=7 |pages=1065–77 |year=1999 |month=July |pmid=10484741 |doi=10.1016/S0041-0101(98)00240-2}}</ref>		The effect of a bloom of ''C. raciborskii'' on an ] pond in ], Australia was assessed in 1997. The pond contained ] ], along with a population of ] ] to control the excess food. Analysis revealed that the water contained both ] and ] CYN, and that the crayfish had accumulated this primarily in the liver but also in the ] tissue. Examination of the gut contents revealed cyanobacterial ], indicating that the crayfish had ] intracellular toxin. An experiment using an extract of the bloom showed that it was also possible to uptake extracellular toxin directly into the tissues. Such ], particularly in the aquaculture industry, was of concern, especially when humans were the end users of the product.<ref name="pmid10484741">{{cite journal |vauthors = Saker ML, Eaglesham GK |title=The accumulation of cylindrospermopsin from the cyanobacterium Cylindrospermopsis raciborskii in tissues of the Redclaw crayfish Cherax quadricarinatus |journal=Toxicon |volume=37 |issue=7 |pages=1065–77 |year=1999 |pmid=10484741 |doi=10.1016/S0041-0101(98)00240-2 }}</ref>
	The impact of cyanobacterial blooms has been assessed in ] terms. In December 1991, the world’s largest algal bloom occurred in Australia, where 1000&nbsp;km of the ]-] River was affected.<ref name=Force1992>{{cite journal		The impact of cyanobacterial blooms has been assessed in ] terms. In December 1991, the world's largest algal bloom occurred in Australia, where 1000&nbsp;km of the ]-] River was affected.<ref name=Force1992>{{cite journal
	| author = Force, N.S.W.B.G.A.T.		| author = Force, N.S.W.B.G.A.T.
	| year = 1992		| year = 1992
	| title = Final report of the NSW Blue-Green Algae Task Force		| title = Final report of the NSW Blue-Green Algae Task Force
	| journal = Parramatta: NSW Department of Water Resources		| journal = Parramatta: NSW Department of Water Resources
	}}</ref> One million people-days of drinking water were lost, and the direct costs incurred totalled more than $1.3M ]. Moreover, 2000 site-days of recreation were also lost, and the economic cost was estimated at $10M AUD, after taking into account indirectly affected industries such as ], ] and ].<ref name=Herath1995>{{cite journal		}}</ref> One million people-days of drinking water were lost, and the direct costs incurred totalled more than ]1.3 million. Moreover, 2000 site-days of recreation were also lost, and the economic cost was estimated at A$10 million, after taking into account indirectly affected industries such as ], ] and ].<ref name=Herath1995>{{cite journal
	| author = Herath, G.		| author = Herath, G.
	| year = 1995		| year = 1995
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	| pages = 77–86		| pages = 77–86
	}}</ref>		}}</ref>
	===Current methods of analysis in water samples===		===Current methods of analysis in water samples===
	Current methods include ] coupled to ] (]),<ref name=Welker2002>{{cite journal |author=Welker M, Bickel H, Fastner J |title=HPLC-PDA detection of cylindrospermopsin--opportunities and limits |journal=Water Research |volume=36 |issue=18 |pages=4659–63 |year=2002 |month=November |pmid=12418670 |doi=10.1016/S0043-1354(02)00194-X}}</ref><ref name=Eaglesham1999>{{cite journal		Current methods include ] coupled to ] (]),<ref name=Welker2002>{{cite journal |vauthors=Welker M, Bickel H, Fastner J |title=HPLC-PDA detection of cylindrospermopsin--opportunities and limits |journal=Water Research |volume=36 |issue=18 |pages=4659–63 |date=November 2002 |pmid=12418670 |doi=10.1016/S0043-1354(02)00194-X|bibcode=2002WatRe..36.4659W }}</ref><ref name=Eaglesham1999>{{cite journal
	| author = Eaglesham, G.K.		| author = Eaglesham, G.K.
	| coauthors = Norris, R.L.; Shaw, G.R.; Smith, M.J.; Chiswell, R.K.; Davis, B.C.; Neville, G.R.; Seawright, A.A.; Moore, M.R.		|author2=Norris, R.L. |author3=Shaw, G.R. |author4=Smith, M.J. |author5=Chiswell, R.K. |author6=Davis, B.C. |author7=Neville, G.R. |author8=Seawright, A.A. |author9= Moore, M.R.
	| year = 1999		| year = 1999
	| title = Use of HPLC-MS/MS to monitor cylindrospermopsin, a blue-green algal toxin, for public health purposes		| title = Use of HPLC-MS/MS to monitor cylindrospermopsin, a blue-green algal toxin, for public health purposes
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	}}</ref> mouse bioassay,<ref name=Falconer1999>{{cite journal		}}</ref> mouse bioassay,<ref name=Falconer1999>{{cite journal
	| author = Falconer, I.R.		| author = Falconer, I.R.
	| coauthors = Hardy, S.J.; Humpage, A.R.; Froscio, S.M.; Tozer, G.J.; Hawkins, P.R.		|author2=Hardy, S.J. |author3=Humpage, A.R. |author4=Froscio, S.M. |author5=Tozer, G.J. |author6= Hawkins, P.R.
	| year = 1999		| year = 1999
	| title = Hepatic and renal toxicity of the blue-green algae (cyanobacterium): cylindrospermosis raciborskii in male swiss albino mice		| title = Hepatic and renal toxicity of the blue-green algae (cyanobacterium): cylindrospermosis raciborskii in male swiss albino mice
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	| pages = 143–150		| pages = 143–150
	| url =		| url =
	| accessdate = 2008-04-30
	| doi = 10.1002/(SICI)1522-7278(199902)14:1<143::AID-TOX18>3.0.CO;2-H		| doi = 10.1002/(SICI)1522-7278(199902)14:1<143::AID-TOX18>3.0.CO;2-H
	}}</ref> protein synthesis inhibition assay, and reverse-phase HPLC-PDA (Photo Diode Array) analysis. A cell free protein synthesis assay has been developed which appears to be comparable to HPLC-MS.<ref name=Froscio2001>{{cite journal |author=Froscio SM, Humpage AR, Burcham PC, Falconer IR |title=Cell-free protein synthesis inhibition assay for the cyanobacterial toxin cylindrospermopsin |journal=Environmental Toxicology |volume=16 |issue=5 |pages=408–12 |year=2001 |month=October |pmid=11594027 |doi=10.1002/tox.1050}}</ref>		|s2cid=85792496 }}</ref> protein synthesis inhibition assay, and reverse-phase HPLC-PDA (Photo Diode Array) analysis. A cell free protein synthesis assay has been developed which appears to be comparable to HPLC-MS.<ref name="Froscio2001">{{cite journal |vauthors=Hosseini A, Barlow GM, Leite G, Rashid M, Parodi G, Wang J, Mathur R, et al. |date=November 2023 |year=2023 |orig-date=2023 Nov 23 |title=Consuming artificial sweeteners may alter the structure and function of duodenal microbial communities |journal=iScience |volume=26 |issue=12 |pages=108530 |bibcode= 2023iSci...26j8530H|doi=10.1016/j.isci.2023.108530 |pmc=10730370 |pmid=38125028 |s2cid=}}</ref>
			==See also==
			*]
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	== References ==		== References ==
	{{Reflist|2}}		{{Reflist|2}}
			{{Cyanotoxins}}
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