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Revision as of 20:41, 16 February 2012 editBeetstra (talk | contribs)Edit filter managers, Administrators172,031 edits Saving copy of the {{chembox}} taken from revid 474200489 of page Alloxan for the Chem/Drugbox validation project (updated: '').		Latest revision as of 14:16, 22 December 2024 edit Preimage (talk | contribs)Extended confirmed users742 editsm →Biological effects: Copyedit: use "type 1 diabetes" (as per Type 1 diabetes)
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	{{ambox | text = This page contains a copy of the infobox ({{tl|chembox}}) taken from revid of page ] with values updated to verified values.}}
	{{Chembox		{{Chembox
			| Verifiedfields = changed
	| Watchedfields = changed		| Watchedfields = changed
	| verifiedrevid = 454765743		| verifiedrevid = 477247988
	| Reference = <ref>'']'', 11th Edition, '''281'''.</ref>		| Reference = <ref>'']'', 11th Edition, '''281'''.</ref>
	| ImageFile = Alloxan.png		| ImageFileL1 =Alloxan, skeletal formula.svg
			| ImageSizeL1 =130
	| ImageSize = 100px
			| ImageCaptionL1 = Alloxan
	| IUPACName = 1,3-Diazinane-2,4,5,6-tetrone
			| ImageFileR1 =Alloxan hydrate structure.png
	| OtherNames = Mesoxalylurea<br>5-Oxobarbituric acid
			| ImageSizeR1 =110
	| Section1 = {{Chembox Identifiers
			| ImageCaptionR1 = Alloxan monohydrate
	| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
			| PIN = 5,5-Dihydroxypyrimidine-2,4,6(1''H'',3''H'',5''H'')-trione
			| OtherNames = 5,5-Dihydroxybarbituric acid
			|Section1={{Chembox Identifiers
			| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
	| ChemSpiderID = 5577		| ChemSpiderID = 5577
	| UNII_Ref = {{fdacite|correct|FDA}}		| UNII_Ref = {{fdacite|correct|FDA}}
	| UNII = 6SW5YHA5NG		| UNII = 6SW5YHA5NG
			| UNII_Comment = (anhydrous)
			| UNII1_Ref = {{fdacite|correct|FDA}}
			| UNII1 = O2AAP9F8B6
			| UNII1_Comment = (monohydrate)
	| InChI = 1/C4H2N2O4/c7-1-2(8)5-4(10)6-3(1)9/h(H2,5,6,8,9,10)		| InChI = 1/C4H2N2O4/c7-1-2(8)5-4(10)6-3(1)9/h(H2,5,6,8,9,10)
	| InChIKey = HIMXGTXNXJYFGB-UHFFFAOYAQ		| InChIKey = HIMXGTXNXJYFGB-UHFFFAOYAQ
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	| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}		| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
	| StdInChIKey = HIMXGTXNXJYFGB-UHFFFAOYSA-N		| StdInChIKey = HIMXGTXNXJYFGB-UHFFFAOYSA-N
	| CASNo_Ref = {{cascite|correct|CAS}}		| ChEBI_Ref = {{ebicite|correct|EBI}}
			| ChEBI = 76451
	| ChEMBL_Ref = {{ebicite|correct|EBI}}		| ChEMBL_Ref = {{ebicite|correct|EBI}}
	| ChEMBL = 1096009		| ChEMBL = 1096009
			| CASNo_Comment = (Anhydrous)
	| ChEMBL2 = 1697709
			| CASNo_Ref = {{cascite|correct|CAS}}
	| CASNo = 50-71-5
			| CASNo = 50-71-5
	| CASOther = {{CAS|2244-11-3}} (Monohydrate)
	| PubChem = 5781		| CASNo1 = 3237-50-1
			| CASNo1_Comment = (monohydrate)
	| SMILES = O=C1C(=O)NC(=O)NC1=O
			| CASNo1_Ref = {{cascite|correct|CAS}}
	| MeSHName = Alloxan
			| EC_number = 200-062-0
	}}
			| PubChem = 5781
	| Section2 = {{Chembox Properties
			| SMILES = C1(=O)C(=O)NC(=O)NC1=O
	| Formula = C<sub>4</sub>H<sub>2</sub>N<sub>2</sub>O<sub>4</sub>
			| MeSHName = Alloxan
	| MolarMass = 142.07 g/mol
			}}
	| Appearance = Solid
			|Section2={{Chembox Properties
	| Density = 1.639 g/cm^3
			| Formula = {{chem2|C4H4N2O5}} (monohydrate)
	| MeltingPt = 256 °C (decomposition)
			| MolarMass = 160.07 g/mol
	| BoilingPt =
			| Appearance = pale yellow solid
	| Solubility = Freely soluble
			| Density = 1.639 g/cm<sup>3</sup> (anhydrous)
	}}
			| MeltingPtC = 254
	| Section3 = {{Chembox Hazards
			| MeltingPt_notes = (decomposition)
	| ExternalMSDS =
	| MainHazards =		| BoilingPt =
			| Solubility = 0.29 g/100 mL<ref name=OS/>
	| FlashPt =
			}}
	| Autoignition =
			|Section3={{Chembox Hazards
	}}
			| ExternalSDS =
			| MainHazards =
			| FlashPt =
			| AutoignitionPt =
			}}
	}}		}}
			'''Alloxan''', sometimes referred to as '''alloxan monohydrate''', is an ] with the formula {{chem2|OC(NHCO)2C(OH)2}}. It is classified as a derivative of ]. The ] derivative {{chem2|OC(NHCO)2CO}} is also known, as well as a dimeric derivative. These are some of the earliest known organic compounds. They exhibit a variety of biological activities.
			==History and literature==
			The compound was discovered by Justus von Liebig and Friedrich Wöhler. It is one of the oldest named organic compounds. It was originally prepared in 1818 by ] (1761-1818)<ref>]; also cited as: Luigi Gaspari Brugnatelli and Luigi Vincenzo Brugnatelli.</ref><ref>See:
			* Gaspare Brugnatelli (1818) (On the changes that occur in uric acid (uric acid) treated with nitric acid (nitric acid)), ''Giornale di Fisica, Chimica, Storia Naturale, Medicina, ed Arti'', 2nd series, '''1''' : 117-129. Brugnatelli called it ''ossieritrico'' (erythric acid) .
			* (Gaspard Brugnatelli) (1818) (On a new acide obtained by treating uric acid with nitric acid), ''Annales de Chimie et de Physique'', 2nd series, '''8''' : 201-204.</ref> and was named in 1838 by ] and ].<ref>F. Wöhler und J. Liebig (1838) (Investigations into the nature of uric acid), ''Annalen der Chemie und Pharmacie'', '''26''' : 241-340. Alloxan is named on p. 252 and its preparation and properties appear on pp. 256 ff.</ref> The name "Alloxan" emerged from an amalgamation of the words "]" and "Oxalsäure" (]). The alloxan model of diabetes was first described in rabbits by Dunn, Sheehan and McLetchie in 1943.<ref>{{cite journal |author1=Dunn, J. S. |author2=Sheehan, H. L. |author3=McLetchie, N. G. B. | title = Necrosis of Islets of Langerhans Produced Experimentally | journal = Lancet | year = 1943 | volume = 241 | issue = 6242 | pages = 484–487 | doi = 10.1016/S0140-6736(00)42072-6 }}</ref> The name is derived from allantoin, a product of ] excreted by the ] into the ], and ] derived from oxalic acid and ], found in ].
			Alloxan was used in the production of the purple dye ], discovered by ] in 1776. Murexide is the product of the complex ''in-situ'' multistep reaction of alloxantin and gaseous ].{{cn|date=January 2021}} Murexide results from the condensation of the unisolated intermediate {{ill|uramil|de}} with alloxan liberated during the course of the reaction.
			:]{{clear left}}
			Scheele sourced ] from human ] (such as ]s) and called the compound lithic acid. ] investigated the compound in 1818 and he used ] excrement with up to 90% ammonium acid urate.
			In the chapter "Nitrogen" of his memoir ], ] tells of his futile attempt to make alloxan for a cosmetics manufacturer who has read that it can cause permanent reddening of the lips. Levi considers the droppings of ] as a source for uric acid for making alloxan, but he is turned down by the director of the ] zoo because the zoo already has lucrative contracts with pharmaceutical companies, so he is obliged to use ]s as his source of uric acid. The synthesis fails, however, "and the alloxan and its resonant name remained a resonant name."<ref>Primo Levi, ''The Periodic Table'' (New York: Schocken, 1984), translated by Raymond Rosenthal, 183.</ref>
			==Synthesis==
			It was originally obtained by oxidation of ] by ]. It is prepared by oxidation of ] by ].<ref>{{OrgSynth | author = Holmgren, A. V. |author2=Wenner, W. | title = Alloxan monohydrate | year = 1952 | volume = 32 | pages = 6 | collvol = 4 | collvolpages = 23 | prep = CV4P0023 }}</ref>
			==Reactions==
			===Hydrolysis===
			Alloxan is highly unstable in aqueous solution, undergoing hydrolysis to ]. Under physiological conditions, alloxan has an estimated half-life of 1.5&nbsp;minutes.<ref>{{cite journal |last1=Lenzen |first1=Sigurd |author-link1=:de:Sigurd Lenzen |last2=Munday |first2=Rex |title=Thiol-group reactivity, hydrophilicity and stability of alloxan, its reduction products and its N-methyl derivatives and a comparison with ninhydrin |journal=Biochemical Pharmacology |date=September 1991 |volume=42 |issue=7 |pages=1385–1391 |doi=10.1016/0006-2952(91)90449-F}}</ref>
			===Reduction===
			Alloxan may be reduced to {{ill|dialuric acid|de|Dialursäure}}, which has a ] structure, similar to ] (Vitamin C).<ref name=Endo1979/><!--Endo et al. (1979) refers to alloxan monohydrate as a reductone, but they clearly mean dialuric acid--> However, unlike ascorbic acid, alloxan and dialuric acid have strong pro-oxidant physiological effects.
			A dimeric derivative '''alloxantin''' can be prepared by partial reduction of alloxan with ].<ref name=OS>{{OrgSynth | author = Tipson, R. S. | title = Alloxantin dihydrate | year = 1953 | volume = 33 | pages = 3 | collvol = 4 | collvolpages = 25 | prep = CV4P0025 }}</ref>
			:]{{clear left}}
			Alloxan monohydrate also undergoes one-electron reduction to form yellow salts containing a stable ]:<ref name=Endo1979>{{cite journal |last1=Endo |first1=Takeshi |last2=Kudo |first2=Akira |last3=Okawara |first3=Makoto |title=Reduction of Alloxan by Cyanide Ion. Isolation of Alloxan Radical Anion Salts and Alloxantin |journal=Bulletin of the Chemical Society of Japan |date=1 November 1979 |volume=52 |issue=11 |pages=3473–3474 |doi=10.1246/bcsj.52.3473}}</ref>
			:{{chem2|2 C4H4N2O5 + 2 KCN -> 2 + (CN)2 + 2 H2O}}
			==Biological effects==
			Alloxan is a toxic ] analogue, which selectively destroys ]-producing cells in the ] (that is, ]s) when administered to ]s and many other animal species. This causes an insulin-dependent ] (called "alloxan diabetes") in these animals, with characteristics similar to type 1 diabetes in humans. Alloxan is selectively toxic to insulin-producing pancreatic beta cells because it preferentially accumulates in beta cells through uptake via the ] glucose transporter. Studies suggest alloxan does not cause diabetes in humans.<ref name=Lenzen2008>{{cite journal | author = Lenzen, S. | title = The Mechanisms of Alloxan- and Streptozotocin-induced Diabetes | journal = Diabetologia | year = 2008 | volume = 51 | issue = 2 | pages = 216–226 | pmid = 18087688 | doi=10.1007/s00125-007-0886-7| doi-access = free }}</ref> Others found a significant difference in alloxan plasma levels in children with and without type 1 diabetes.<ref name="literature2">{{cite journal |author1=Mrozikiewicz, A. |author2=Kielstrokczewska-Mrozikiewicz, D. |author3=Lstrokowicki, Z. |author4=Chmara, E. |author5=Korzeniowska, K. |author6=Mrozikiewicz, P. M. | title = Blood Levels of Alloxan in Children with Insulin-dependent Diabetes Mellitus | journal = Acta Diabetologica | year = 1994 | volume = 31 | issue = 4 | pages = 236–237 | pmid = 7888696 |doi=10.1007/bf00571958 |s2cid=12726659 }}</ref>
			===Reactive oxygen species generation===
			Alloxan ({{chem2|C4H2N2O4}}) readily undergoes ] with its one-electron ({{chem2|C4H3N2O4<sup>•</sup>}} ]) and two-electron (dialuric acid, {{chem2|C4H4N2O4}}) reduction products.<ref name=mechanistic>{{cite journal |last1=Czerwiñska |first1=Małgorzata |last2=Sikora |first2=Adam |last3=Szajerski |first3=Piotr |last4=Adamus |first4=Jan |last5=Marcinek |first5=Andrzej |last6=Gȩbicki |first6=Jerzy |last7=Bednarek |first7=Paweł |title=Mechanistic Aspects of Alloxan Diabetogenic Activity: A Key Role of Keto−Enol Inversion of Dialuric Acid on Ionization |journal=The Journal of Physical Chemistry A |date=1 June 2006 |volume=110 |issue=22 |pages=7272–7278 |doi=10.1021/jp0614594}}</ref> In the presence of intracellular reductants such as ] (or other ]s), this generates ] (ROS) via interaction of alloxan reduction products with molecular oxygen and other redox-active species.<ref name=Lenzen2008/> The beta cell toxic action of alloxan is initiated by ]s formed in these ]s:<ref name=Lenzen2008/>
			:{{chem2|C4H2N2O4 + GSH -> C4H3N2O4<sup>•</sup> + GS<sup>•</sup>}}
			:{{chem2|C4H3N2O4<sup>•</sup> + GSH -> C4H4N2O4 + GS<sup>•</sup>}}
			:{{chem2|C4H4N2O4 + O2 -> C4H3N2O4<sup>•</sup> + O2<sup>•</sup>- + H+}}
			:{{chem2|C4H3N2O4<sup>•</sup> + O2 -> C4H2N2O4 + O2<sup>•</sup>- + H+}}
			===Impact upon beta cells===
			Because it selectively kills the ]-producing ] found in the pancreas, alloxan is used to induce ] in laboratory animals.<ref>{{cite journal | author = Danilova I.G. |author2=Sarapultsev P.A. |author3=Medvedeva S.U. |author4=Gette I.F. |author5=Bulavintceva T.S. |author6=Sarapultsev A.P. | year = 2014 | title = Morphological Restructuring of Myocardium During the Early Phase of Experimental Diabetes Mellitus | journal = Anat. Rec. | volume = 298| issue = 2| pages = 396–407| doi = 10.1002/ar.23052 | pmid = 25251897 | hdl = 10995/73117 | s2cid = 205412167 | hdl-access = free }}</ref><ref>{{Cite book |url=https://www.taylorfrancis.com/books/mono/10.1201/9781420093278/experimental-surgical-models-laboratory-rat-veronica-di-loreto-alfredo-rigalli |title=Experimental Surgical Models in the Laboratory Rat |date=2009-05-12 |publisher=CRC Press |isbn=978-0-429-14721-0 |editor2=Loreto, Veronica Di |editor1=Alfredo Rigalli |location=Boca Raton |doi=10.1201/9781420093278}}</ref> This occurs most likely because of selective uptake of the compound due to its structural similarity to ] as well as the beta-cell's highly efficient uptake mechanism (GLUT2). In addition, alloxan has a high affinity to SH-containing cellular compounds and, as a result, reduces glutathione content. Furthermore, alloxan inhibits glucokinase, a SH-containing protein essential for insulin secretion induced by glucose.<ref>{{cite journal | author = Szkudelski T | year = 2001 | title = The mechanism of alloxan and streptozotocin action in B cells of the rat pancreas | journal = Physiol Res | volume = 50 | issue = 6 | pages = 536–546 | pmid = 11829314 }}</ref>
			Most studies have shown that alloxan is not toxic to the human beta-cell, even in very high doses, probably because of differing glucose uptake mechanisms in humans and rodents.<ref>{{cite journal |author1=Tyrberg, B. |author2=Andersson, A. |author3=Borg, L. A. | title = Species Differences in Susceptibility of Transplanted and Cultured Pancreatic Islets to the β-Cell Toxin Alloxan | journal = General and Comparative Endocrinology | year = 2001 | volume = 122 | issue = 3 | pages = 238–251 | pmid = 11356036 | doi = 10.1006/gcen.2001.7638 }}</ref><ref>{{cite journal |author1=Eizirik, D. L. |author2=Pipeleers, D. G. |author3=Ling, Z. |author4=Welsh, N. |author5=Hellerström, C. |author6=Andersson, A. | title = Major Species Differences between Humans and Rodents in the Susceptibility to Pancreatic β-Cell Injury | journal = Proceedings of the National Academy of Sciences of the United States of America| year = 1994 | volume = 91 | issue = 20 | pages = 9253–9256 | pmid = 7937750 | doi = 10.1073/pnas.91.20.9253 | pmc=44790|bibcode=1994PNAS...91.9253E |doi-access=free }}</ref>
			Alloxan is, however, toxic to the ] and the ] in high doses, as these are tissues where the GLUT2 transporter is expressed in humans.<ref name=Lenzen2008/>
			==See also==
			* ]
			==References==
			{{Reflist}}
			==External links==
			*{{cite journal | author = McLetchie, N. G. | url = http://www.rcpe.ac.uk/journal/issue/journal_32_2/L%20Paper%209HistAllox.pdf | title = Alloxan Diabetes, a Discovery, albeit a Minor one | journal = ] | year = 2002 | volume = 32 | issue = 2 | pages = 134–142 | pmid = 12434795 }}
			* {{Webarchive|url=https://web.archive.org/web/20130505133028/http://www.chriscooksey.demon.co.uk/murexide/index.html |date=2013-05-05 }}
			]
			]
			]
			]