{{Chembox | Verifiedfields = changed | Watchedfields = changed | verifiedrevid = 477247988 | Reference = <ref>''Merck Index'', 11th Edition, '''281'''.</ref> | ImageFileL1 =Alloxan, skeletal formula.svg | ImageSizeL1 =130 | ImageCaptionL1 = Alloxan | ImageFileR1 =Alloxan hydrate structure.png | ImageSizeR1 =110 | ImageCaptionR1 = Alloxan monohydrate | 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 | UNII_Ref = {{fdacite|correct|FDA}} | 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) | InChIKey = HIMXGTXNXJYFGB-UHFFFAOYAQ | StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChI = 1S/C4H2N2O4/c7-1-2(8)5-4(10)6-3(1)9/h(H2,5,6,8,9,10) | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} | StdInChIKey = HIMXGTXNXJYFGB-UHFFFAOYSA-N | ChEBI_Ref = {{ebicite|correct|EBI}} | ChEBI = 76451 | ChEMBL_Ref = {{ebicite|correct|EBI}} | ChEMBL = 1096009 | CASNo_Comment = (Anhydrous) | CASNo_Ref = {{cascite|correct|CAS}} | CASNo = 50-71-5 | CASNo1 = 3237-50-1 | CASNo1_Comment = (monohydrate) | CASNo1_Ref = {{cascite|correct|CAS}} | EC_number = 200-062-0 | PubChem = 5781 | SMILES = C1(=O)C(=O)NC(=O)NC1=O | MeSHName = Alloxan }} |Section2={{Chembox Properties | Formula = {{chem2|C4H4N2O5}} (monohydrate) | MolarMass = 160.07 g/mol | Appearance = pale yellow solid | Density = 1.639 g/cm<sup>3</sup> (anhydrous) | MeltingPtC = 254 | MeltingPt_notes = (decomposition) | BoilingPt = | Solubility = 0.29 g/100 mL<ref name=OS/> }} |Section3={{Chembox Hazards | ExternalSDS = [http://www.palomar.edu/ehs/Chemistry%20MSDS/ALLOXAN%20MONOHYDRATE.pdf MSDS] | MainHazards = | FlashPt = | AutoignitionPt = }} }}

'''Alloxan''', sometimes referred to as '''alloxan monohydrate''', is an organic compound with the formula {{chem2|OC(NHCO)2C(OH)2}}. It is classified as a derivative of pyrimidine. The anhydrous 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 Luigi Valentino Brugnatelli (1761-1818)<ref>Luigi Valentino Brugnatelli; also cited as: Luigi Gaspari Brugnatelli and Luigi Vincenzo Brugnatelli.</ref><ref>See: * Gaspare Brugnatelli (1818) [http://babel.hathitrust.org/cgi/pt?id=chi.097296757;view=1up;seq=123 "Sopra i cangiamenti che avvengono nell' ossiurico (ac. urico) trattato coll' ossisettonoso (ac. nitroso)"] (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) [p. 117]. * (Gaspard Brugnatelli) (1818) [http://babel.hathitrust.org/cgi/pt?id=ien.35556014128250;view=1up;seq=205 "Sur un acide nouveau obtenu en traitant l'acide urique par acid nitrique"] (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 Wöhler and Liebig.<ref>F. Wöhler und J. Liebig (1838) [http://babel.hathitrust.org/cgi/pt?id=uva.x002457907;view=1up;seq=613 "Untersuchungen über die Natur der Harnsäure"] (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 "Allantoïn" and "Oxalsäure" (oxalic acid). 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 uric acid excreted by the fetus into the allantois, and oxaluric acid derived from oxalic acid and urea, found in urine.

Alloxan was used in the production of the purple dye murexide, discovered by Carl Wilhelm Scheele in 1776. Murexide is the product of the complex ''in-situ'' multistep reaction of alloxantin and gaseous ammonia.{{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.

thumb|center|upright=1.9|class=skin-invert-image|Murexide dye (right) from reaction of alloxantin (left) Scheele sourced uric acid from human calculi (such as kidney stones) and called the compound lithic acid. William Prout investigated the compound in 1818, and he used boa constrictor excrement with up to 90% ammonium acid urate.

In the chapter "Nitrogen" of his memoir ''The Periodic Table'', Primo Levi 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 pythons as a source for uric acid for making alloxan, but he is turned down by the director of the Turin zoo because the zoo already has lucrative contracts with pharmaceutical companies, so he is obliged to use chickens 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 uric acid by nitric acid. It is prepared by oxidation of barbituric acid by chromium trioxide.<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 alloxanic acid. 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 |pmid=1930261 }}</ref>

===Reduction=== Alloxan may be reduced to {{ill|dialuric acid|de|Dialursäure}}, which has a reductone structure, similar to ascorbic acid (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 hydrogen sulfide.<ref name=OS>{{OrgSynth | author = Tipson, R. S. | title = Alloxantin dihydrate | year = 1953 | volume = 33 | pages = 3 | collvol = 4 | collvolpages = 25 | prep = CV4P0025 }}</ref> thumb|center|upright=1.5|class=skin-invert-image|Alloxane (left) with dialuric acid (center) and alloxantin (right)

Alloxan monohydrate also undergoes one-electron reduction to form yellow salts containing a stable radical anion:<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 [K+][C4H2N2O4<sup>•</sup>-] + (CN)2 + 2 H2O}}

==Biological effects== Alloxan is a toxic glucose analogue, which selectively destroys insulin-producing cells in the pancreas (that is, beta cells) when administered to rodents and many other animal species. This causes an insulin-dependent diabetes mellitus (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 GLUT2 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 redox cycling with its one-electron ({{chem2|C4H3N2O4<sup>•</sup>}} semiquinone) 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 |pmid=16737280 |bibcode=2006JPCA..110.7272C }}</ref> In the presence of intracellular reductants such as glutathione (or other thiols), this leads to the generation of toxic reactive oxygen species (ROS) via the interaction of alloxan reduction products with molecular oxygen and related species:<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 insulin-producing beta-cells found in the pancreas, alloxan is used to induce diabetes 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 glucose 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 liver and the kidneys in high doses, as these are tissues where the GLUT2 transporter is expressed in humans.<ref name=Lenzen2008/>

==See also== * Streptozotocin

==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 = Journal of the Royal College of Physicians of Edinburgh | year = 2002 | volume = 32 | issue = 2 | pages = 134–142 | doi = 10.1177/1478271520023202014 | pmid = 12434795 }} *[http://www.chriscooksey.demon.co.uk/murexide/index.html The history and chemistry of the Murexide dye] {{Webarchive|url=https://web.archive.org/web/20130505133028/http://www.chriscooksey.demon.co.uk/murexide/index.html |date=2013-05-05 }}

Category:Pyrimidines Category:Lactams Category:Acylureas Category:Conjugated ketones