Alloxan, sometimes referred to as alloxan monohydrate, is an

organic compound Some chemical authorities define an organic compound as a chemical compound that contains a carbon–hydrogen or carbon–carbon bond; others consider an organic compound to be any chemical compound that contains carbon. For example, carbon-co ...

with the formula . It is classified as a derivative of

pyrimidine Pyrimidine (; ) is an aromatic, heterocyclic, organic compound similar to pyridine (). One of the three diazines (six-membered heterocyclics with two nitrogen atoms in the ring), it has nitrogen atoms at positions 1 and 3 in the ring. The oth ...

. The

anhydrous A substance is anhydrous if it contains no water. Many processes in chemistry can be impeded by the presence of water; therefore, it is important that water-free reagents and techniques are used. In practice, however, it is very difficult to achie ...

derivative 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) and was named in 1838 by Wöhler and Liebig. The name "Alloxan" emerged from an amalgamation of the words " Allantoïn" and "Oxalsäure" (

oxalic acid Oxalic acid is an organic acid with the systematic name ethanedioic acid and chemical formula , also written as or or . It is the simplest dicarboxylic acid. It is a white crystalline solid that forms a colorless solution in water. Its name i ...

). The alloxan model of diabetes was first described in rabbits by Dunn, Sheehan and McLetchie in 1943. The name is derived from allantoin, a product of

uric acid Uric acid is a heterocyclic compound of carbon, nitrogen, oxygen, and hydrogen with the Chemical formula, formula C5H4N4O3. It forms ions and salts known as urates and acid urates, such as ammonium acid urate. Uric acid is a product of the meta ...

excreted by the

fetus A fetus or foetus (; : fetuses, foetuses, rarely feti or foeti) is the unborn offspring of a viviparous animal that develops from an embryo. Following the embryonic development, embryonic stage, the fetal stage of development takes place. Pren ...

into the allantois, and oxaluric acid derived from oxalic acid and

urea Urea, also called carbamide (because it is a diamide of carbonic acid), is an organic compound with chemical formula . This amide has two Amine, amino groups (–) joined by a carbonyl functional group (–C(=O)–). It is thus the simplest am ...

, found in

urine Urine is a liquid by-product of metabolism in humans and many other animals. In placental mammals, urine flows from the Kidney (vertebrates), kidneys through the ureters to the urinary bladder and exits the urethra through the penile meatus (mal ...

. Alloxan was used in the production of the purple dye murexide, discovered by

Carl Wilhelm Scheele Carl Wilhelm Scheele (, ; 9 December 1742 – 21 May 1786) was a Swedish Pomerania, German-Swedish pharmaceutical chemist. Scheele discovered oxygen (although Joseph Priestley published his findings first), and identified the elements molybd ...

in 1776. Murexide is the product of the complex ''in-situ'' multistep reaction of alloxantin and gaseous

ammonia Ammonia is an inorganic chemical compound of nitrogen and hydrogen with the chemical formula, formula . A Binary compounds of hydrogen, stable binary hydride and the simplest pnictogen hydride, ammonia is a colourless gas with a distinctive pu ...

. Murexide results from the condensation of the unisolated intermediate with alloxan liberated during the course of the reaction. : Scheele sourced

from human calculi (such as

kidney stone Kidney stone disease (known as nephrolithiasis, renal calculus disease, or urolithiasis) is a crystallopathy and occurs when there are too many minerals in the urine and not enough liquid or hydration. This imbalance causes tiny pieces of cr ...

s) and called the compound lithic acid. William Prout investigated the compound in 1818 and he used

boa constrictor The boa constrictor (scientific name also ''Boa constrictor''), also known as the common boa, is a species of large, non-venomous, heavy-bodied snake that is frequently kept and bred in captivity. The boa constrictor is a member of the Family (b ...

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 Turin ( , ; ; , then ) is a city and an important business and cultural centre in northern Italy. It is the capital city of Piedmont and of the Metropolitan City of Turin, and was the first Italian capital from 1861 to 1865. The city is main ...

zoo because the zoo already has lucrative contracts with pharmaceutical companies, so he is obliged to use

chicken The chicken (''Gallus gallus domesticus'') is a domesticated subspecies of the red junglefowl (''Gallus gallus''), originally native to Southeast Asia. It was first domesticated around 8,000 years ago and is now one of the most common and w ...

s as his source of uric acid. The synthesis fails, however, "and the alloxan and its resonant name remained a resonant name."

Synthesis

It was originally obtained by oxidation of

nitric acid Nitric acid is an inorganic compound with the formula . It is a highly corrosive mineral acid. The compound is colorless, but samples tend to acquire a yellow cast over time due to decomposition into nitrogen oxide, oxides of nitrogen. Most com ...

. It is prepared by oxidation of

barbituric acid Barbituric acid or malonylurea or 6-hydroxyuracil is an organic compound based on a pyrimidine heterocyclic skeleton. It is an odorless powder soluble in water. Barbituric acid is the parent compound of barbiturate drugs, although barbituric acid i ...

chromium trioxide Chromium trioxide (also known as chromium(VI) oxide or chromic anhydride) is an inorganic compound with the formula . It is the acidic anhydride of chromic acid, and is sometimes marketed under the same name. This compound is a dark-purple solid ...

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 minutes.

Reduction

Alloxan may be reduced to , which has a reductone structure, similar to

ascorbic acid Ascorbic acid is an organic compound with formula , originally called hexuronic acid. It is a white solid, but impure samples can appear yellowish. It dissolves freely in water to give mildly acidic solutions. It is a mild reducing agent. Asco ...

(Vitamin C). 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 Hydrogen sulfide is a chemical compound with the formula . It is a colorless chalcogen-hydride gas, and is toxic, corrosive, and flammable. Trace amounts in ambient atmosphere have a characteristic foul odor of rotten eggs. Swedish chemist ...

. : Alloxan monohydrate also undergoes one-electron reduction to form yellow salts containing a stable radical anion: :

Biological effects

Alloxan is a toxic

glucose Glucose is a sugar with the Chemical formula#Molecular formula, molecular formula , which is often abbreviated as Glc. It is overall the most abundant monosaccharide, a subcategory of carbohydrates. It is mainly made by plants and most algae d ...

analogue, which selectively destroys

insulin Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the insulin (''INS)'' gene. It is the main Anabolism, anabolic hormone of the body. It regulates the metabol ...

-producing cells in the

pancreas The pancreas (plural pancreases, or pancreata) is an Organ (anatomy), organ of the Digestion, digestive system and endocrine system of vertebrates. In humans, it is located in the abdominal cavity, abdomen behind the stomach and functions as a ...

(that is,

beta cell Beta cells (β-cells) are specialized endocrine cells located within the pancreatic islets of Langerhans responsible for the production and release of insulin and amylin. Constituting ~50–70% of cells in human islets, beta cells play a vi ...

s) when administered to

rodent Rodents (from Latin , 'to gnaw') are mammals of the Order (biology), order Rodentia ( ), which are characterized by a single pair of continuously growing incisors in each of the upper and Mandible, lower jaws. About 40% of all mammal specie ...

s and many other animal species. This causes an insulin-dependent

diabetes mellitus Diabetes mellitus, commonly known as diabetes, is a group of common endocrine diseases characterized by sustained hyperglycemia, high blood sugar levels. Diabetes is due to either the pancreas not producing enough of the hormone insulin, or th ...

(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 2 (GLUT2) also known as solute carrier family 2 (facilitated glucose transporter), member 2 (SLC2A2) is a transmembrane carrier protein that enables protein facilitated glucose movement across cell membranes. It is the princi ...

glucose transporter. Studies suggest alloxan does not cause diabetes in humans. Others found a significant difference in alloxan plasma levels in children with and without type 1 diabetes.

Reactive oxygen species generation

Alloxan () readily undergoes redox cycling with its one-electron ( semiquinone) and two-electron (dialuric acid, ) reduction products. In the presence of intracellular reductants such as glutathione (or other

thiol In organic chemistry, a thiol (; ), or thiol derivative, is any organosulfur compound of the form , where R represents an alkyl or other organic substituent. The functional group itself is referred to as either a thiol group or a sulfhydryl grou ...

s), this generates

reactive oxygen species In chemistry and biology, reactive oxygen species (ROS) are highly Reactivity (chemistry), reactive chemicals formed from diatomic oxygen (), water, and hydrogen peroxide. Some prominent ROS are hydroperoxide (H2O2), superoxide (O2−), hydroxyl ...

(ROS) via interaction of alloxan reduction products with molecular oxygen and other redox-active species. The beta cell toxic action of alloxan is initiated by

free radical A daughter category of ''Ageing'', this category deals only with the biological aspects of ageing. Ageing Biogerontology Biological processes Causes of death Cellular processes Gerontology Life extension Metabolic disorders Metabolism ...

s formed in these

redox reaction Redox ( , , reduction–oxidation or oxidation–reduction) is a type of chemical reaction in which the oxidation states of the reactants change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is ...

s: : : : :

Impact upon beta cells

Because it selectively kills the

-producing beta-cells found in the pancreas, alloxan is used to induce

diabetes Diabetes mellitus, commonly known as diabetes, is a group of common endocrine diseases characterized by sustained high blood sugar levels. Diabetes is due to either the pancreas not producing enough of the hormone insulin, or the cells of th ...

in laboratory animals. 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. 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. Alloxan is, however, toxic to the

liver The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...

and the

kidneys In humans, the kidneys are two reddish-brown bean-shaped blood-filtering organs that are a multilobar, multipapillary form of mammalian kidneys, usually without signs of external lobulation. They are located on the left and right in the retro ...

in high doses, as these are tissues where the GLUT2 transporter is expressed in humans.

References

External links

*
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 Pyrimidines Lactams Ureas Conjugated ketones