Aspergillic acid is an

organic Organic may refer to: * Organic, of or relating to an organism, a living entity * Organic, of or relating to an anatomical organ Chemistry * Organic matter, matter that has come from a once-living organism, is capable of decay or is the product ...

chemical compound A chemical compound is a chemical substance composed of many identical molecules (or molecular entities) containing atoms from more than one chemical element held together by chemical bonds. A molecule consisting of atoms of only one element ...

with the molecular formula C₁₂H₂₀N₂O₂. It has a pale yellow

crystalline A crystal or crystalline solid is a solid material whose constituents (such as atoms, molecules, or ions) are arranged in a highly ordered microscopic structure, forming a crystal lattice that extends in all directions. In addition, macrosc ...

appearance. Aspergillic acid is most commonly known as an

antibiotic An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting bacterial infections, and antibiotic medications are widely used in the treatment and prevention of ...

and

antifungal An antifungal medication, also known as an antimycotic medication, is a pharmaceutical fungicide or fungistatic used to treat and prevent mycosis such as athlete's foot, ringworm, candidiasis (thrush), serious systemic infections such as crypto ...

agent that is derived from certain strains of the fungus ''

Aspergillus flavus ''Aspergillus flavus'' is a saprotrophic and pathogenic fungus with a cosmopolitan distribution. It is best known for its colonization of cereal grains, legumes, and tree nuts. Postharvest rot typically develops during harvest, storage, and/or t ...

''.

History

In 1940 Edwin C. White and Justina H. Hill discovered that a fungal strain of ''Aspergillus flavus'' growing in a surface culture on a

tryptone Tryptone is the assortment of peptides formed by the digestion of casein by the protease trypsin. Tryptone is commonly used in microbiology to produce lysogeny broth (LB) for the growth of '' E. coli'' and other microorganisms. It provides a so ...

salt Salt is a mineral composed primarily of sodium chloride (NaCl), a chemical compound belonging to the larger class of salts; salt in the form of a natural crystalline mineral is known as rock salt or halite. Salt is present in vast quantitie ...

was capable of producing a

bactericidal A bactericide or bacteriocide, sometimes abbreviated Bcidal, is a substance which kills bacteria. Bactericides are disinfectants, antiseptics, or antibiotics. However, material surfaces can also have bactericidal properties based solely on their ...

filtrate Filtration is a physical separation process that separates solid matter and fluid from a mixture using a ''filter medium'' that has a complex structure through which only the fluid can pass. Solid particles that cannot pass through the filter m ...

. It has also been shown to be a bactericidal for some Gram-negative as well as Gram-positive bacteria. Over the next few years they worked off this discovery and succeeded to isolate the active material in the crystalline form. In 1943 they managed to isolate this antibiotic compound and called it aspergillic acid primarily because of its origin and

acidic In computer science, ACID ( atomicity, consistency, isolation, durability) is a set of properties of database transactions intended to guarantee data validity despite errors, power failures, and other mishaps. In the context of databases, a sequ ...

properties. Scientists have since been working with the ''Aspergillus flavus'' strain to produce various types of

antibacterial An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting bacterial infections, and antibiotic medications are widely used in the treatment and prevention of ...

substances.

Structure

The structure of aspergillic acid was made by Dutcher and Spring and his co-workers. They suggested that it is a cyclic hydroxamic acid related to

pyridine Pyridine is a basic heterocyclic organic compound with the chemical formula . It is structurally related to benzene, with one methine group replaced by a nitrogen atom. It is a highly flammable, weakly alkaline, water-miscible liquid with a d ...

. It can be reduced to a neutral deoxyaspergillic acid, which is a

racemization In chemistry, racemization is a conversion, by heat or by chemical reaction, of an optically active compound into a racemic (optically inactive) form. This creates a 1:1 molar ratio of enantiomers and is referred too as a racemic mixture (i.e. con ...

product found by Newbold, et al. to be identical with 3-isobutyl-6-sec-butyl-2-hydroxypyrazine. Because of this, aspergillic acid has been assigned the corresponding l-oxide or

tautomeric Tautomers () are structural isomers (constitutional isomers) of chemical compounds that readily interconvert. The chemical reaction interconverting the two is called tautomerization. This conversion commonly results from the relocation of a hyd ...

pyridine hydroxamic acid structure show below. Aspergillic acid analog

Toxicity

The toxicity of aspergillic acid is controlled by the hydroxamic acid functionality, and there is little effect on toxicity observed between the differences in the 3 and 6 position side chain substituents.

Chelation Chelation is a type of bonding of ions and molecules to metal ions. It involves the formation or presence of two or more separate coordinate bonds between a Denticity, polydentate (multiple bonded) ligand and a single central metal atom. These l ...

of physiologically important ions, such as

calcium Calcium is a chemical element with the symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar to ...

by aspergillic acid appears to be the likely mechanism of its toxic action.

Synthesis

Different ''

Aspergillus ' () is a genus consisting of several hundred mold species found in various climates worldwide. ''Aspergillus'' was first catalogued in 1729 by the Italian priest and biologist Pier Antonio Micheli. Viewing the fungi under a microscope, Miche ...

'' strains are capable of making various hydroxypyrazine

derivative In mathematics, the derivative of a function of a real variable measures the sensitivity to change of the function value (output value) with respect to a change in its argument (input value). Derivatives are a fundamental tool of calculus. F ...

s. ''Aspergillus flavus'' is used to produce an antibiotic substance called flavacol. Flavacol is then added to cultures of '' A. selerotiorum'' and is ''N''-hydroxylated into neoaspergillic acid. It is then

hydroxylated In chemistry, hydroxylation can refer to: *(i) most commonly, hydroxylation describes a chemistry, chemical process that introduces a hydroxyl group () into an organic compound. *(ii) the ''degree of hydroxylation'' refers to the number of OH gr ...

in the side-chain in order to make neohydroxyaspergillic acid Other studies show that aspergillic acid can also be derived from one molecule of L-leucine and one molecule of L-isoleucine in ''Aspergillus flavus''.

Reactions

When aspergillic acid reactions with

iron trichloride Iron(III) chloride is the inorganic compound with the formula . Also called ferric chloride, it is a common compound of iron in the +3 oxidation state. The anhydrous compound is a crystalline solid with a melting point of 307.6 °C. The colo ...

(FeCl₃), there is the formation of green cupric salt. This suggests that aspergillic acid is a hydroxamic acid derivative, which is also confirmed by the formation of deoxyaspergillic acid by

dry distillation Dry distillation is the heating of solid materials to produce gaseous products (which may condense into liquids or solids). The method may involve pyrolysis or thermolysis, or it may not (for instance, a simple mixture of ice and glass could be se ...

with

copper chromite Copper chromite is an inorganic compound with the formula Cu2Cr2O5. It is a black solid that is used to catalyze reactions in organic synthesis. History The material was first described in 1908. The catalyst was developed in North America by Home ...

catalyst Catalysis () is the process of increasing the rate of a chemical reaction by adding a substance known as a catalyst (). Catalysts are not consumed in the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recyc ...

. Bromination of aspergillic acid followed by reduction with

zinc Zinc is a chemical element with the symbol Zn and atomic number 30. Zinc is a slightly brittle metal at room temperature and has a shiny-greyish appearance when oxidation is removed. It is the first element in group 12 (IIB) of the periodi ...

and

acetic acid Acetic acid , systematically named ethanoic acid , is an acidic, colourless liquid and organic compound with the chemical formula (also written as , , or ). Vinegar is at least 4% acetic acid by volume, making acetic acid the main component ...

gives a

diketopiperazine A diketopiperazine (DKP), also known as a ''dioxopiperazine'' or ''piperazinedione'', is a class of organic compounds related to piperazine but containing two amide linkages. DKP's are the smallest known class of cyclic peptide. Despite their name, ...

Hydrolysis Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution reaction, substitution, elimination reaction, elimination, and solvation reactions in which water ...

with HBr yields a mixture of DL-leucine and DL-isoleucine. These reaction schemes can be seen below: Aspergillic acid reactions 2

References

{{reflist Antibiotics Organic acids Conjugated ketones Pyrazines