Pulvinone, an

organic compound In chemistry, organic compounds are generally any chemical compounds that contain carbon-hydrogen or carbon-carbon bonds. Due to carbon's ability to catenate (form chains with other carbon atoms), millions of organic compounds are known. The ...

belonging to the

ester In chemistry, an ester is a compound derived from an oxoacid (organic or inorganic) in which at least one hydroxyl group () is replaced by an alkoxy group (), as in the substitution reaction of a carboxylic acid and an alcohol. Glycerides ar ...

lactone Lactones are cyclic carboxylic esters, containing a 1-oxacycloalkan-2-one structure (), or analogues having unsaturation or heteroatoms replacing one or more carbon atoms of the ring. Lactones are formed by intramolecular esterification of the co ...

alcohol Alcohol most commonly refers to: * Alcohol (chemistry), an organic compound in which a hydroxyl group is bound to a carbon atom * Alcohol (drug), an intoxicant found in alcoholic drinks Alcohol may also refer to: Chemicals * Ethanol, one of sev ...

s and

butenolide Butenolides are a class of lactones with a four-carbon heterocyclic ring structure.Joule JA, Mills K. (2000). Heterocyclic Chemistry 4th ed. Blackwell Science Publishing: Oxford, UK They are sometimes considered oxidized derivatives of furan. The ...

s classes, is a yellow crystalline

solid Solid is one of the State of matter#Four fundamental states, four fundamental states of matter (the others being liquid, gas, and Plasma (physics), plasma). The molecules in a solid are closely packed together and contain the least amount o ...

. Although the pulvinone is not a

natural product A natural product is a natural compound or substance produced by a living organism—that is, found in nature. In the broadest sense, natural products include any substance produced by life. Natural products can also be prepared by chemical syn ...

, several naturally occurring hydroxylated

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 are known. These hydroxylated pulvinones are produced by

fungal A fungus ( : fungi or funguses) is any member of the group of eukaryotic organisms that includes microorganisms such as yeasts and molds, as well as the more familiar mushrooms. These organisms are classified as a kingdom, separately from th ...

species, such as the in Europe common

Larch Bolete The name larch bolete is used to describe a number of fungi in the order Boletales which occur in association with species of larch, conifers in the genus ''Larix''. These fungi include: *members of the genus ''Suillus'': **''Suillus cavipes, S. ...

(''Boletus elegans'', also known as ''

Suillus ''Suillus'' is a genus of basidiomycete fungi in the family Suillaceae and order Boletales. Species in the genus are associated with trees in the pine family (Pinaceae), and are mostly distributed in temperate locations in the Northern Hemispher ...

grevillei''), or by moulds such as ''

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 ...

terreus''.

History

Fungi A fungus ( : fungi or funguses) is any member of the group of eukaryotic organisms that includes microorganisms such as yeasts and molds, as well as the more familiar mushrooms. These organisms are classified as a kingdom, separately from ...

(such as boleti), moulds and

lichen A lichen ( , ) is a composite organism that arises from algae or cyanobacteria living among filaments of multiple fungi species in a mutualistic relationship.monomer In chemistry, a monomer ( ; ''mono-'', "one" + '' -mer'', "part") is a molecule that can react together with other monomer molecules to form a larger polymer chain or three-dimensional network in a process called polymerization. Classification Mo ...

) or several (

oligomers In chemistry and biochemistry, an oligomer () is a molecule that consists of a few repeating units which could be derived, actually or conceptually, from smaller molecules, monomers.Quote: ''Oligomer molecule: A molecule of intermediate relative ...

) units of

pulvinic acid Pulvinic acids are natural chemical pigments found in some lichens, derived biosynthetically from the aromatic amino acids phenylalanine and tyrosine, via dimerization and oxidative ring-cleavage of aryl pyruvic acids, a process that also produ ...

. In 1831, in the course of a study of the constituents of lichens (''Cetraria Vulpina''), the French chemist and pharmacist Antoine Bebert discovered a compound named ''vulpinic acid'', the first known naturally occurring methyl ester of pulvinic acid. More details about the structure of this pigment were disclosed in 1860 by the German chemists

Franz Möller Franz may refer to: People * Franz (given name) * Franz (surname) Places * Franz (crater), a lunar crater * Franz, Ontario, a railway junction and unorganized town in Canada * Franz Lake, in the state of Washington, United States – see Fran ...

and

Adolph Strecker Adolph Strecker (October 21, 1822 – November 7, 1871) was a German chemist who is remembered primarily for his work with amino acids. Life and work Strecker was born in Darmstadt, the son of Friedrich Ludwig Strecker, an archivist working fo ...

.''Canstatt's Jahresbericht über die Fortschritte in der Pharmacie und verwandte Wissenschaften in allen Ländern'', Harvard Universität, Jahrgang 10 (1861). While trying to elucidate the structure of vulpinic acid, the German chemist Adolf SpiegelA. Spiegel, ''Ber. Dtsch. Chem. Ges.'' 1880, ''13'', 2, 1629-1635 .A. Spiegel, ''Ber. Dtsch. Chem. Ges.'' 1880, ''13'', 2, 2219-2221 .A. Spiegel, ''Ber. Dtsch. Chem. Ges.'' 1881, ''14'', 1, 873-874 .A. Spiegel, ''Ber. Dtsch. Chem. Ges.'' 1881, ''14'', 2, 1686-1696 . found in 1880 that the

vulpinic acid Vulpinic acid is a natural product first found in and important in the symbiosis underlying the biology of lichens. It is a simple methyl ester derivative of its parent compound, pulvinic acid, and a close relative of pulvinone, both of which de ...

could be saponified to a diacid. He named the resulting diacid

. The German chemist

Jacob Volhard Jacob Volhard (4 June 1834 – 14 January 1910) was the German chemist who discovered, together with his student Hugo Erdmann, the Volhard–Erdmann cyclization reaction. He was also responsible for the improvement of the Hell–Volhard–Zel ...

J. Volhard, ''Annal. Chem.'' 1894, ''282'', 1-21 . elucidated the constitution of pulvinic acid by synthesizing it through the basic hydrolysis of a corresponding dicyanocompound. In the process, he also obtained small amounts of a side-product. One year later

Ludwig Claisen Rainer Ludwig Claisen (; 14 January 1851 – 5 January 1930) was a German chemist best known for his work with condensations of carbonyls and sigmatropic rearrangements. He was born in Cologne as the son of a jurist and studied chemistry at the u ...

and Thomas EwanL. Claisen, Th. Ewan, ''Annal. Chem.'', 1895, ''284'', 245-299 . achieved the synthesis of this side-product and characterized it as the 5-benzylidene-4-hydroxy-3-phenylfuran-2(5H)-one. Claisen and Ewan described it as ''das der Pulvinsäure zu Grunde liegende Lacton'' (the lactone underlying the structure of pulvinic acid): that was the origin of the name pulvinone.

Natural occurrence

It was a century after the synthesis of the first pulvinone that the word ''pulvinone'' turned into a collective term. In 1973, Edwards and Gill isolated the first naturally occurring hydroxylated pulvinone derivative.R. L. Edwards, M. Gill, ''J. Chem. Soc., Perkin Trans. 1'' 1973, 1921-1929. . This trihydroxylated pulvinone was found as one of the main pigments responsible for the yellow colour of the stem and caps of the European mushroom

(''Boletus elegans'', also known as ''

Suillus grevillei ''Suillus grevillei'' ( commonly known as Greville's bolete and larch bolete) is a mycorrhizal mushroom with a tight, brilliantly coloured cap, shiny and wet looking with its mucous slime layer. The hymenium easily separates from the flesh of t ...

''). In the very same year 1973, Seto and coworkers also found hydroxylated pulvinones in cultures of the mould

Aspergillus terreus ''Aspergillus terreus'', also known as ''Aspergillus terrestris'', is a fungus (mold) found worldwide in soil. Although thought to be strictly asexual until recently, ''A. terreus'' is now known to be capable of sexual reproduction. This saprotr ...

.N. Ojima, S. Takenaka, S. Seto, ''Phytochemistry (

Elsevier Elsevier () is a Dutch academic publishing company specializing in scientific, technical, and medical content. Its products include journals such as ''The Lancet'', ''Cell'', the ScienceDirect collection of electronic journals, '' Trends'', th ...

)'' 1973, ''12'', 2527-2529.N. Ojima, K. Ogura, S. Seto, ''J. Chem. Soc., Chem. Commun.'' 1975, 717-718.N. Ojima, S. Takenaka, S. Seto, ''Phytochemistry (

)'' 1975, ''14'', 573-576. To insist on their origin - and thereby differentiate them from the hydroxylated pulvinones found in ''

'' - Seto and coworkers named these compounds ''Aspulvinones''.N. Ojima, I. Takahashi, K. Ogura, S. Seto, ''Tetrahedron Lett.'' 1976, ''17'', 1013-1014.I. Takahashi, N. Ojima, K. Ogura, S. Seto, ''Biochemistry'' 1978, ''17'', 2696-2702.M. Kobayashi, N. Ojima, K. Ogura, S. Seto, ''Chem. Lett.'' 1979, 579-582.H. Sugiyama, N. Ojima, M. Kobayashi, Y. Senda, J. Ishiyama, S. Seto, ''Agric. Biol. Chem.'' 1979, ''43'', 403-4. The ''aspulvinone'' terminology also incorporates a letter, indicating the order of chromatographic elution of these compounds (hence, the least polar aspulvinone was named Aspulvinone A, the one eluting next Aspulvinone B, etc...). Like many other yellow pigments in fungi and lichens, pulvinones can be traced back from the pulvinic acid pathway. The ''pulvinone'' structural unit is found in a number of natural products. All monomeric (such as ''pulvinic acid'' itself, ''vulpinic acid'', ''comphidic acid'', the ''aspulvinones'' and the ''Kodaistatins''L. Vértesy, H.-J. Burger, J. Kenja, M. Knauf, H. Kogler, E. F. Paulus, N. V. S. Ramakrishna, K. H. S. Swamy, E. K. S. Vijayakumar, P. Hammann, ''J. Antibiot.'' 2000, ''53'', 677-686.) or oligomeric (''Badiones'',B. Steffan, W. Steglich, ''Angew. Chem. Int. Ed.'' 1984, 23, 6, 445-447. . ''Norbadione'',M. Gill, D. A. Lally, ''Phytochemistry'' 1985, ''24'', 1351-1354. .T. Le Gall, C. Mioskowski, B. Amekraz ''et al.'' ''Angew. Chem. Int. Ed.'' 2003, 42, 11, 1289-1293. . ''Aurantricholon''D. Klostermeyer, L. Knops, T. Sindlinger, K. Polborn, W. Steglich ''Eur. J. Org. Chem.'' 2000, 4, 603-609. .) derivatives of the pulvinic acid contain the ''pulvinone'' structural element. So far, all naturally occurring pulvinone derivatives were found to be ''Z''-configured.

Pharmacological properties

* Rehse ''et al.''K. Rehse, J. Wagenknecht, N. Rietbrock, ''Arch. Pharm. (Weinheim, Ger.)'' 1978, ''311'', 986-991.K. Rehse, U. Emisch, ''Arch. Pharm. (Weinheim, Ger.)'' 1982, ''315'', 1020-1025.K. Rehse, J. Schinke, G. Bochert, ''Arch. Pharm. (Weinheim, Ger.)'' 1979, ''312'', 390-394.K. Rehse, J. Lehmke, ''Arch. Pharm. (Weinheim, Ger.)'' 1985, ''318'', 11-14. showed the anti-coagulant activity of some pulvinones in rats. * At the beginning of the 80s, the companies ICI and Smith Kline & French patented a large number of derivatives of the vulpinic acid because of their anti-inflammatory, anti-fever and pain-killing properties. Yet vulpinic acid - as well as many of its derivatives - is a

cytotoxic Cytotoxicity is the quality of being toxic to cells. Examples of toxic agents are an immune cell or some types of venom, e.g. from the puff adder (''Bitis arietans'') or brown recluse spider (''Loxosceles reclusa''). Cell physiology Treating cells ...

compound. Since pulvinones exhibit a lower cytotoxicity compared to vulpinic acid and its derivatives,

Organon The ''Organon'' ( grc, Ὄργανον, meaning "instrument, tool, organ") is the standard collection of Aristotle's six works on logical analysis and dialectic. The name ''Organon'' was given by Aristotle's followers, the Peripatetics. The si ...

investigated the pharmaceutical potential of more than 100 pulvinones.A. C. Campbell, M. S. Maidment, J. H. Pick, D. F. M. Stevenson, ''J. Chem. Soc., Perkin Trans. 1'' 1985, 1567-1576. . To date, the results of these studies were not fully disclosed. * In 2005, the

Wyeth Wyeth, LLC was an American pharmaceutical company. The company was founded in Philadelphia, Pennsylvania, in 1860 as ''John Wyeth and Brother''. It was later known, in the early 1930s, as American Home Products, before being renamed to Wyeth in ...

company patented biphenyl-substituted pulvinonesC. E. Caufield, S. A. Antane, K. M. Morris, S. M. Naughton, D. A. Quagliato, P. M. Andrae, A. Enos, J. F. Chiarello, J. (Wyeth, and Brother Ltd., USA), ''WO 2005019196'', ''US 2005054721'', 2005.S. A. Antane, C. E. Caufield, W. Hu, D. Keeney, P. Labthavikul, K. M. Morris, S. M. Naughton, P. J. Petersen, B. A. Rasmussen, G. Singh, Y. Yang, ''Bioorg. Med. Chem. Lett.'' 2006, 176-180. . due to their promising activity against Gram-positive bacteria, including otherwise resistant bacteria. However, pulvinone-based antibiotics were so far only patented for animal use.

Chemical properties

Pulvinone is a

, more precisely an intramolecular ester of the ''trans-1,4-diphenyl-2,3-dihydroxy-1,3-butadiene-1-carboxylic acid'', from which it can be prepared through removal of one

equivalent Equivalence or Equivalent may refer to: Arts and entertainment *Album-equivalent unit, a measurement unit in the music industry *Equivalence class (music) *''Equivalent VIII'', or ''The Bricks'', a minimalist sculpture by Carl Andre *''Equivale ...

of water: The central 5-membered ring core of pulvinone reveals a 4-hydroxy-

structure. They are essentially found in their

enol In organic chemistry, alkenols (shortened to enols) are a type of reactive structure or intermediate in organic chemistry that is represented as an alkene ( olefin) with a hydroxyl group attached to one end of the alkene double bond (). The te ...

form, which exhibits acidic properties due to the relative lability of the hydroxylic proton. 4-hydroxy-

s such as pulvinones are therefore referred to as tetronic acids, and belong to the larger category of

vinylogous In organic chemistry, vinylogy is the transmission of electronic effects through a conjugated organic bonding system. The concept was introduced in 1926 by Ludwig Claisen to explain the acidic properties of formylacetone and related ketoaldehyde ...

acids.

Biosynthesis

The fungal biosynthesis starts from aromatic aminoacids such as

phenylalanine Phenylalanine (symbol Phe or F) is an essential α-amino acid with the formula . It can be viewed as a benzyl group substituted for the methyl group of alanine, or a phenyl group in place of a terminal hydrogen of alanine. This essential amino a ...

and

tyrosine -Tyrosine or tyrosine (symbol Tyr or Y) or 4-hydroxyphenylalanine is one of the 20 standard amino acids that are used by cells to synthesize proteins. It is a non-essential amino acid with a polar side group. The word "tyrosine" is from the Gr ...

; after oxydeamination to the corresponding arylpyruvic acid, the pulvinone skeleton is formed by a sequence of dimerisation, oxidative ring-cleavage and decarboxylation.

Total synthesis

was the first to synthesise vulpinic acid, pulvinic acid and pulvinone. To date, 11

total syntheses Total synthesis is the complete chemical synthesis of a complex molecule, often a natural product, from simple, commercially-available precursors. It usually refers to a process not involving the aid of biological processes, which distinguishes ...

of pulvinones were reported: * 1895 by Claisen and Ewan, * 1975 and 1979 by Knight and Pattenden,D. W. Knight, G. Pattenden, ''J. Chem. Soc., Chem. Commun.'' 1975, 876-877 .D. W. Knight, G. Pattenden, ''J. Chem. Soc., Perkin Trans. 1'' 1979, 70-76 . * 1979 by Jerris, Wovkulich and Amos B. Smith III,P. J. Jerris, P. M. Wovkulich, A. B. Smith III, ''Tetrahedron Lett.'' 1979, 20, 4517-20 . * 1984 by Ramage ''et al.'', * 1985 by Campbell ''et al.'', * 1990 by Gill ''et al.'',M. Gill, M. J. Kiefel, D. A. Lally, A. Ten, ''Aust. J. Chem.'' 1990, ''43'', 1497-518. * 1991 by Pattenden, Turvill and Chorlton,G. Pattenden, M. W. Turvill, A. P. Chorlton, ''J. Chem. Soc., Perkin Trans. 1'' 1991, ''10'', 2357-2361. . * 2005 by Caufield ''et al.'', * 2006 by Antane ''et al.'', * 2007 by Kaczybura and Brückner,N. Kaczybura, R. Brückner ''Synthesis'' 2007, 118-130. . * 2007 by Bernier, Moser and Brückner.D. Bernier, F. Moser, R. Brückner ''Synthesis'' 2007, 15, 2240-2248. .D. Bernier, R. Brückner ''Synthesis'' 2007, 15, 2249-2272. .

Sources

{{Analgesics Enols Anticoagulants Antibiotics Analgesics Furanones Phenyl compounds