Flavonoid

File:2-Phenyl-1,4-benzopyrone.svg

Molecular structure of the flavone backbone (2-phenyl-1,4-benzopyrone)

Isoflavan structure

Neoflavonoids structure

Flavonoids (or bioflavonoids) (from the Latin word flavus meaning yellow, their color in nature) are a class of plant and fungus secondary metabolites.

Chemically, they have the general structure of a 15-carbon skeleton, which consists of two phenyl rings (A and B) and heterocyclic ring (C). This carbon structure can be abbreviated C6-C3-C6. According to the IUPAC nomenclature, they can be classified into:

• flavonoids or bioflavonoids
• isoflavonoids, derived from 3-phenylchromen-4-one (3-phenyl-1,4-benzopyrone) structure
• neoflavonoids, derived from 4-phenylcoumarine (4-phenyl-1,2-benzopyrone) structure

The three flavonoid classes above are all ketone-containing compounds, and as such, are anthoxanthins (flavones and flavonols). This class was the first to be termed bioflavonoids. The terms flavonoid and bioflavonoid have also been more loosely used to describe non-ketone polyhydroxy polyphenol compounds which are more specifically termed flavanoids. The three cycle or heterocycles in the flavonoid backbone are generally called ring A, B and C. Ring A usually shows a phloroglucinol substitution pattern.

Biosynthesis

Main article: Flavonoid biosynthesis

Functions of flavonoids in plants

Flavonoids are widely distributed in plants, fulfilling many functions. Flavonoids are the most important plant pigments for flower coloration, producing yellow or red/blue pigmentation in petals designed to attract pollinator animals. In higher plants, flavonoids are involved in UV filtration, symbiotic nitrogen fixation and floral pigmentation. They may also act as chemical messengers, physiological regulators, and cell cycle inhibitors. Flavonoids secreted by the root of their host plant help Rhizobia in the infection stage of their symbiotic relationship with legumes like peas, beans, clover, and soy. Rhizobia living in soil are able to sense the flavonoids and this triggers the secretion of Nod factors, which in turn are recognized by the host plant and can lead to root hair deformation and several cellular responses such as ion fluxes and the formation of a root nodule. In addition, some flavonoids have inhibitory activity against organisms that cause plant diseases, e.g. Fusarium oxysporum.

Subgroups

Over 5000 naturally occurring flavonoids have been characterized from various plants. They have been classified according to their chemical structure, and are usually subdivided into the following subgroups (for further reading see ):

Anthoxanthins

Anthoxanthins are divided into two groups:

Group	Skeleton				Examples
	Description	Functional groups		Structural formula
		3-hydroxyl	2,3-dihydro
Flavone	2-phenylchromen-4-one	✗	✗		Luteolin, Apigenin, Tangeritin
Flavonol or 3-hydroxyflavone	3-hydroxy-2-phenylchromen-4-one	✓	✗		Quercetin, Kaempferol, Myricetin, Fisetin, Galangin, Isorhamnetin, Pachypodol, Rhamnazin, Pyranoflavonols, Furanoflavonols,

Flavanones

Flavanones

Group	Skeleton				Examples
	Description	Functional groups		Structural formula
		3-hydroxyl	2,3-dihydro
Flavanone	2,3-dihydro-2-phenylchromen-4-one	✗	✓		Hesperetin, Naringenin, Eriodictyol, Homoeriodictyol

Flavanonols

Flavanonols

Group	Skeleton				Examples
	Description	Functional groups		Structural formula
		3-hydroxyl	2,3-dihydro
Flavanonol or 3-Hydroxyflavanone or 2,3-dihydroflavonol	3-hydroxy-2,3-dihydro-2-phenylchromen-4-one	✓	✓		Taxifolin (or Dihydroquercetin), Dihydrokaempferol

Flavans

Flavan structure

Include flavan-3-ols (flavanols), flavan-4-ols and flavan-3,4-diols.

Skeleton	Name
	Flavan-3-ol (flavanol)
	Flavan-4-ol
	Flavan-3,4-diol (leucoanthocyanidin)

• Flavan-3-ols (flavanols)
  • Flavan-3-ols use the 2-phenyl-3,4-dihydro-2H-chromen-3-ol skeleton

  Examples: Catechin (C), Gallocatechin (GC), Catechin 3-gallate (Cg), Gallocatechin 3-gallate (GCg)), Epicatechins (Epicatechin (EC)), Epigallocatechin (EGC), Epicatechin 3-gallate (ECg), Epigallocatechin 3-gallate (EGCg)

  • Theaflavin

  Examples: Theaflavin-3-gallate, Theaflavin-3'-gallate, Theaflavin-3,3'-digallate

  • Thearubigin
  • Proanthocyanidins are dimers, trimers, oligomers, or polymers of the flavanols

Anthocyanidins

Flavylium skeleton of anthocyanidins

• Anthocyanidins

  Anthocyanidins are the aglycones of anthocyanins; they use the flavylium (2-phenylchromenylium) ion skeleton

  Examples: Cyanidin, Delphinidin, Malvidin, Pelargonidin, Peonidin, Petunidin

Isoflavonoids

• Isoflavonoids
  • Isoflavones use the 3-phenylchromen-4-one skeleton (with no hydroxyl group substitution on carbon at position 2)

  Examples: Genistein, Daidzein, Glycitein

  • Isoflavanes
  • Isoflavandiols
  • Isoflavenes
  • Coumestans
  • Pterocarpans

Dietary sources

Parsley is a source of flavones.

Blueberries are a source of dietary anthocyanidins.

A variety of flavonoids are found in citrus fruits, including grapefruit.

Flavonoids (specifically flavanoids such as the catechins) are "the most common group of polyphenolic compounds in the human diet and are found ubiquitously in plants". Flavonols, the original bioflavonoids such as quercetin, are also found ubiquitously, but in lesser quantities. The widespread distribution of flavonoids, their variety and their relatively low toxicity compared to other active plant compounds (for instance alkaloids) mean that many animals, including humans, ingest significant quantities in their diet. Foods with a high flavonoid content include parsley, onions, blueberries and other berries, black tea, green tea and oolong tea, bananas, all citrus fruits, Ginkgo biloba, red wine, sea-buckthorns, and dark chocolate (with a cocoa content of 70% or greater). Further information on dietary sources of flavonoids can be obtained from the US Department of Agriculture flavonoid database.

Parsley

Parsley, both fresh and dried, contains flavones.

Blueberries

Blueberries are a dietary source of anthocyanidins.

Black tea

Black tea is a rich source of dietary flavan-3-ols.

Citrus

The citrus flavonoids include hesperidin (a glycoside of the flavanone hesperetin), quercitrin, rutin (two glycosides of the flavonol quercetin), and the flavone tangeritin.

Wine

Main article: Polyphenols in wine

Cocoa

Main article: Health effects of chocolate

Flavonoids exist naturally in cocoa, but because they can be bitter, they are often removed from chocolate, even dark chocolate. Although flavonoids are present in milk chocolate, milk may interfere with their absorption, although this conclusion has been questioned.

Peanut

Peanut (red) skin contains significant polyphenol content, including flavonoids.

Food source	Flavones	Flavonols	Flavanones
Red onion	0	4 - 100	0
Parsley, fresh	24 - 634	8 - 10	0
Thyme, fresh	56	0	0
Lemon juice, fresh	0	0 - 2	2 - 175

Research

Though there is ongoing research into the potential health benefits of individual flavonoids, neither the Food and Drug Administration (FDA) nor the European Food Safety Authority (EFSA) has approved any health claim for flavonoids or approved any flavonoids as pharmaceutical drugs. Moreover, several companies have been cautioned by the FDA over misleading health claims.

In vitro

Flavonoids have been shown to have a wide range of biological and pharmacological activities in in vitro studies. Examples include anti-allergic, anti-inflammatory, antioxidant, anti-microbial (antibacterial, antifungal, and antiviral), anti-cancer, and anti-diarrheal activities. Flavonoids have also been shown to inhibit topoisomerase enzymes and to induce DNA mutations in the mixed-lineage leukemia (MLL) gene in in vitro studies. However, in most of the above cases no follow up in vivo or clinical research has been performed, leaving it impossible to say if these activities have any beneficial or detrimental effect on human health. Biological and pharmacological activities which have been investigated in greater depth are described below.

Antioxidant

Research at the Linus Pauling Institute and the European Food Safety Authority shows that flavonoids are poorly absorbed in the human body (less than 5%), with most of what is absorbed being quickly metabolized and excreted. These findings suggest that flavonoids have negligible systemic antioxidant activity, and that the increase in antioxidant capacity of blood seen after consumption of flavonoid-rich foods is not caused directly by flavonoids, but is due to production of uric acid resulting from flavonoid depolymerization and excretion.

Inflammation

Inflammation has been implicated as a possible origin of numerous local and systemic diseases, such as cancer, cardiovascular disorders, diabetes mellitus, and celiac disease.

Preliminary studies indicate that flavonoids may affect anti-inflammatory mechanisms via their ability to inhibit reactive oxygen or nitrogen compounds. Flavonoids have also been proposed to inhibit the pro-inflammatory activity of enzymes involved in free radical production, such as cyclooxygenase, lipoxygenase or inducible nitric oxide synthase, and to modify intracellular signaling pathways in immune cells, or in brain cells after a stroke.

Procyanidins, a class of flavonoids, have been shown in preliminary research to have anti-inflammatory mechanisms including modulation of the arachidonic acid pathway, inhibition of gene transcription, protein expression and activity of inflammatory enzymes, as well as secretion of anti-inflammatory mediators.

Cancer

Clinical studies investigating the relationship between flavonoid consumption and cancer prevention/development are conflicting for most types of cancer, probably because most studies are retrospective in design and use a small sample size. Two apparent exceptions are gastric carcinoma and smoking-related cancers. Dietary flavonoid intake is associated with reduced gastric carcinoma risk in women, and reduced aerodigestive tract cancer risk in smokers.

Cardiovascular diseases

Among the most intensively studied of general human disorders possibly affected by dietary flavonoids, preliminary cardiovascular disease research has revealed the following mechanisms under investigation in patients or normal subjects:

• inhibit coagulation, thrombus formation or platelet aggregation
• reduce risk of atherosclerosis
• reduce arterial blood pressure and risk of hypertension
• reduce oxidative stress and related signaling pathways in blood vessel cells
• modify vascular inflammatory mechanisms
• improve endothelial and capillary function
• modify blood lipid levels
• regulate carbohydrate and glucose metabolism
• modify mechanisms of aging

Listed on the clinical trial registry of the US National Institutes of Health (November 2013) are 36 human studies completed or underway to study the dietary effects of plant flavonoids on cardiovascular diseases.

Antibacterial

Flavonoids have been shown to have (a) direct antibacterial activity, (b) synergistic activity with antibiotics, and (c) the ability to suppress bacterial virulence factors in numerous in vitro and a limited number of in vivo studies. Noteworthy among the in vivo studies is the finding that oral quercetin protects guinea pigs against the Group 1 carcinogen Helicobacter pylori. Researchers from the European Prospective Investigation into Cancer and Nutrition have speculated this may be one reason why dietary flavonoid intake is associated with reduced gastric carcinoma risk in European women. Additional in vivo and clinical research is needed to determine if flavonoids could be used as pharmaceutical drugs for the treatment of bacterial infection, or whether dietary flavonoid intake offers any protection against infection.

Synthesis, detection, quantification, and semi-synthetic alterations

Availability through microorganisms

Several recent research articles have demonstrated the efficient production of flavonoid molecules from genetically engineered microorganisms.

Tests for detection

Shinoda test

Four pieces of magnesium fillings are added to the ethanolic extract followed by few drops of concentrated hydrochloric acid. A pink or red colour indicates the presence of flavonoid. Colours varying from orange to red indicated flavones, red to crimson indicated flavonoids, crimson to magenta indicated flavonones.

Sodium hydroxide test

About 5 mg of the compound is dissolved in water, warmed and filtered. 10% aqueous sodium hydroxide is added to 2 ml of this solution. This produces a yellow coloration. A change in color from yellow to colorless on addition of dilute hydrochloric acid is an indication for the presence of flavonoids.

p-Dimethylaminocinnamaldehyde test

A colorimetric assay based upon the reaction of A-rings with the chromogen p-dimethylaminocinnamaldehyde (DMACA) has been developed for flavanoids in beer that can be compared with the vanillin procedure.

Quantification

Lamaison and Carnet have designed a test for the determination of the total flavonoid content of a sample (AlCI₃ method). After proper mixing of the sample and the reagent, the mixture is incubated for 10 minutes at ambient temperature and the absorbance of the solution is read at 440 nm. Flavonoid content is expressed in mg/g of quercetin.

Semi-synthetic alterations

Immobilized Candida antarctica lipase can be used to catalyze the regioselective acylation of flavonoids.

See also

• Phytochemical
• List of antioxidants in food
• List of phytochemicals in food
• Phytochemistry
• Secondary metabolites
• Homoisoflavonoids, related chemicals with a 16 carbons skeleton

Further reading

• Andersen, Ø.M. / Markham, K.R. (2006). Flavonoids: Chemistry, Biochemistry and Applications. CRC Press. ISBN 978-0-8493-2021-7
• Grotewold, Erich (2007). The Science of Flavonoids. Springer. ISBN 978-0-387-74550-3
• Comparative Biochemistry of the Flavonoids, by J.B. Harborne, 1967 (Google Books)
• The systematic identification of flavonoids, by T.J. Mabry, K.R. Markham and M.B. Thomas, 1970, doi:10.1016/0022-2860(71)87109-0

External links

• Micronutrient Information Center – Flavonoids, Linus Pauling Institute, Oregon State University, Corvallis, 2015

Databases

• USDA Database for the Flavonoid Content of Selected Foods, Release 3.1 (December 2013); data for 506 foods in the 5 subclasses of flavonoids provided in a separate PDF updated May 2014

1. REDIRECT Template:Phenylpropanoid