Flavones

Last updated May 17, 2024

Flavones (from Latin flavus "yellow") are a class of flavonoids based on the backbone of 2-phenylchromen-4-one (2-phenyl-1-benzopyran-4-one) (as shown in the first image of this article).^[1]^[2]

Flavones are common in foods, mainly from spices, and some yellow or orange fruits and vegetables.^[1] Common flavones include apigenin (4',5,7-trihydroxyflavone), luteolin (3',4',5,7-tetrahydroxyflavone), tangeritin (4',5,6,7,8-pentamethoxyflavone), chrysin (5,7-dihydroxyflavone), and 6-hydroxyflavone.^[1]

Intake and elimination

The estimated daily intake of flavones is about 2 mg per day.^[1] Following ingestion and metabolism, flavones, other polyphenols, and their metabolites are absorbed poorly in body organs and are rapidly excreted in the urine, indicating mechanisms influencing their presumed absence of metabolic roles in the body.^[1]^[3]

Drug interactions

Flavones have effects on CYP (P450) activity,^[4]^[5] which are enzymes that metabolize most drugs in the body.

Biosynthesis

The biosynthesis of flavones proceeds from the phenylpropanoid pathway, which uses L-phenylalanine as a starting point.^[6] Phenylalanine ammonia lyase facilitates the deamination of L-phenylalanine to (E)-cinnamate,^[6] which is then oxidized by cinnamate 4-hydroxylase to yield p-Coumaric acid.^[7] Coenzyme A is attached to the carboxylate facilitated by 4-Coumarate-CoA ligase, forming (Coumaroyl-CoA).^[6] A chalcone synthase then facilitates a series of condensation reactions in the presence of 3 malonyl CoA ending with a ring-forming Claisen condensation yielding a chalcone (naringenin chalcone is shown), ^[8] which is subsequently isomerized by chalcone isomerase resulting in a flavanone (naringenin is shown).^[9] It is at this point that the flavanone can undergo further modifications (such as glycosylation or methylation at the various points of the backbone. The subsequent modified flavanones are then transformed into flavones by flavone synthase, which generates a double bond between the C-2 and C-3 positions (the synthesis of apigenin is shown).^[10]

Organic chemistry

In organic chemistry several methods exist for the synthesis of flavones:

Another method is the dehydrative cyclization of certain 1,3-diaryl diketones.^[11]

Wessely–Moser rearrangement

The Wessely–Moser rearrangement (1930)^[12] has been an important tool in structure elucidation of flavonoids. It involves the conversion of 5,7,8-trimethoxyflavone into 5,6,7-trihydroxyflavone on hydrolysis of the methoxy groups to phenol groups. It also has synthetic potential for example:^[13]

This rearrangement reaction takes place in several steps: A ring opening to the diketone, B bond rotation with formation of a favorable acetylacetone-like phenyl-ketone interaction and C hydrolysis of two methoxy groups and ring closure.

Common flavones

Flavones and their structure ^[14]
Name	Structure	R³	R⁵	R⁶	R⁷	R⁸	R^2'	R^3'	R^4'	R^5'	R^6'
Flavone backbone		–	–	–	–	–	–	–	–	–	–
Primuletin		–	–OH	–	–	–	–	–	–	–	–
Chrysin		–	–OH	–	–OH	–	–	–	–	–	–
Tectochrysin		–	–OH	–	–OCH₃	–	–	–	–	–	–
Primetin		–	–OH	–	–	–OH	–	–	–	–	–
Apigenin		–	–OH	–	–OH	–	–	–	–OH	–	–
Acacetin		–	–OH	–	–OH	–	–	–	–OCH₃	–	–
Genkwanin		–	–OH	–	–OCH₃	–	–	–	–OH	–	–
Echioidinin		–	–OH	–	–OCH₃	–	–OH	–	–	–	–
Baicalein		–	–OH	–OH	–OH	–	–	–	–	–	–
Oroxylin A		–	–OH	–OCH₃	–OH	–	–	–	–	–	–
Negletein		–	–OH	–OH	–OCH₃	–	–	–	–	–	–
Norwogonin		–	–OH	–	–OH	–OH	–	–	–	–	–
Wogonin		–	–OH	–	–OH	–OCH₃	–	–	–	–	–
Liquiritigenin ^[15]		–	–	–	–OH	–	–	–	–OH	–	–
Naringenin ^[15]		–	–OH	–	–OH	–	–	–	–OH	–	–
Geraldone		–	–	–	–OH	–	–	–OCH₃	–OH	–	–
Tithonine		–	–	–	–OCH₃	–	–	–OH	–OCH₃	–	–
Luteolin		–	–OH	–	–OH	–	–	–OH	–OH	–	–
6-Hydroxyluteolin		–	–OH	–OH	–OH	–	–	–OH	–OH	–	–
Chrysoeriol		–	–OH	–	–OH	–	–	–OCH₃	–OH	–	–
Diosmetin		–	–OH	–	–OH	–	–	–OH	–OCH₃	–	–
Pilloin		–	–OH	–	–OCH₃	–	–	–OH	–OCH₃	–	–
Velutin		–	–OH	–	–OCH₃	–	–	–OCH₃	–OH	–	–
Norartocarpetin		–	–OH	–	–OH	–	–OH	–	–OH	–	–
Artocarpetin		–	–OH	–	–OCH₃	–	–OH	–	–OH	–	–
Scutellarein		–	–OH	–OH	–OH	–	–	–	–OH	–	–
Hispidulin		–	–OH	–OCH₃	–OH	–	–	–	–OH	–	–
Sorbifolin		–	–OH	–OH	–OCH₃	–	–	–	–OH	–	–
Pectolinarigenin		–	–OH	–OCH₃	–OH	–	–	–	–OCH₃	–	–
Cirsimaritin		–	–OH	–OCH₃	–OCH₃	–	–	–	–OH	–	–
Mikanin		–	–OH	–OCH₃	–OCH₃	–	–	–	–OCH₃	–	–
Isoscutellarein		–	–OH	–	–OH	–OH	–	–	–OH	–	–
Zapotinin		–	–OH	–OCH₃	–	–	–OCH₃	–	–	–	–OCH₃
Zapotin		–	–OCH₃	–OCH₃	–	–	–OCH₃	–	–	–	–OCH₃
Cerrosillin		–	–OCH₃	–OCH₃	–	–	–	–OCH₃	–	–OCH₃	–
Alnetin		–	–OH	–OCH₃	–OCH₃	–OCH₃	–	–	–	–	–
Tricetin		–	–OH	–	–OH	–	–	–OH	–OH	–OH	–
Tricin		–	–OH	–	–OH	–	–	–OCH₃	–OH	–OCH₃	–
Corymbosin		–	–OH	–	–OCH₃	–	–	–OCH₃	–OCH₃	–OCH₃	–
Nepetin		–	–OH	–OCH₃	–OH	–	–	–OH	–OH	–	–
Pedalitin		–	–OH	–OH	–OCH₃	–	–	–OH	–OH	–	–
Nodifloretin		–	–OH	–OH	–OH	–	–	–OCH₃	–OH	–	–
Jaceosidin		–	–OH	–OCH₃	–OH	–	–	–OCH₃	–OH	–	–
Cirsiliol		–	–OH	–OCH₃	–OCH₃	–	–	–OH	–OH	–	–
Eupatilin		–	–OH	–OCH₃	–OH	–	–	–OCH₃	–OCH₃	–	–
Cirsilineol		–	–OH	–OCH₃	–OCH₃	–	–	–OCH₃	–OH	–	–
Eupatorin		–	–OH	–OCH₃	–OCH₃	–	–	–	–OCH₃	–OH	–
Sinensetin		–	–OCH₃	–OCH₃	–OCH₃	–	–	–	–OCH₃	–OCH₃	–
Hypolaetin		–	–OH	–	–OH	–OH	–	–OH	–OH	–	–
Onopordin		–	–OH	–	–OH	–OCH₃	–	–OH	–OH	–	–
Wightin		–	–OH	–	–OCH₃	–OCH₃	–OCH₃	–OH	–	–	–
Nevadensin		–	–OH	–OCH₃	–OH	–OCH₃	–	–	–OCH₃	–	–
Xanthomicrol		–	–OH	–OCH₃	–OCH₃	–OCH₃	–	–	–OH	–	–
Tangeretin		–	–OCH₃	–OCH₃	–OCH₃	–OCH₃	–	–	–OCH₃	–	–
Serpyllin		–	–OH	–	–OCH₃	–OCH₃	–OCH₃	–OCH₃	–OCH₃	–	–
Sudachitin		–	–OH	–OCH₃	–OH	–OCH₃	–	–OCH₃	–OH	–	–
Acerosin		–	–OH	–OCH₃	–OH	–OCH₃	–	–OH	–OCH₃	–	–
Hymenoxin		–	–OH	–OCH₃	–OH	–OCH₃	–	–OCH₃	–OCH₃	–	–
Gardenin D		–	–OH	–OCH₃	–OCH₃	–OCH₃	–	–OH	–OCH₃	–	–
Nobiletin	–	–	–OCH₃	–OCH₃	–OCH₃	–OCH₃	–	–OCH₃	–OCH₃	–	–
Scaposin	–	–	–OH	–OCH₃	–OH	–OCH₃	–	–OCH₃	–OCH₃	–OH
Name	Structure	R³	R⁵	R⁶	R⁷	R⁸	R^2'	R^3'	R^4'	R^5'	R^6'

Research

In one preliminary 2021 study, flavone intake was associated with lower odds of subjective cognitive decline after adjustment for age, total energy intake, major nondietary factors, and specific dietary factors.^[16]

Related Research Articles

<span class="mw-page-title-main">Flavonoid</span> Class of plant and fungus secondary metabolites

Flavonoids are a class of polyphenolic secondary metabolites found in plants, and thus commonly consumed in the diets of humans.

Isoflavones are substituted derivatives of isoflavone, a type of naturally occurring isoflavonoids, many of which act as phytoestrogens in mammals. Isoflavones are produced almost exclusively by the members of the bean family, Fabaceae (Leguminosae).

<span class="mw-page-title-main">Naringenin</span> Chemical compound

Naringenin is a flavanone from the flavonoid group of polyphenols. It is commonly found in citrus fruits, especially as the predominant flavonone in grapefruit.

Rutin is the glycoside combining the flavonol quercetin and the disaccharide rutinose. It is a flavonoid glycoside found in a wide variety of plants, including citrus.

<span class="mw-page-title-main">Cyanidin</span> Anthocyanidin pigment in flowering plant petals and fruits

Cyanidin is a natural organic compound. It is a particular type of anthocyanidin. It is a pigment found in many red berries including grapes, bilberry, blackberry, blueberry, cherry, chokeberry, cranberry, elderberry, hawthorn, loganberry, açai berry and raspberry. It can also be found in other fruits such as apples and plums, and in red cabbage and red onion. It has a characteristic reddish-purple color, though this can change with pH; solutions of the compound are red at pH < 3, violet at pH 7-8, and blue at pH > 11. In certain fruits, the highest concentrations of cyanidin are found in the seeds and skin. Cyanidin has been found to be a potent sirtuin 6 (SIRT6) activator.

Hesperidin is a flavanone glycoside found in citrus fruits. Its aglycone is hesperetin. Its name is derived from the word "hesperidium", for fruit produced by citrus trees.

<span class="mw-page-title-main">Apigenin</span> Chemical compound

Apigenin (4′,5,7-trihydroxyflavone), found in many plants, is a natural product belonging to the flavone class that is the aglycone of several naturally occurring glycosides. It is a yellow crystalline solid that has been used to dye wool.

<span class="mw-page-title-main">Kaempferol</span> Chemical compound

Kaempferol (3,4′,5,7-tetrahydroxyflavone) is a natural flavonol, a type of flavonoid, found in a variety of plants and plant-derived foods including kale, beans, tea, spinach, and broccoli. Kaempferol is a yellow crystalline solid with a melting point of 276–278 °C (529–532 °F). It is slightly soluble in water and highly soluble in hot ethanol, ethers, and DMSO. Kaempferol is named for 17th-century German naturalist Engelbert Kaempfer.

The phenylpropanoids are a diverse family of organic compounds that are biosynthesized by plants from the amino acids phenylalanine and tyrosine in the shikimic acid pathway. Their name is derived from the six-carbon, aromatic phenyl group and the three-carbon propene tail of coumaric acid, which is the central intermediate in phenylpropanoid biosynthesis. From 4-coumaroyl-CoA emanates the biosynthesis of myriad natural products including lignols, flavonoids, isoflavonoids, coumarins, aurones, stilbenes, catechin, and phenylpropanoids. The coumaroyl component is produced from cinnamic acid.

<span class="mw-page-title-main">Daidzein</span> Chemical compound

Daidzein is a naturally occurring compound found exclusively in soybeans and other legumes and structurally belongs to a class of compounds known as isoflavones. Daidzein and other isoflavones are produced in plants through the phenylpropanoid pathway of secondary metabolism and are used as signal carriers, and defense responses to pathogenic attacks. In humans, recent research has shown the viability of using daidzein in medicine for menopausal relief, osteoporosis, blood cholesterol, and lowering the risk of some hormone-related cancers, and heart disease. Despite the known health benefits, the use of both puerarin and daidzein is limited by their poor bioavailability and low water solubility.

The flavanones, a type of flavonoids, are various aromatic, colorless ketones derived from flavone that often occur in plants as glycosides.

Chalcone synthase or naringenin-chalcone synthase (CHS) is an enzyme ubiquitous to higher plants and belongs to a family of polyketide synthase enzymes (PKS) known as type III PKS. Type III PKSs are associated with the production of chalcones, a class of organic compounds found mainly in plants as natural defense mechanisms and as synthetic intermediates. CHS was the first type III PKS to be discovered. It is the first committed enzyme in flavonoid biosynthesis. The enzyme catalyzes the conversion of 4-coumaroyl-CoA and malonyl-CoA to naringenin chalcone.

Flavonoids are synthesized by the phenylpropanoid metabolic pathway in which the amino acid phenylalanine is used to produce 4-coumaroyl-CoA. This can be combined with malonyl-CoA to yield the true backbone of flavonoids, a group of compounds called chalcones, which contain two phenyl rings. Conjugate ring-closure of chalcones results in the familiar form of flavonoids, the three-ringed structure of a flavone. The metabolic pathway continues through a series of enzymatic modifications to yield flavanones → dihydroflavonols → anthocyanins. Along this pathway, many products can be formed, including the flavonols, flavan-3-ols, proanthocyanidins (tannins) and a host of other various polyphenolics.

<span class="mw-page-title-main">Tricin</span> Chemical compound

Tricin is a chemical compound. It is an O-methylated flavone, a type of flavonoid. It can be found in rice bran and sugarcane.

<span class="mw-page-title-main">Fisetin</span> Chemical compound

Fisetin (7,3′,4′-flavon-3-ol) is a plant flavonol from the flavonoid group of polyphenols. It can be found in many plants, where it serves as a yellow/ochre colouring agent. It is also found in many fruits and vegetables, such as strawberries, apples, persimmons, onions and cucumbers. Its chemical formula was first described by Austrian chemist Josef Herzig in 1891.

<span class="mw-page-title-main">Aurone</span> Chemical compound

An aurone is a heterocyclic chemical compound, which is a type of flavonoid. There are two isomers of the molecule, with (E)- and (Z)-configurations. The molecule contains a benzofuran element associated with a benzylidene linked in position 2. In aurone, a chalcone-like group is closed into a 5-membered ring instead of the 6-membered ring more typical of flavonoids.

Coumaroyl-coenzyme A is the thioester of coenzyme-A and coumaric acid. Coumaroyl-coenzyme A is a central intermediate in the biosynthesis of myriad natural products found in plants. These products include lignols, flavonoids, isoflavonoids, coumarins, aurones, stilbenes, catechin, and other phenylpropanoids.

<span class="mw-page-title-main">Xanthohumol</span> Chemical compound

Xanthohumol is a natural product found in the female inflorescences of Humulus lupulus, also known as hops. This compound is also found in beer and belongs to a class of compounds that contribute to the bitterness and flavor of hops. Xanthohumol is a prenylated chalconoid, biosynthesized by a type III polyketide synthase (PKS) and subsequent modifying enzymes.

<span class="mw-page-title-main">Chalconoid</span> Natural phenols related to chalcone

Chalconoids, also known as chalcones, are natural phenols derived from chalcone. They form the central core for a variety of important biological compounds.

The biosynthesis of phenylpropanoids involves a number of enzymes.

References

1 2 3 4 5 "Flavonoids". Micronutrient Information Center, Linus Pauling Institute, Oregon State University, Corvallis, OR. November 2015. Retrieved 30 March 2018.
↑ "Flavone". ChemSpider, Royal Society of Chemistry. 2015. Retrieved 30 March 2018.
↑ David Stauth (5 March 2007). "Studies force new view on biology of flavonoids". EurekAlert!; Adapted from a news release issued by Oregon State University.
↑ Cermak R, Wolffram S (Oct 2006). "The potential of flavonoids to influence drug metabolism and pharmacokinetics by local gastrointestinal mechanisms". Curr Drug Metab. 7 (7): 729–744. doi:10.2174/138920006778520570. PMID 17073577.
↑ Si D, Wang Y, Zhou YH, et al. (March 2009). "Mechanism of CYP2C9 inhibition by flavones and flavonols". Drug Metab. Dispos. 37 (3): 629–34. doi:10.1124/dmd.108.023416. PMID 19074529. S2CID 285706. Archived 2008-12-17 at the Wayback Machine
1 2 3 Ferrer JL, Austin MB (2008). "Structure and function of enzymes involved in the biosynthesis of phenylpropanoids". Plant Physiol. Biochem. 46 (3): 356–370. doi:10.1016/j.plaphy.2007.12.009. PMC 2860624 . PMID 18272377.
↑ Mizutani M, Ohta D, Sato R (1997). "Isolation of a cDNA and a genomic clone encoding cinnamate 4-hydroxylase from Arabidopsis and its expression manner in plants". Plant Physiology. 113 (3): 755–763. doi:10.1104/pp.113.3.755. PMC 158193 . PMID 9085571. S2CID 10059931.
↑ Ferrer JL, Jez JM (1999). "Structure of chalcone synthase and the molecular basis of plant polyketide biosynthesis". Nat. Struct. Biol. 6 (8): 775–784. doi:10.1038/11553. PMID 10426957. S2CID 23408591.
↑ Jez JM, Bowman ME (2000). "Structure and mechanism of the evolutionarily unique plany enzyme chalcone isomerase". Nat. Struct. Biol. 7 (9): 786–791. doi:10.1038/79025. PMID 10966651. S2CID 22198011.
↑ Martens S, Mithofer A (2005). "Flavones and flavone synthases". Phytochemistry. 66 (20): 2399–2407. doi:10.1016/j.phytochem.2005.07.013. PMID 16137727.
↑ Sarda SR, Pathan MY, Paike VV, Pachmase PR, Jadhav WN, Pawar RP (2006). "A facile synthesis of flavones using recyclable ionic liquid under microwave irradiation". Arkivoc . xvi (16): 43–8. doi: 10.3998/ark.5550190.0007.g05 . hdl: 2027/spo.5550190.0007.g05 .
↑ Wessely F, Moser GH (December 1930). "Synthese und Konstitution des Skutellareins". Monatshefte für Chemie. 56 (1): 97–105. doi:10.1007/BF02716040. S2CID 95833443.
↑ Larget R, Lockhart B, Renard P, Largeron M (April 2000). "A convenient extension of the Wessely-Moser rearrangement for the synthesis of substituted alkylaminoflavones as neuroprotective agents in vitro" (PDF). Bioorg. Med. Chem. Lett. 10 (8): 835–8. doi:10.1016/S0960-894X(00)00110-4. PMID 10782697.
↑ Harborne, Jeffrey B.; Marby, Helga; Marby, T. J. (1975). The Flavonoids - Springer. doi:10.1007/978-1-4899-2909-9. ISBN 978-0-12-324602-8. S2CID 33487001.
1 2 Dewick, Paul M. (2009). "The Shikimate Pathway: Aromatic Amino Acids and Phenylpropanoids". Medicinal Natural Products. A Biosynthetic Approach. Chichester, UK: John Wiley & Sons. pp. 137–186. doi:10.1002/9780470742761.ch4. ISBN 978-0-470-74276-1.
↑ Yeh, Tian-Shin; Yuan, Changzheng; Ascherio, Alberto; Rosner, Bernard A.; Willett, Walter C.; Blacker, Deborah (2021-09-07). "Long-term Dietary Flavonoid Intake and Subjective Cognitive Decline in US Men and Women". Neurology. 97 (10): e1041–e1056. doi: 10.1212/WNL.0000000000012454 . ISSN 0028-3878. PMC 8448553 . PMID 34321362.

External links

Flavones at the U.S. National Library of Medicine Medical Subject Headings (MeSH)

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[lpi-flav-1] 1 2 3 4 5 "Flavonoids". Micronutrient Information Center, Linus Pauling Institute, Oregon State University, Corvallis, OR. November 2015. Retrieved 30 March 2018.

[2] "Flavone". ChemSpider, Royal Society of Chemistry. 2015. Retrieved 30 March 2018.

[LPI-3] David Stauth (5 March 2007). "Studies force new view on biology of flavonoids". EurekAlert!; Adapted from a news release issued by Oregon State University.

[4] Cermak R, Wolffram S (Oct 2006). "The potential of flavonoids to influence drug metabolism and pharmacokinetics by local gastrointestinal mechanisms". Curr Drug Metab. 7 (7): 729–744. doi:10.2174/138920006778520570. PMID 17073577.

[5] Si D, Wang Y, Zhou YH, et al. (March 2009). "Mechanism of CYP2C9 inhibition by flavones and flavonols". Drug Metab. Dispos. 37 (3): 629–34. doi:10.1124/dmd.108.023416. PMID 19074529. S2CID 285706. Archived 2008-12-17 at the Wayback Machine

[Ferrer_Austin_2008-6] 1 2 3 Ferrer JL, Austin MB (2008). "Structure and function of enzymes involved in the biosynthesis of phenylpropanoids". Plant Physiol. Biochem. 46 (3): 356–370. doi:10.1016/j.plaphy.2007.12.009. PMC 2860624 . PMID 18272377.

[7] Mizutani M, Ohta D, Sato R (1997). "Isolation of a cDNA and a genomic clone encoding cinnamate 4-hydroxylase from Arabidopsis and its expression manner in plants". Plant Physiology. 113 (3): 755–763. doi:10.1104/pp.113.3.755. PMC 158193 . PMID 9085571. S2CID 10059931.

[8] Ferrer JL, Jez JM (1999). "Structure of chalcone synthase and the molecular basis of plant polyketide biosynthesis". Nat. Struct. Biol. 6 (8): 775–784. doi:10.1038/11553. PMID 10426957. S2CID 23408591.

[9] Jez JM, Bowman ME (2000). "Structure and mechanism of the evolutionarily unique plany enzyme chalcone isomerase". Nat. Struct. Biol. 7 (9): 786–791. doi:10.1038/79025. PMID 10966651. S2CID 22198011.

[10] Martens S, Mithofer A (2005). "Flavones and flavone synthases". Phytochemistry. 66 (20): 2399–2407. doi:10.1016/j.phytochem.2005.07.013. PMID 16137727.

[11] Sarda SR, Pathan MY, Paike VV, Pachmase PR, Jadhav WN, Pawar RP (2006). "A facile synthesis of flavones using recyclable ionic liquid under microwave irradiation". Arkivoc . xvi (16): 43–8. doi: 10.3998/ark.5550190.0007.g05 . hdl: 2027/spo.5550190.0007.g05 .

[12] Wessely F, Moser GH (December 1930). "Synthese und Konstitution des Skutellareins". Monatshefte für Chemie. 56 (1): 97–105. doi:10.1007/BF02716040. S2CID 95833443.

[13] Larget R, Lockhart B, Renard P, Largeron M (April 2000). "A convenient extension of the Wessely-Moser rearrangement for the synthesis of substituted alkylaminoflavones as neuroprotective agents in vitro" (PDF). Bioorg. Med. Chem. Lett. 10 (8): 835–8. doi:10.1016/S0960-894X(00)00110-4. PMID 10782697.

[14] Harborne, Jeffrey B.; Marby, Helga; Marby, T. J. (1975). The Flavonoids - Springer. doi:10.1007/978-1-4899-2909-9. ISBN 978-0-12-324602-8. S2CID 33487001.

[Dewick-15] 1 2 Dewick, Paul M. (2009). "The Shikimate Pathway: Aromatic Amino Acids and Phenylpropanoids". Medicinal Natural Products. A Biosynthetic Approach. Chichester, UK: John Wiley & Sons. pp. 137–186. doi:10.1002/9780470742761.ch4. ISBN 978-0-470-74276-1.

[16] Yeh, Tian-Shin; Yuan, Changzheng; Ascherio, Alberto; Rosner, Bernard A.; Willett, Walter C.; Blacker, Deborah (2021-09-07). "Long-term Dietary Flavonoid Intake and Subjective Cognitive Decline in US Men and Women". Neurology. 97 (10): e1041–e1056. doi: 10.1212/WNL.0000000000012454 . ISSN 0028-3878. PMC 8448553 . PMID 34321362.

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