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1
Dr. Pran Kishore Deb
Dr. Balakumar ChandrasekaranAssistant Professor
Pharmaceutical Medicinal Chemistry
Faculty of Pharmacy, Philadelphia University-Jordan
Email: [email protected]
Learning Outcomes
At the end of this lesson students will be able to
Define flavonoids
Explain the chemistry of flavonoids
Classify flavonoids
Outline examples of various classes of flavonoids
Describe the biosynthesis, extraction and isolation of flavonoids
Outline the significance of flavonoids
Outline natural distribution of flavonoids
Explain the mechanism of actions of flavonoids
Explain the botanical name, family name, medicinal uses of
Rutin, Hesperidin, Genistein, Daidzein2
FLAVONOIDS
Represents diverse class of naturally occurring polyphenolic
secondary metabolites
Found either in free form or as glycosides
About 10,000 flavonoids have been recorded
Represents the third largest group of natural products
Following the alkaloids (12,000) and terpenoids (30,000)
3
FLAVONOIDS
Flavonoids = from the Latin word flavus meaning YELLOW
Also contribute to many other colours found in nature
Responsible for the colour of flowers, fruits, leaves
4
• They have 15-carbon atoms in their basic skeleton
• Arranged in the form C6-C3-C6
• Consists of two aromatic rings (A & B) linked by 3 carbon atoms
• 3 carbon atoms (C3) may be an aliphatic chain (e.g. chalcone)
• 3 C-atoms may give rise to a third ring C (mostly pyran / pyrone ring)
5
Chemistry of Flavonoids
• Classification based on the
• Position of phenyl ring B
• Degree of oxidation and
• Saturation present in the heterocyclic C-ring
6
Classification of Flavonoids
• Based on the position of aromatic (phenyl) ring B to benzopyran moiety
7
Classification of Flavonoids
8
Classification of Flavonoids
9
Classification of Flavonoids
10
Examples of Different Classes of Flavonoids
11
Examples of Different Classes of Flavonoids
12
Examples of Different Classes of Flavonoids
13
Which of the following structure belongs to flavonol group?
√
×Flavone
group
×Flavanonol
group
×FlavAnol
group
14
Which of the following represents an isoflavone structure?
A B
C D
√
×
15
Biosynthesis of Flavonoids
Biosynthesis of Flavonoids
• Flavonoids are products of mixed biosynthesis
• Cinnamoyl-CoA (C6C3, precursor from the shikimate pathway)
• Three (3) molecules of malonyl-CoA (from acetate pathways)
• Triketide starter unit undergoes cyclization by the enzyme chalconesynthase to generate the chalcone group of flavonoids
• Cyclization of chalcone then occur to give a pyranone ringcontaining flavanone nucleus
• Flavonone can either undergo
• Oxidation of C2-C3 bond of pyranone ring to give the flavone or
• Hydroxylation at C3 of pyranone ring to give the flavanonol
• Flavanonol may then further oxidized to give anthocyanidin
17
Biosynthesis of Flavonoids
Glycosides are formed by introduction of sugar
unit/s to the hydroxyl groups of flavonoids
Examples of Flavonoid Glycosides
Pelargonin
Naringin (Bitter)
Naringin dihydrochalcone
(1000 times sweeter than sucrose)
Rutin
capillary fragility,
dermatitis
Hesperidin
Vitamin P
Extraction and Isolation of Flavonoids
• Extraction: extracted from plants with ethanol, methanol or water
• Since they are highly hydroxylated
• Purification: with alkaline solution or precipitation with lead acetate
• Separation: Different classes of flavonoids can be separated by
• Column chromatography
Significance of Flavonoids
Ecological importance in nature
Aid to plant pollination and seed dispersal
An essential step in the reproductive process of plants
Pollination depends on
Action of abiotic forces (20%): wind and water
Rely on animals (80%): flies, birds, beetles and other insects
Flavonoids act as colour attractants to insects and birds
20
FLAVONOIDS
Even the colourless flavonoids absorb light in the UV spectrum
due to their extensive chromophores - visible to many insects
Human recognizes the colour of a compound by perceiving
reflected or transmitted light of wavelength 380 and 730 nm
Insects can recognise the light of shorter wavelengths
21
FLAVONOIDS
Studies on flavonoids by UV spectroscopy
Most flavonoids consist of two major absorption maxima
Band II (240–285 nm) - benzoyl system of the A ring
Band I (300–400 nm) - cinnamoyl system of the B ring
22
Band II
(240–285 nm)
Band I
(300–400 nm)
Significance of Flavonoids
Taste of foods
Naringin (flavanone glycoside) - bitter and astringent
Occurs in the peels of grapefruit
Naringin dihydrochalcone (no pyranone ring) - exceptionally sweet
1000 times sweeter than table sugar (sucrose).
23
Naringin (Bitter) Naringin dihydrochalcone
(1000 times sweeter than sucrose)
Significance of Flavonoids
Plants defense system
Protection against fungal parasites, pathogens, herbivores, UV
radiation (e.g. Rotenone)
Allelopathy
Definition: It is a process by which compounds are released from
the metabolism of a plant, preventing the germination, growth and
development of other neighboring plants.
Flavonoids influence, in the vegetation and succession of plants,
by inhibiting the germination and growth of other seedlings
24
Significance of Flavonoids
Examples - Flavonoids with allelopathic properties
Plant organism – Oryza sativa L. (rice)
Family - Poaceae
25
Flavonoids Functions
Allelopathic inhibitor of weeds and pathogens
Weeds of species – Cyperus difformis, C. iria
Allelopathic inhibitor of seed germination
Significance of Flavonoids
Allelopathy of Weeds
Impose limitations on the development of agricultural activity
Difficult to eradicate
Able to produce, store and release chemicals with
allelopathic properties to the environment
Biopesticides based on flavonoids display allelopathic properties
against weeds
Considered as an efficient natural defense against them
26
Significance of Flavonoids
Dietary significance
Acts as strong natural antioxidant (being polyphenolic)
Many diseases can be aggravated due to the presence of free
radicals
Flavonoids scavenge free-radicals, inactivates peroxides
27
Significance of Flavonoids
Biological and pharmacological activities
antioxidant, antidiabetic
cytotoxic, anticancer, antifungal
antibacterial, antiviral, antimalarial
antileishmanial, antitrypanosomal and antiamebial
anti-inflammatory, antiallergic
antithrombotic, cardioprotective
hepatoprotective, neuroprotective28
29
Class Flavonoids Dietary source
Flavanols Catechin, epicatechin,
epigallocatechin,
chrysin, epigenin
Tea, red wine, cocoa,
chocolates, grapes, blackberry
etc.
Flavones Rutin, luteolin, luteolin
glycoside
Fruit skins, red wine,
buckwheat, red pepper,
tomato skin
Flavonols Kaempferol, quercetin,
myricetin, temarixetin
Onion, red wine, olive oil,
berries, grapefruits
Flavanones Naringin, naringenin,
taxifolin, hesperidin
Citrus fruits, grapefruits,
lemon, oranges
Isoflavones Genistin, daidzin Soyabean
Anthocyanidins Apigenidin, cyanidin Cherry, strawberry, blue berry
Classification and Food Sources of Some
Dietary Flavonoids
• Rutin was first isolated from the leaves of Ruta graveolens
• Family - Rutaceae
• Rutin is usually isolated from Fagopyrum esculentum or Buckwheat
• Family - Polygonaceae
Fagopyrum esculentumRuta graveolens
RUTIN
Rutin
(5,7,3’,4’-tetrahydroxy-flavonol-3-rhamnoglucoside)
Rutinose
6-O-α-L-rhamnosyl-D-glucose
(C12H22O10)
Hydrolysis
Rhamnodiastase
Uses of Rutin1. Decrease capillary fragility and permeability
In cases of hypertension and radiation injuries
2. Anti-inflammatory properties
Beneficial for various types of dermatitis
3. According to the University of Maryland Medical Center:
50 to 250 mg of a rutin supplement two or three times a day
Relieve symptoms of allergic skin reactions, and eczema
Seborrheic dermatitis which causes dandruff
4. Treatment of various types of erythema
• Usually found in the peels of species of citrus fruits like
• Citrus aurantium (Bitter Orange)
• Citrus sinensis
• Family: Rutaceae
Citrus aurantium Citrus sinensis
HESPERIDIN
HESPERIDIN
• It is also called citrin or Vitamin P or permeability vitamin
• Chemically it is hesperitin-7-rutinoside (flavone glycoside)
GENISTEIN
• It is an isoflavone
• Found in plants of Genista species (Genista tinctoria, Dyer's Broom)
• Glycine max, (Soybean in USA and Europe)
• Family: Fabaceae or leguminosae
Uses of Genistein
• Genistin is a phytoestrogen
• Given as a diet supplement
• Contrast the side effect caused by lack of estrogen
• Specially for women during their menopause
• It prevents osteoporosis
• It prevents estrogen dependent cancer like breast cancer
• It also has anti-atherosclerotic and anti-viral properties
DAIDZEIN
• An isoflavone
• Also called phytoestrogen
• Structurally similar to estrogen
• It has similar effects as the Genistein
• Source - leguminous plants such as soybean and mung bean
SoyabeanSoyabean Mung bean
Daidzein – Mechanism of Actions
• Binds to estrogen receptors (ER)
• Shows weak estrogenic effects (weak agonists or partial agonists)
• Shows weak anti-estrogenic effects (antagonist)
• Exerts protective effects against some diseases which are linked to the
regulation of estrogen
Breast cancer
Daidzein – Mechanism of Actions
• Prostate cancer
• Growth of prostate cancer is androgen dependent
• Daidzein has anti-androgen activity
• Prostate androgen-regulated transcript-1 gene (PART-1) is a new gene
• responsive to androgens
• used as a biomarker of prostate cancer
• Daidzein inhibits dihydrotestosterone (DHT)-induced expression
of the PART-1 dose-dependently
• Diabetes - Regulate glucose and lipid metabolism
• Activation of peroxisome proliferator-activated receptors (PPAR)
Glucoside
(inactive)
• Stomach (acid hydrolysis)
• Intestine (bacterial enzymes)
Metabolized
(intestinal bacteria)
Aglycone
(active)
• More potent antioxidant than daidzein
• Binds to ER with a greater affinity
• Anti-atherosclerotic effects
Chemo-preventive role in UVB
induced non-melanoma skin cancer
• Anticancer activity
• Breast cancer
• Prostate cancer
• Other cancer (colon, skin)
• Anti-cardiovascular disease
• Anti-osteoporosis
• Anti-diabetic activity
• Anti-oxidant activity
• Anti-inflammatory activity
• Neuroprotective activity
Soyabean
Mung bean
Reference: Sun et al., Afr J Tradit Complement Altern Med. (2016), 13(3):117-132
DAIDZEIN
42
The French Paradox and the Mediterranean Diet
• French population - low incidence of CHD despite of high fat intake
• Difference between French and non-Mediterranean diet
• Higher consumption of Red wine - a rich source of flavonoids
• Mediterranean Diet, also contains other flavonoids and polyphenol-
rich foods such as olive oil, fruits, and nuts
43
The French Paradox and the Mediterranean Diet
• Red wine - reported mechanisms of action:
• Attenuation of myocardial ischemic reperfusion injury
• Inhibition of platelet aggregation
• Promotion of endothelial nitric oxide synthase (eNOS), inhibition
of thromboxane synthesis, modulation of lipoprotein secretion,
• Inhibition of low-density lipoprotein (LDL) oxidation,
phospholipase A2 (PLA2), COX and phosphodiesterase (PDE)
• Inhibition of protein kinases involved in cell signaling
• Inhibition of carcinogenesis
Reference - Fernandes, et al. (2017). Wine flavonoids in health and disease
prevention. Molecules, 22, 292. https://doi.org/10.3390/molecules22020292
44
Mechanism of Actions of Flavonoids
Antioxidant activity
• Protects body against free radicals and reactive oxygen species
(ROS)
• Free radicals and ROS:
• Associated with large number of human diseases
• Flavones & catechins:
• Most powerful flavonoids protecting against ROS
45
Antioxidant activity of flavones: require three factors
1. A 3′,4′-dihydroxy (catechol) structure in the B ring
• favors the electron delocalization
2. An unsaturated 2-3 bond in conjugation with a 4-keto group
• provides electron delocalization from the B ring
3. Hydroxyl groups at positions 3 and 5
• forming intra-molecular hydrogen bonding to the keto group
46
Antioxidant activity of flavonoids: require three factors
1. A 3′,4′-dihydroxy (catechol) structure in the B ring
• favors the electron delocalization
2. An unsaturated 2-3 bond in conjugation with a 4-keto group
• provides electron delocalization from the B ring
3. Hydroxyl groups at positions 3 and 5
• forming intra-molecular hydrogen bonding to the keto group
• These 3 effects lead to the increase of the radical scavenging
• Either by delocalization of electrons or by donation of hydrogen
47
Mechanism of Actions of Flavonoids
Clinical study example
• Quercetin reduces plasma urate, in moderately hyperuricemic men
• By inhibition of xanthine oxidoreductase
• A major producer of intracellular superoxide and
• Driver of uric acid synthesis
• Reference: Shi, Y., & Williamson, G. (2016). Quercetin lowers uric acid in pre-hyperuricaemic males: A randomized,
double-blinded placebo-controlled, cross-over trial. British Journal of Nutrition, 115, 800–806.
https://doi.org/10.1017/S0007114515005310
48
Mechanism of Actions of Flavonoids
Anti-inflammatory Activity
• Inhibit the expression of inducible nitric oxide synthase (iNOS),
cyclooxygenase (COX-2), and lipooxygenase (LOX)-
• Inhibit the production of nitric oxide (NO), prostanoids, leukotrienes
• Inhibit other mediators of the inflammatory process - cytokines,
chemokines
Inhibits COX-2, LOX, iNOS Inhibits NF-kꞵInhibits IL-6, 8 production &
prostaglandin synthesis
49
Mechanism of Actions of Flavonoids
• Flavonoids inhibits phosphodiesterase (PDE) enzymes
• PDEs breaks phosphodiester bonds (e.g. cAMP & cGMP)
• Important regulators of signal transduction
• There are many other families of PDEs
• Phospholipases C and D, autotaxin, sphingomyelin
phosphodiesterase, DNases, RNases, & restriction endonucleases
(break the phosphodiester backbone of DNA or RNA)
cGMPcAMP
50
Mechanism of Actions of Flavonoids
• Flavonoids inhibits PDEs - acts as potential therapeutics
• Pulmonary arterial hypertension, coronary heart disease, asthma,
COPD, protozoal infections (including malaria), dementia,
depression and schizophrenia
• Examples: Naringenin and 3,5,7,4-tetrahydroxy-flavanone
• Inhibits phosphodiesterase-1 (PDE1) which is involved in
airway smooth muscle activity and airway inflammation
51
Anticancer Activity of Flavonoids
• Downregulation of mutant p53 protein
• lead to arrest the cancer cells in the G2-M phase of the cell cycle
• Mutations of p53 - most common genetic abnormalities in human
cancers
• Inhibition of heat shock proteins
• Heat shock proteins form a complex with mutant p53
• Allows tumor cells to bypass normal mechanisms of cell cycle
arrest and apoptosis
• Allows improved cancer cell survival under different bodily
stresses
Mechanism of Actions of Flavonoids
52
• Inhibition of EGFR-Tyrosine kinase (e.g. quercetin)
• Inhibition of Estrogen receptor binding capacity
• Inhibition of expression of Ras-proteins
• Consumption of onions and /or apples - major sources of quercetin
• Inversely associated with the incidence of cancers of the
• Prostate, lung, stomach, and breast
Anticancer Activity of Flavonoids
Mechanism of Actions of Flavonoids
53
Mechanism of Actions of Flavonoids
Antiviral Activity
• 5,6,7-Trihydroxyflavone-7-O-glucoside
• Inhibits the human T-cell leukemia virus type-1 (HTLV-1)
• Effective against human immunodeficiency virus (HIV)
• Inhibition of HIV-1 reverse transcriptase (e.g. flavone-o-glucoside)
• Inhibition of HIV-1 proteinase (e.g. gardenin A and robinetin)
• Inhibition of DNA polymerase (e.g. catechins)
• Effective against dengue virus type-2 (DENV-2)
• Inhibition of viral polymerase
• E.g. quercetin, hesperetin, diadzein
1. Williamson G, Colin D.K, and Alan C. The Bioavailability, Transport, and
Bioactivity of Dietary Flavonoids: A Review from a Historical Perspectiv.
Comprehensive Reviews in Food Science and Food Safety, 2018, 17, 1054–1112.
2. Katarzyna Małgorzata Brodowska. Natural flavonoids: classification, potential
role, and application of flavonoid analogues. European Journal of Biological
Research 2017, 7 (2): 108-123.
3. Shashank K, and Abhay K.P. Chemistry and Biological Activities of Flavonoids:
An Overview. The Scientific World Journal (Hindawi), 2013, 162750, 1-16.
4. Oyvind M. Andersen and Kenneth R. Markham (Eds.). BOOK: FLAVONOIDS
Chemistry, Biochemistry and Applications. CRC Press, Taylor & Francis,
London, 2006.
5. Erich Grotewold (Ed.). BOOK: The Science of Flavonoids. Springer, United
States of America, 2006.
REFERENCES
1. Meng-Yao Suna, Ying Ye, Ling Xiao, Khalid Rahman, Wei Xia, Hong Zhang.
DAIDZEIN: A review of pharmacological effects. Afr J Tradit Complement
Altern Med., 2016, 13(3):117-132.
2. Shi, Y., & Williamson, G. Quercetin lowers uric acid in pre-hyperuricaemic
males: A randomized, double-blinded placebo-controlled, cross-over trial.
British Journal of Nutrition, 2016, 115, 800–806.
https://doi.org/10.1017/S0007114515005310
3. Iva Fernandes, Rosa Pérez-Gregorio, Susana Soares, Nuno Mateus and Victor de
Freitas. Wine flavonoids in health and disease prevention. Molecules, 2017, 22,
292. https://doi.org/10.3390/molecules22020292
4. https://www.herbs2020.com/herbs/herbs_soy.htm
REFERENCES