Dr. Mohammed N. Sabir 2021 - suli-pharma.com
Transcript of Dr. Mohammed N. Sabir 2021 - suli-pharma.com
Phenylpropanoids
Dr. Mohammed N. SabirDecember 2021
2Lecture outline
• Introduction to phenylpropanoids.
• Chemistry and biosynthetic origin.
• Classes.
• Medicinal significance.
• Herbal products.
Biomolecules formed from a
C6C3 unit [originally made-up
from the aromatic amino
acids, L-Phenyl alanine, and
L-Tyrosine].
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Source,https://www.sciencedirect.com/topics/food-science/phenylpropanoid
The L-phenyl alanine will undergo deamination
and a double bond formation at carbon number.
The formed cinnamic acid will be the trans isomer
(the most common isomer).
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L-Phenyl alanine
L-Tyrosine
Trans-cinnamic acid
P-Hydroxy coumaric acid
NH3
NH3
L-Ph. ala. ammonia lyase (PAL)
Tyr. ammonia lyase (TAL)
Various post-synthesis modifications may take
place according to the species involved. These
include, different oxygenation levels, cyclization,
condensation, and substitution leading to a vast
number of secondary metabolites termed as
phenylpropanoids.
These molecules serve important roles to the producing
species and show interesting medicinal values.
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Vargas-Tah A. and Gosset G., 2015, Front. Bioeng. Biotechnol.,Source: https://www.frontiersin.org/articles/10.3389/fbioe.2015.00116/full
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The classes of
Phenylpropanoids
Source,https://www.frontiersin.org/research-topics/14215/phenylpropanoid-systems-biology-and-biotechnology
8Flavonoids
Source,https://www.naturesbest.co.uk/images/blog/flavonoids_and_vision_2.jpg
• The largest group of naturally occurring phenolic compounds.
They occur in different plant parts including, fruits, stem, barks,
root, leaves, heartwood, flowers, rhizomes and seed.
• Flavonoids are plant pigments or co-pigments (the yellow-
orange color of many fruits) exist in different plant families
including, Rutaceae, Rosacea, Astraceae, Lamiaceae,
Moraceae, Rubiaceae, and Myrtaceae.
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Classes of
flavonoids
The flavonoids’ biosynthesis
Obtained from two pathways,
• Shikimate [Phenyl propanoids (4-hydroxy coumaric acid)].
• Acetate [Malonyl-CoA (3 Acetyl-CoA)].
https://en.wikipedia.org/wiki/Flavonoid_biosynthesis
The role of flavonoids in plants include,
1. Insect attractant (pollinating agents).
2. Plant pigments.
3. Growth regulators.
4. Antioxidants.
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The medicinal values of flavonoids include,
•Antioxidants (free radical scavengers).
•Antimicrobial.
•Anti-inflammatory
•Mitochondrial adhesion inhibitors.
•Antiulcer.
•Estrogen receptor binding.
•Cell cycle arrest.
•Topoisomerase inhibitors.
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Structure-activity relationship (SAR) 14
Source,https://static-01.hindawi.com/articles/bmri/volume-2017/8386065/figures/8386065.fig.005.svgz
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Source,https://www.mdpi.com/antioxidants/antioxidants-10-01262/article_deploy/html/images/antioxidants-10-01262-g006.png
Antioxidant mechanism of flavonoids 16
Ivonne et al. “The pro-oxidant chemistry of the natural antioxidants vitamin C, vitamin E, carotenoids and flavonoids.” Environmental Toxicology and Pharmacology. 2002. Vol. 11(3–4). P:321-333
17Antimicrobial activity of flavonoids
Gomiac I. et al. “Comprehensive review of antimicrobial activities of plant flavonoids.” Phytochemistry Reviews. 2019. 18:241–272.
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Yatoo et al. “Beneficial health applications and medicinal values of Pedicularis plants: A review.” Biomedicine & pharmacotherapy. 2017. 95:1301-1313
Anti-inflammatory action of flavonoids
• Quercetin.
• Naringin.
• Hesperidin.
• Rutin.
• Resveratrol.
19Some examples of known bioflavonoids
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https://www.researchgate.net/profile/Mohammed-Hossain-47/publication/301332394/figure/fig3/AS:351878010425347@1460905663391/Cla
ssification-and-example-of-flavonoids-and-their-chemical-structures-Flavonoids-are.png
21Quercetin
A plant bioflavonoid found in onions, apples, green tea, red wine,
and berries.
The compound shows antioxidant, anti-inflammatory,
antimicrobial, antitumor, antidiabetic, and cardiovascular
protectant.
Recent studies showed that quercetin inhibits SARS-CoV 19
cellular entrance through inhibition of Angiotensin receptor.
Used as a reference agent for antioxidant comparison in research
protocols.
Naringin
From Citrus paradisi
Fam: Rutaceae
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Naringin is an aldose reductase inhibitor which means that it
can help to fight diabetic retinopathy.
https://www.wisegeek.com/what-is-citrus-paradisi.htm
Naringin enhance our perception for taste by
stimulating the taste buds; that's why some
people consume a small amount of grapefruit
juice before a meal.
Citrus aurantium Peels
Fam: Rutaceae
Uses:-
Hesperidin and Naringin inhibits capillary
bleeding through epithelial protection
(membrane stabilizer)
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Source,https://www.alibaba.com/product-
detail/Bitter-Orange-Oil-Citrus-Aurantium_148711980.html
24Rutin
A bioflavonoids obtained from apples,
buckwheat, citrus, figs, and both black
and green.
Rutin demonstrate antioxidant
properties and enhance collagen
production when used with vitamin C.
The drug interactions of flavonoids,
1. Calcium channel blockers.
2. Sedatives.
3. Cholesterol lowering drugs.
4. Caffeine.
5. Estrogen.
6. Antacids.
7. Minerals and proteins.
Metabolic
interaction through
interfering
metabolism of these
drugs and increasing
their t1/2.
The side effects of flavonoids include,
1. Diarrhea.
2. Allergy.
3. Photosensitivity.
4. At large doses may cause iron deficiency.
27Flavonolignans
Phenylpropanoids formed from
condensation of a flavonoid and a
lignan.
Both, the flavonoid and the lignan
are obtained from shikimic acid.
These compounds are considered as
rare products and isolated from
Silymarin.
Silymarin (Silybum marianum L.)
Milk Thistle
Fam: Astraceae
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Source,https://www.ebay.com/itm/Silybum-
marianum-Culinary-and-Medi-50-Seeds-Milk-Thistle-Seeds-Organic-
/283341110690
Source,https://www.alamy.com/stock-photo-blessed-milk-thistle-our-ladys-
thistle-silybum-marianum-seeds-one-25262647.html
The plant seed contains the
heist concentrations of the
flavonoids. The most
abundant flavonolignans are
Silybin A and B.
Mechanisms of action of Silybins
1. As antioxidant (inhibit lipid-peroxidation) through free
radical scavenging (antioxidant) Key mechanism.
2. Regulators of intracellular content of glutathione.
3. Cell membrane stabilizer and permeability regulator that prevent entrance of toxins.
4. Promoters of ribosomal RNA synthesis and stimulating liver regeneration (Hepatocytes protein synthesis).
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Mechanisms of action of Silybins
5. Inhibits transformation of stellate hepatocytes into myofibroblasts.
6. Decrease the activity of tumor promoters.
7. Enhances apoptosis.
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Hepatotoxic agents
•Carbon tetrachloride (CCl4).
•Chloroform (CHCl3).
•Acetaminophen (Paracetamol©).
•Amanita phalloides.
•Xenobiotics.
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Fatty degeneration in Rat Liver after exposure to CCl4.
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Sabir M. “Pharmacognostic Study of Silybum marianum,” Lambert Academic Publishing, Germany, 1st Ed. 2014.
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▪ Water solubility problems of silybin and methods for
solubility enhancement.
▪ Water solubility affects bioavailability and its efficacy.
Product Milk Thistle HerbSilybum marianum
Size - Mg. Silymarin Silybin Silymarin / Silybin
- Fruit referred to as seed one cap/tab Percent of product % in mg.
Maximum Milk Thistle (Siliphos) (Natural Wellness)
Dried extract(Siliphos)
240 mg. 33% 80 mg.
Thisilyn(Nature's Way)
Dried extract 175 mg. 80% 140 mg.
Legalon(Madaus, Germany)
Dried extract (40:1) 90 mg. 80% 70 mg.
Silymarin 80(Planetary Formula)
Seed Extractplus Milk Thistle seed
210 mg.(plus 50 mg.)
80% 168 mg.
Milk Thistle(Kroeger)
Seed Extractplus Milk Thistle seed
175 mg. (plus 275 mg.)
80% 140 mg.
Silymarin(MediHerb, Australia)
Extract (70:1) 210 mg. 80% 168 mg.
Milk Thistle Seed (Gaia Herbs)
Liquid extract (1:1) 35 mg. 50% 17.5 mg.
Milk Thistle (generic)limited information
Extract 200 mg. 80% 160 mg.
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Tannins 37
Source,https://www.fs.fed.us/wildflowers/ethnobotany/images/tannins/persimmon.jpg
A large group of phenolic non-nitrogenous biomolecules
exhibiting astringent properties (precipitate proteins).
Because of their multiple polar functional groups, these
compounds are water-soluble.
Most are water-soluble, the multiple phenolic hydroxyls and carboxylic groups
are responsible for astringency and bitterness.
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Tannins are sub-classified into two groups,
1- Hydrolysable tannins
2- Non-hydrolysable tannins
1-The hydrolysable tannins, which are formed by the
esterification of sugars (e.g., glucose) with gallic acid.
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Tannic acid is an example of hydrolysable tannin. The gallic acid
molecules are attached to the D-glucose moiety through an ester
linkage.
2-The non-hydrolysable tannins (condensed tannins) expressed
through a polymerization (condensation) reactions between
flavonoids.
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n
One flavonoid molecule act as a core for which other
flavonoids will condense.
Flavonoids are formed from condensation of one p-
hydroxy-cis cinnamic acid with three acetate molecules.
42Isolation
Both hydrolysable and condensed tannins are highly water and
alcohol soluble but insoluble in organic solvents such as ether,
chloroform and benzene. Accordingly, these compounds are
extracted with water using maceration or percolation.
The general method for the extraction of tannic acid from various
Galls is either with water-saturated ether, or with mixture of water,
alcohol and ether.
43Acetone is added to the extraction procedure to inhibit
interaction between tannins and proteins or interfere with the
hydrogen bonding between them, thus increasing the yield.
After extraction, the aqueous and ethereal layers are separately
concentrated, dried, and subjected to further isolation by
sequential chromatographic purification.
The hydrolysable tannins are hydrolyzed in basic medium to their
simple acids and sugars.
44Tannins are isolated by open or flash column
chromatography and HPLC. The mobile phases varies
according to the chemical nature of the tannin, however
ethyl acetate, water, acetic acid, n-butanol are
commonly used.
A key feature of tannins is their ability to bind to
proteins, and they have been used to tan leather, clarify
beer and as astringent preparations in pharmacy.
They have a wide distribution in plants and produced as
a feeding deterrent, as their binding to proteins may
reduce the dietary value of the plant as a food.
Some of these tannins are also plant pigments like
anthocyanidins.
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Source: https://www.mdpi.com/2076-3921/8/6/182/htm
Chemical tests for tannin identification,
• Reaction with FeCl3.
• Goldbeater's skin test.
• Stiasny's method using Folin-Ciocalteu reagent.
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Tannic acid is a mixture of gallic acid esters of glucose
obtained from nutgall, which is an abnormal tissue
growth of the Oak tree, Quercus robur (Fagaceae)
.as a response of larvae inoculation by insects (داربەڕوو)
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Quercus infectoriaمازووAlepo Oak
Ferdinand Vietz Icones Plantarum 1800-1822Source: https://www.panteek.com/Vietz/pages/vi403-7a1.htm
Source: https://pansari.pk/aleppo-oak/
The galls are harvested and extracted with solvents
(ether and water); the aqueous layer is collected and
evaporated to yield tannic acid, which is further purified
and used as a topical preparation for cold sores.
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https://scienceline.org/2006/09/ask-leibach-herpes/comment-page-4/
Epigallocatechin gallate (EGCG), epigallocatechin-3-
gallate, is the ester of epigallocatechin and gallic acid and
is a type of catechin.
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EGCG is the most abundant catechin in tea and is a potent
antioxidant that have therapeutic applications in (e.g., cancer). It
is found in green tea but not black tea.
In black tea production, the catechins are converted to
theaflavins and thearubigins under high temperature, an
epimerization change is more likely to occur.
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https://www.sciencedirect.com/science/article/abs/pii/S0304416505000619
Theaflavin derivatives in black tea and catechin derivatives in green tea inhibit
HIV-1 entry by targeting gp41,
Liu et al., 2005, BBA, Vol. 1723(1–3); 270-281.
52In addition to the antioxidant and antiviral actions, tannins
also exhibit antimicrobial activity.
Tannin toxicity for fungi, bacteria and yeasts is attributed to
the bellow proposed mechanisms,
▪ Inhibition of extracellular microbial enzymes,
deprivation of the substrates required for microbial
growth.
▪ Direct action on microbial metabolism through
inhibition of oxidative phosphorylation.
▪ Iron chelation.
53Many microorganisms can overcome plant defenses
based on tannins through,
➢ Synthesis of tannin complexing polymers.
➢ Oxidation, tannin biodegradation.
➢ Synthesis of siderophores.
See the reference…
https://www.researchgate.net/publication/223084771_Antimicrobial_properties_of_tannin [accessed Apr 1, 2017].
Important herbs that are rich with tannins and used in
the treatment of diarrhoea include,
- Sangisorba officinalis L.
- Acacia catechu Willd.
- Oak bark
- Quercus robur L.
- Potentilla erecta (L.) Rausch.
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Tannin-containing medications are generally
safe, but care should be taken with concurrent
administration of other drugs since tannins are
not compatible with alkalis or alkaloids and form
complexes with proteins and amino acids and
some metals.
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In general, tannins are used for,
-Precipitate proteins in their solutions (astringent property).
-Hypolipidemia.
-Hypertension.
-Identification of Alkaloids.
-Tanning leather.
-Burns treatment.
-Diarrhea treatment.
-Antioxidant property.
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Tannins in Herbal Medicine,
Punica garnatum (Lythraceae)
In the ancient Ayurveda medicine, the pomegranate
has extensively been used as a source of traditional
remedies for thousands of years.
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Source,http://recipes.beewild.buzz/fermented-pomegranate-
honey/
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Hamamelis Leaf (Witch hazel leaves)
Dried leaf of Hamamelis virginiana (Hamamelidaceae)
Hama = sametime
Melis = leaf
Distilled witch hazel extract: prepared by steam hydroalcoholic distillation of
the dried leaves and twigs of H. virginiana. Contains the volatile oil of the
plant.
https://en.wikipedia.org/wiki/Hamamelis_virginiana
59Toxicities of tannins
High intake tannins in diet may cause,
hypoproteinemia, constipation, bowel obstruction
(surgical interpretation may be required), decrease
minerals’ absorption (Fe+2, Fe+3, Ca+2, Al+3, Mg+2, etc.),
and drug interaction with cytochrome P-450
metabolized drugs.
60Presence of tannins in fresh water
https://commons.wikimedia.org/wiki/File:Tannin_rich_fresh_water_draining_into_Cox_Bight_from_Freney_Lagoon.jpg
Lecture overview… 61
Thanks for listening…
Any questions?
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