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10-Jan-17 1
Mohammed N. Sabir January 2017
Glycosides
Pharmacognosy I Lecture: 5, Glycosides
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Lecture outlines…
• Chemistry and classification of glycosides
• biosynthesis of glycosides
• Methods for isolation
• Examples
• Review of the lecture
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Pharmacognosy I Lecture: 5, Glycosides
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Introduction to glycosides…
Secondary metabolites with critical biological uses for plants,
abundant in plant Kingdome and some animals.
Upon hydrolysis, yield aglycone (nonsugar) also called genin (biologically
active) and one or more glycones (usually reducing sugar).
Pharmacognosy I Lecture: 5, Glycosides
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ROSugar
RCSugar
Nitrogen (N)
Sulfur (S)
May be also involved but a less extent
Pharmacognosy I Lecture: 5, Glycosides
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Hydrolysis of glycosides
Pharmacognosy I Lecture: 5, Glycosides
D-Glucose Saligenine Salicin
5
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In some cases, false sugars like (glucouronic acid,
galactouronic acid) or aminosugars may be involved.
Pharmacognosy I Lecture: 5, Glycosides
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Pharmacognosy I Lecture: 5, Glycosides
The functions of glycosides in the plants
1. Detoxifying agents through converting toxic
metabolites to non or less toxic. How?
Give examples on similar mechanisms in humans.
7
The functions of glycosides in the plants
2. Source of energy (sugar reservoir).
3. Growth regulators.
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Pharmacognosy I Lecture: 5, Glycosides
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The functions of glycosides in the plants
4. Pollinating agents.
5. Protecting agents (some are toxic while other have
antibacterial activities).
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Pharmacognosy I Lecture: 5, Glycosides
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Bitter Almond
Bacteria
HCN Amygdalin
Myrosinase
hydrolysis
Example on plant defense strategy using glycosides to combat bacterial infections.
Pharmacognosy I Lecture: 5, Glycosides
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Physicochemical properties
• Water soluble compounds
• Insoluble in organic solvents
• Hydrolyzed by mineral acids or strong oxidizing
agents or enzymes.
• The aglycone part is water insoluble but soluble in
organic solvents*.
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Pharmacognosy I Lecture: 5, Glycosides
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Glycosides hydrolyzed by using mineral acids and
temperature or by using enzymes such as:
a- Myrosin or Myrosinase Black Mustard Seeds.
b- Rhamnase glycosides containing D-Rhamnose as sugar
part.
c- Glycosidases.
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Pharmacognosy I Lecture: 5, Glycosides
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The chemistry of glycosides…
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O
H
HO
H
HO
H
H
OHHOH
OH
OH
H
H
H OH
HO H
O
H
HOHO
β-Pyranose
form
α-Furanose
form
H
OH
H
H OH
HO H
O
H
HOHO
β-Furanose
formD-Glucose
CHO
OHH
HHO
OHH
OHH
CH2OH
O
H
HO
H
HO
H
OH
OHHH
OH
FischerProjection
α-Pyranose
form
Pharmacognosy I Lecture: 5, Glycosides
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The chemistry of glycosides…
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D-Galactose
CHO
OHH
HHO
HHO
OHH
CH2OH
O
OH
H
H
HO
H
OH
OHHH
OH
FischerProjection
α-Pyranose
form
O
OH
H
H
HO
H
H
OHHOH
OH
β-Pyranose
form
OH
HH
H OH
HO H
O
HOHO
H
α-Furanose
form
H
OHH
H OH
HO H
O
HOHO
H
β-Furanose
form
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O
H
HO
H
HO
H
OH
OHHH
OHEquitorial
EquitorialEquitorial
4C1
O
H
HO
OH
H
OH
OH
HHH
OHEquitorial
Axial
Axial
O OH
HO
OH
HOH
OH
Equitorial
Equitorial
Axial
4C11C4
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Neutralization by Using alkaline
OH-
Filtration
Org. Solvent CHCl3/ Upper
Hydrolysis
+ HCL (dil.)
Separation of glycosides
O
CH2OH
HO
HO
HOHO
HOOH
Glycone Aglycone
+ + HCl Glycone + Aglycone + H2O + Salt
Aq. Phase/ lower
Aglycone + Org. Solv.
Aglycone Mohammed N. Sabir 2014
Pharmacognosy I Lecture: 5, Glycosides
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We can separate them by using separatory funnel
Then use suitable organic solvent which is:
A- Immiscible in water.
B- Always presents in the upper layer (except when the solvent is CHCl3),
Why?
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Water miscible solvents like alcohol and acetone are
avoided during separation of glycosides. Why?
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Physicochemical properties
• Colorless, solid, amorphous, nonvolatile (flavonoid- yellow,
anthraquinone-red or orange).
• Give positive reaction with Molisch's and Fehling's solution
test (after hydrolysis). Why?
• Odorless except saponin (glycyrrhizin).
• Glycosides with poly sugars has less solubility in water. Why?
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Important
During production of crude drugs containing glycosides, the
process of pruning, collection, drying, storage and extraction
should be handled with extra care. Why?
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Nomenclature of glycosides
• Depending on pharmacologic actions
• Depending on the sugar moiety
• Depending on the aglycone part
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In nomenclature of glycosides, some are ending with
“in”. While the name indicate the source of the
glycoside.
Ex:
- Digoxin from Digitalis
- Salicin from Salix
- Prunasin from Prunus. The systemic nomenclature are usually formed by replacing the “ose” suffix of
parent sugar with “oside”
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The anomeric prefix (α- or β-) and the configuration
prefix (D or L) immediately precede the sugar stem
name.
The chemical name of the aglycone precedes the name
of the sugar.
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β,D-3-Digitoxoside
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Classes of glycosides
• Saponin glycosides
• Anthraquinone (anthracene) glycosides
• Cyanogenic glycosides
• Steroidal (triterpenoid) glycosides
• Alcohol glycosides
• Phenolic glycosides
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Classes of glycosides
• Aldehyde glycosides
• Flavonoid glycosides
• Lactone glycosides
• Isothiocyanate glycosides
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Glycosidic linkage is formed between the oxygen of one
of the hydroxyl groups of the sugar moiety (mostly
anomeric) and the free hydroxyl of the aglycone part.
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O
HO
HOHO
HO OH
Anomeric hydroxyl
O
O
OHOH
OH
- H2O
Enz.
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Pharmacognosy I Lecture: 5, Glycosides
Classes of glycosides and medicinal plants
containing glycoside compounds…
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Anthraquinone glycosides The aglycone part is anthracene nucleus Upon oxidation it forms anthraquinone
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The biosynthetic pathway comes from acetate-β-
polyketide pathway [condensation of acetates through
head-to-tail] which gives rise to various oxygenated
aromatic compounds.
Glycosylation occurs at late stage in the pathway.
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Pharmacognosy I Lecture: 5, Glycosides
Biosynthesis of anthraquinone glycosides
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These anthraquinones are produced by some plants
belongs to the Rhmnaceae family and some fungi like
Aspergillus spp.
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Anthraquinone glycosides upon hydrolysis yields a sugar and anthraquinone. The planner tricyclic structure is essential for the pharmacologic action. Related drugs; - Cascara - Frangula - Aloe - Rhubarb - Senna
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Although anthraquinone glycosides possess
antibacterial, antiviral and cytotoxic actions, but most
are used as cathartics.
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Upon hydrolysis in bowel (by the action of the normal
flora), the tetrahydroxyquinone nucleus or its
derivatives will:-
• Induce laxative action through direct stimulation to the GIT
(increasing the tone of the smooth muscles).
• Increasing water and electrolyte secretion from GIT and
defecation.
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It also induces cell apoptosis in leukemia cells (Alexander D. et. al., 2005). This is through diminish survival signaling (protein kinase-β dependent signaling pathway).
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Side effects of anthraquinone glycosides:-
Abdominal cramps and chelation of metals like (ferrous
and calcium) causing osteoporosis and iron deficiency
anemia especially in infants.
Should not be used in pregnant, lactating women and infants.
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When they are in form of glycosides, they are water
soluble.
After hydrolysis, their water solubility decreases.
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They occur as yellow crystalline powders with high
melting points. They are stable but incompatible with
strong oxidizing agents.
The conjugated system absorbs UV radiation and could
be detected by UV-Vis spectrometers.
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Because of non-elective actions on DNA (planner
tricyclic rings), and presence of oxalic acid in their
extract.
They have toxicities in which varies according to the
active constituent involved.
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In Senna, the anthraquinone glycosides will be
dimerized to form dianthrone, which has more toxicity.
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For the extraction of these glycosides, they are
dissolved in water, then the glycosidic linkage break in
acidic medium. The aglycone then isolated using
organic solvent.
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Products:- 1- Cascara, is the dried bark of Cascara sagrada, Rhamnus purshianus [Rhamnaceae] The dried bark should be aged at least one year before use in medicinal preparations.
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Reduced form of the aloe emodine-type glycoside are present in
the fresh bark; during the minimum 1-year storage period, these
glycosides are converted to monomeric oxidized glycosides
which exhibit a milder cathartic action.
The plant is a tree that attains a height of 10m.
Indigenous to pacific coast of N. America, most
market supplies comes from Oregon,
Washington, Southern British Colombia.
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Barks processing
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The bark extract contains four major types of glycosides:-
Cascaroside A
Cascaroside B
Cascaroside C
Cascaroside D [A], R= OH (10S)
[B], R= OH (10R)
[C], R= H (10S)
[D], R= H (10R)
R
H
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Cascara is a cathartic used for correction of habitual
constipation; in which restores the tone of bowl.
The bitter taste is reduced by treating the extract with
alkaline earth metals or magnesium oxide.
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2- Frangula, dried barks of Rhamnus frangula [Rhamnaceae]. Contain Frangulin-A
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3- Aloe, is the dried latex (juice) of the leaves of Aloe
barbadensis, Aloe vera. [Liliaceae].
(Shining bitter substance)
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About 300 species of Aloe are known and are indigenous to
Africa.
The latex is evaporated in a copper kittle and upon proper
consistency, is poured into metal container and allowed to
harden.
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Production areas: Venezuela, Haiti, South Africa The latex taste is nauseating and bitter with disagreeable odor.
The colorless mucilaginous gel
(Aloe vera gel) obtained from
the central portion of Aloe leaf
that is used as a wound heeling
agent and to treat burns.
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Marginal latex constituents:- Aloin-A Aloin-B
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The active constituents of aloe varies qualitatively and
quantitatively according to the species from which the drug is
obtained.
Aloe is a pharmaceutical aid for the compound Benzoin tincture,
and is also used as cathartic.
The fresh mucilaginous gel contained in the paranchymatous
tissues in the center of the leaves used for the treatment of
burns and abrasions.
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The polysaccharide-rich composition of Aloe vera
extracts (Aloe barbadensis Miller), often used in
cosmetic formulations, may impart moisturizing
properties to the product.
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Aloe polysaccharides show potentials as immune
enhancer and antioxidant.
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4- Rhubarb, consist of the dried rhizome and root of
Rheum officinalis and R. emodi (Indian)
[Polygonaceae].
Used as cathartic.
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5- Senna, is the dried leaves (leaflets) of Cassia
acutifolia or C. angustifolia [Fabaceae]. Angustifolia = narrow leaf
The plant is indigenous for:- Somalia
Egypt
Sudan
India
Senna is graded according to the size of the leaf an the color of the leaflets;
Blue-green leaves are the best , while the yellowish leaves are poorest.
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The principal active constituents of Senna are dimeric glycosides
whose aglycones are composed of rhein.
The highest concentration glycosides are:-
A. Sennidin A
B. Sennidin B
Which are pair of stereoisomers whose aglycone are rhein
dianthrone.
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Senna has more laxative action when compared to
cascara, but with more gripping.
It is widely used because it is less coasty.
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Saponin glycosides
Complex organic compounds, widely distributed in higher plants.
These compounds form colloidal solutions in water (soap-like)
that foam upon shaking, hence the name saponin.
Some of these compounds are toxic, therefore; termed as sapotoxins.
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1- Glycyrrhiza (licorice) (÷ Ó◊Ód) Is the dried rhizome and roots of Glycyrrhiza glabra and G. glandulifera (Fam: Fabaceae)
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Glycyrrhiza = Sweet roots Glabra = Smoothe The extract contains Glycyrrhizic acid
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Glycyrrhizic acid is about 50 times is sweet as sugar.
Therefore; it is used in pharmaceuticals as flavoring and
sweetener.
Other medicinal actions:-
Demulcent
Expectorant
Anti-inflammatory
Used in peptic ulcer
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Addison’s disease (chronic adrenocortical
insufficiency)
Dyspepsia
Used as hepatoprotectant in hepatitis and cirrhosis
(Japan)
Antiviral action (H. simplex)
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Side effects
Water and salt retention
Hypertension
Edema
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2- Ginseng
The dried roots of Panax ginseng (Asia) and P.
quinquefolius (American) (Fam: Araliaceae)
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Ginseng was used in Chinese herbal medicine, also was
used by Native Americans for treatment of various
disease state.
The plant is a perennial herb needs about six years for growth
and formation of the active constituents.
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Used as:
- General tonic.
- Carminative.
- Expectorant.
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Recently used as:
- Anti stress/increases physical stamina (elevates the
body threshold for stress), also called adaptogenic.
- Increases blood supply to the brain (used after CVA).
- Amnesia (resulted from brain damage).
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The proposed mechanism is:
Increasing metabolism in CNS resulting in increasing
the sympathetic activities which leads to increase
alertness.
Although neuronal stem cell regeneration is proposed.
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- Also used in type II diabetes (some metabolites found
in the plant like the Ginkolides A and B have blood
sugar lowering action), while the mechanism is
unknown.
- It also regulates the functions of the adrenal cortex
and thyroid gland.
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- Some research works show ability to increase libido
in men through direct CNS stimulation.
The plant contains important glycosides like:-
1- Ginsenoside (ginkgolides).
2- Panaxoside.
3- Chikusitsusaponin.
4- Phytoestrogens.
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Ginsenoside (Rg1)
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The drug should undergo Q.C. because there are many
related species that vary in the composition of their
active constituents.
Bad storage conditions also decrease the activity.
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The plant or its extract should not be coadministerd with:- 1- Antihypertensive agents. 2- NSAIDs. 3- Heparin. 4- Oral anticoagulants.
Side effects:- Vomiting, diarrhea and in some cases; skin rashes.
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Alcohol glycosides When the aglycone part is an alcohol. Ex: Salicin Salix purpurea S. Fragilis (Fam: Salicaceae) Upon hydrolysis yield Salicylic acid.
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Pharmacognosy I Lecture: 5, Glycosides
Hydrolysis of Salicin to Salicylic acid
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Salicin interfere with pain and inflammation, therefore;
it has been used as a model for production of other
anti-inflammatory analgesics (like ibuprofen), which
might be oxidized in the body to SA.
SA is non-selective drug, acting on both COX 1 & 2
through inhibition.
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Aldehyde glycosides
Ex:
Vanillin
Is a volatile mixture used as food
additive and in pharmaceuticals as
flavoring agent.
Mainly found in Mexico and Tahiti
(Vanilla tahitensis) (Fam: Orchidaceae)
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Phenol glycosides
Arbutin (bearberry) (Skin
lightening agent)
Arctostaphylos alpina
(Fam: Ericaceae)
The glycoside is hydrolyzed to
hydroquinone.
Inhibits tyrosinase enz. and
consequently inhibit the formation
of melanin.
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Uses: Skin hyperpigmentations (melasma). Erythematous eczema. Antiseptic. Antidandruff. Psoriasis.
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Mechanism of action:- Inhibit melanogenesis
-
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Aminated derivative (Metol) and
resorcinol.
Used in dermatitis and as developer
in photography.
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Hydroquinone has potential carcinogenic action on
thyroid (thyroid follicular cell hyperplasia),
hepatocelluar adnomas and renal tubular adenomas
and skin.
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Cyanogenic glycosides These glycosides upon hydrolysis yield hydrocyanic acid and sugar.
H-C=N is very toxic. It interferes with respiratory chain in RBCs,
the victim will be unable to utilize oxygen and consequently dies
because of hypoxia, cyanosis, brain damage and coma.
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Releasing hydrocyanic acid is utilized by plants as
antibacterial antifungal agent.
Example of plant that contains cyanogenic glycosides:-
• Bitter almond.
• Apricot.
• Peach.
• Herring
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Amygdalin, from Prunus amygdalus, P. serotina
[Rosaceae].
Is a chemical compound is a cyanogenic glycoside, when it be in
direct contact with glycosylase enzymes, yield mandilonitril and
glucose. In the next step hydrocyanic acid and the conjugated
sugar.
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These compounds also possess anticancer activity
through HCN release and cell damage.
At low concentration they are used as flavoring agents.
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Thank you
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