glycosides - · pdf file• odorless except saponin (glycyrrhizin ). • glycosides with...

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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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).


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ROSugar

RCSugar

Nitrogen (N)

Sulfur (S)

May be also involved but a less extent


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Hydrolysis of glycosides


D-Glucose Saligenine Salicin

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In some cases, false sugars like (glucouronic acid,

galactouronic acid) or aminosugars may be involved.


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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.

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2. Source of energy (sugar reservoir).

3. Growth regulators.

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4. Pollinating agents.

5. Protecting agents (some are toxic while other have

antibacterial activities).

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Bitter Almond

Bacteria

HCN Amygdalin

Myrosinase

hydrolysis

Example on plant defense strategy using glycosides to combat bacterial infections.


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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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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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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


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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


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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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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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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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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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