3-Phenolic glycosides - part 2 Anthracene glycosides .pptx

ANTHRACENE GLYCOSIDES
ASSOC. PROF. DR. MOSTAFA MAHMOUD HEGAZY

 content
 Anthracene glycosides
 mechanism of Action
 Chemistry
 Tests for Identification of anthracene glycosides
 I- Anthraquinones (alizarin, aloe-emodin and rhein)
 Metabolism of Diacerein (1-8 Diacetyl Rhein)
 II- Anthranols and anthrones (Chrysarobin and Barbaloin)
 III- Dianthrones (Sennosides A-D and Hypericin)

Glycosides Dr. Mostafa Hegazy
Anthracene glycosides (anthraquinone glycosides)
Def.: they are oxygenated derivatives of pharmacological importance that
are used as laxatives or cathartics, anti-inflammatory, antibacterial,
antifungal and also as natural dyes.
alizarin

Mechanism of Action as stimulating hydragogue laxative
By increasing the tone of the smooth muscle in the wall of the
colon (peristalsis) and stimulating the secretion of water and
electrolytes into the large intestine.

Chemistry
 Anthracene derivatives occur as(O-
or C-glycosides) and at different
oxidation levels viz.,
anthraquinone, anthranol ,
anthrone, and oxanthrone
derivatives.
 Glycosides of anthranols and
anthrones have a more drastic
action than the corresponding
anthraquinone glycosides.

Tests for Identification of anthracene glycosides
1- Microsublimation test for free anthraquinones
2- Bornträger's test for anthraquinone glycosides
3- Modified Bornträger's test
4- Schontenten's test for anthranols
1- Microsublimation test for free anthraquinones
Drugs containing free anthraquinones give on microsublimation
needle-like crystals which give a characteristic red color with alkali.

2- Bornträger's test for anthraquinone
• The powdered drug (0.1g) is boiled for 10 minutes with about 5
ml of dilute acid (hydrolysis of glycosides), filter and cool
(aglycones are soluble in hot but not in cold water).
• Shake the filtrate with an immiscible organic solvent (benzene,
ether or chloroform).
• Separate the organic layer (anthraquinone aglycones) and
shake vigorously with ammonium hydroxide (10 %); the
aqueous layer becomes rose pink or cherry red immediately.

3- Modified Bornträger's test
I- Anthranols
• By addition of oxidizing agents such as a drop
of H2O2 (c.f. FeCl3 not used) will speed the
oxidation process.
• Anthranols give an initial yellow-orange colour
in alkali, however they are air-oxidized to yield
the corresponding anthraquinone and thus
produce a red color only on standing for
longtime (c.f. anthraquinones). Anthranol
glycosides should, therefore, be subjected to a
process of oxidative hydrolysis to give a positive
response.

• II- Dianthrones
• In case of dianthrones (such as sennosides), the powdered drug is
boiled with alcoholic KOH (hydrolysis, formation of K salts of
aglycones and cleavage of the C-C linkage) and filtered.
• The filtrate is treated with dilute HCl (acidification), extracted with
ether and the ethereal layer treated with ammonia; a rose-red to
intense red color is produced in the aqueous layer.
4- Schontenten's test for anthranols:
• When a solution of borax is added to an aqueous extract of the crude
drug (Aloe), a green fluorescence is produced.

• Quantitative determination of anthracene glycosides
• The most commonly used methods are the colorimetric and biological
methods, gravimetric determination is sometimes carried out.
1- Colorimetric method for determination of total anthraquinones
• After hydrolysis with acid, the aglycone is extracted with ethyl acetate
and is allowed to react with KOH to give red or violet color.
• The intensity of this color is directly proportional to the concentration of
anthraquinone, and can be measured colorimetrically.
• Anthranol content can, similarly, be determined but after oxidation
with H2O2.

• 2- Fluorimetric method
• Schontenten’s test for anthranols can be used for Fluorimetric estimation of
the anthranol and anthrone contents in crude drugs.
3- Biological method
• Since anthraquinones induce laxation after oral administration to experimental
animals, the concentration of these compounds can be determined by
measuring the water content in feces of animals given certain doses of
anthraquinones as compared to that obtained after administration of a standard
laxative compound.

I: Anthraquinones
• Anthraquinones are the most widely distributed anthracene derivatives in plant
kingdom. They give a positive Bornträger's test.
• The most common examples of this group are: alizarin, aloe-emodin and rhein.
• Most naturally occurring anthraquinones are present together with their 8-O-
glucoside derivatives (e.g. aloe-emodin 8-O-glucoside and rhein 8-O-glucoside).

• Metabolism of anthraquinone glycosides
• Anthraquinones and their glycosides are reduced to the more active
anthranols and anthrones by the action of specific bacterial enzymes in
the large intestine.
• Glycosides are first hydrolyzed then their aglycone reduced to yield the
laxative principle e.g. the metabolism of Rhein and its derivatives:
• Metabolism of Rhein–8-O-glucoside
• Rhein–8-O-glucoside is hydrolyzed to rhein (by the effect of intestinal
bacterial b-glucosidase enzyme) and then transformed to rhein anthrone that
is the final laxative principle of both rhein and its glucoside.

• Metabolism of anthraquinone glycosides
• Rhein or rhein glucoside by themselves are not effective as laxative,
but must be transformed first to rhein anthrone (i.e. after hydrolysis
and/or reduction by intestinal bacteria).
• Rhein anthrone could be prepared from rhein by the treatment with
SnCl2 in acid medium. Yet, the synthetic rhein anthrone is unstable
and readily oxidized to rhein or polymerized by the effect of light and
oxygen.

• Metabolism of Diacerein (1-8 Diacetyl Rhein)
• Diacerein (1,8-Diacetylrhein) is a synthetic diacetyl derivative of rhein.
• Diacerein exerts both analgesic and anti-inflammatory activities, and is
clinically used for the treatment of osteoarthritis.
• Diacerein is deacetylated by intestinal bacteria to yield rhein, which is the
active compound and produces two different effects according to the site of
absorption:
• When absorbed from the upper intestine to the blood stream it exerts an anti-
inflammatory activity.
• The non-absorbed part of rhein undergoes reduction to rhein anthrone in the
large intestine by the effect of intestinal bacteria and acts as laxative (this
pathway leads to diarrhea in some of the patients taking diacerein).

Metabolism of Diacerein (1-8 Diacetyl Rhein)
except for moderate and transient digestive disturbances (soft stools, diarrhoea)

• Preparation of rhein from rhubarb
• Extract the powder with water (to remove water-soluble
impurities such as tannins, sugars etc...).
• Extract the marc with methyl isobutyl ketone (to extract rhein).
• Shake the extract with NaHCO3 (rhein as water-soluble sodium
salt).
• Accordingly, any anthraquinone containing a free COOH
group, e.g. Rhein can be separated from an organic solution by
adding NaHCO3.
• Acidify with acetic acid (to precipitate rhein).
• Wash with water followed by acetone (to remove pigments),
• Crystallize rhein from acetone.

Why the drug is diacerin not rhein?

• Chrysophanic acid (Chrysophanol)
• It occurs in the barks of Cassia, Rumex spp, cascara, frangula and
rhubarb.
• Uses It is also used as antimicrobial and cathartic agent.
• It is used for commercial production of Chrysarobin by reacting
chrysophanol with Zn dust/acetic acid.

• Carminic acid
• Red pigment present in scale insect (Cocchineal),
Coccus cacti.
• Carminic acid is an anthraquinone C-glucoside.
• It is soluble in water and alcohol.
• Uses:
• In color photography and painting.
• As a natural color for foods and drugs.
• As a stain for bacteria.

• II- Anthranols and anthrones
• These are reduced anthraquinones and occur either free or
combined.
• Oxidation of these compounds may take place during storage of
specially powdered crude drugs.
• Examples are Chrysarobin and Barbaloin.

CHRYSAROBIN (CHRYSOPHANIC ACID ANTHRANOL)
• It is obtained from the roots of Cassia spp and Rumex spp.
• Uses
• Chrysarobin is used as antipsoriatic for the treatment of skin
diseases, but may cause renal damage.
• It has antifungal and keratolytic properties

• Barbaloin
• It is a mild laxative C-glucoside isolated from
Aloes.
• Barbaloin by itself is not laxative but must be
transformed first to aloe-emodin anthrone that is
the intestinal bacterial metabolite responsible for
the laxative effect of barbaloin.

• III- Dianthrones
• These are derived from two molecules of anthrone
• The molecules may be identical or different.
• They occur in Senna, Rhubarb and Hypericum (in the free
state and in glycosidal combination).
• Examples are: Sennosides A-D and Hypericin.

• Sennosides A-D are glucosides isolated from Senna leaves and
pods (Cassia angustifolia, Leguminosae).
• The aglycones of these compounds are called sennidins A-D,
respectively.

• Sennosides A and C are optically active (levorotatory, trans
isomers), while sennoside B is the meso isomer (being
intramolecularly compensated).
• All are soluble in NaHCO3 (that is used for extracting
sennosides from plant) as they all contain free carboxylic
groups).
• Sennoside A is insoluble in water, while sennoside B is water-
soluble (this can be used for separating a mixture of A & B).
• Uses
• Sennosides are used as irritant laxative.

• Rhein anthrone, the ultimate laxative principle of sennosides A and B, is
liberated by the effect of intestinal bacteria after oral administration of
sennosides.
• Sennosides A and B can be used for semi-synthesis of Rhein anthrone as
follows:
• Hydrolysis with dilute HCl or H2SO4 (to liberate the aglycones,
sennidins).
• Adjustment of the pH of the medium to 7-8 with NaHCO3 (to help
reductive cleavage of sennidins to rhein anthrone), and finally addition of
FeCl3/H2O2 (to help in oxidation of rhein anthrone to rhein).

• Structure-Activity Relationship:
• Glycosylation is essential for activity.
• Hydroxylation at C-1 and C-8 is essential for activity.
• Oxidation level at C-9 and C-10 is important:
• Highest level of oxidation (anthraquinones) have the lowest activity.
• Oxanthrones are less active than anthrones.
• Complete reduction of C-9 and C-10 eliminates the activity.
• Substitution at C-3 have great impact on activity:
CH2OH > CH3 > COOH

• Hypericin
• It is isolated from the dried flowering tops of Hypericum
perforatum.
• It is an example of aromatic polycyclic dianthrones.

• Uses
• Hypericin is used as
tranquilizer, antidepressant
(MAO inhibitor), and antiviral
(anti-HIV).
• Caution: Hypericin is a
photosensitizing agent, so
sunray (UV) and solarium
treatment, especially in people
with fair skin.

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