Glycosides

Salicin, a glycoside related to aspirin

 History
• Willow bark has been used as a traditional
medicine for more than 3500 years. Unknown to
the ancient Sumerians and Egyptians who made
use of it, the active agent within willow bark was
salicin, which would later form the basis of the
discovery of aspirin.
 Introduction
• In chemistry, a glycoside is a molecule in which a sugar is bound
to another functional group via a glycosidic bond.
• Glycosides play numerous important roles in living organisms.
Many plants store chemicals in the form of inactive
glycosides,These can be activated by enzyme hydrolysis, which
causes the sugar part to be broken off, making the chemical
available for use.
• Many such plant glycosides are used as medications. Several
species of Heliconius butterfly are capable of incorporating these
plant compounds as a form of chemical defense against
predators.
• In animals and humans, poisons are often bound to sugar
molecules as part of their elimination from the body.
 Glycosides
• more important in medicine than a lot of drugs
• occur in higher plant tissues in very small
amounts
• formed by a biochemical reaction that makes a
water insoluble compound more polar than a
water soluble molecule
• hence can be removed from an organic system

Glycosides consist of a sugar residue

covalently bound to a different structure
called the aglycone
• Almost all plants that contain glycosides also
contain enzymes that bring their hydrolysis
(glycosidases).
• Glycosidases are enzymes that normally
break glycosidic bonds during glycoprocessing
or catabolism of oligosaccharides,
• but by placing glycosidases under certain
controlled reaction conditions they can be
utilized to form, rather than break, glycosidic
bonds
• higher plant glycosides used therapeutically
• have a bio-action
– therapeutic in low doses, toxic in excess
– have a narrow therapeutic index

• Glycosides =
– aglycone / ‘genin’ - hydrocarbon part
– + glycone - sugar part (water soluble)
carbohydrate part

• Ether linked:
– X-OH + R-OH ↔ X-O-R + H20 (glycosidic bond)
– unstable
– Hydrolyzed by (dilute acid, enzymes)
• The sugar moiety can be joined to the
aglycone in various ways:
1.Oxygen (O-glycoside)
2.Sulphur (S-glycoside)
3.Nitrogen (N-glycoside)
4.Carbon (C­glycoside
Oxygen (O-glycoside)
They are common in higher in plants. Example: Senna,
Rhubarb (Fig. 1.5). They are hydrolysed by treatment with
acid or alkali into glycone and aglycone portions.
• S-(a thioglycoside),
Glucosinolates are examples of S-glycosides widely present in the
Brassica family (cauliflower, sprouts, cabbage, and other), and are
hydrolyzed by enzymes to volatile flavors when cellular structure is
disrupted.
The occurrence of this glycoside is in isothiocyanate glycoside like
sinigrin in black mustard formed by the condensation of
sulphohydryl group aglycone to OH group of glycone

• S-Linkage of Sinigrin in Black Mustard

 • N- (a glycosylamine),
They are mostly present in the nucleoside where the amino group reacts with the
OH group of ribose or deoxyribose resulting in N-glycoside

N-Linkage of Nucleoside
 C- (a C-glycoside)
• In this regard, major examples of clinically approved C-
glycoside drugs for the treatment of type II diabetes are
dapagliflozin, canagliflozin, empagliflozin, and an anti-
aging cosmetic Pro-Xylane.

dapagliflozin, Pro-Xylane.
– direct C-C (aloes)
• resistant to hydrolysis
• oxidise C link with ferric chloride and split bond
• They do not hydrolyse by heating with dilute acid or
alkalis but occur by oxidative hydrolysis with FeCl3.

What is C Glucosides?
• C-Glycosides, in which a sugar moiety is linked via
a carbon-carbon (C-C) bond to a non-sugar moiety
(aglycone), are found in our food and medicine.

• The C-C bond is cleaved by intestinal microbes and

the resulting aglycones exert various bioactivities.
Examples
Carminic acid is a red glucosidal hydroxyanthrapurin that
occurs naturally in some scale insects. The insects produce the
acid as a deterrent to predators.
An aluminum salt of carminic acid is the coloring agent in
carmine, a pigmenn

Carminic acid
Examples
• Aloin:

Aloin, is a bitter, yellow-brown colored compound noted

in the exudate of at least 68 Aloe species at levels from
0.1 to 6.6% of leaf dry weight

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• important to determine which isomer has the activity
– α or β glycosidal bond from an α or β pyranose sugar ring

– natural glycosides tend to have β-linkage

– acid hydrolysis to cleave α or β glycosides
• The difference between alpha and beta forms of pyranose ring
is that.
• In the β form, the OH group in the 1 position (the far right) is
up, and, in the α form, the OH group in the 1 position (the far
right) is down
Sugars vary
– glucose, rhamnose, xylose, etc

– simple one or more units polysaccharides

– can be branched
• (To determine non-linear linkages)
– acetylate or methylate the sugar
– above taken up by all free –OH groups
 Solubility
• Glycosides are usually soluble in water
and in polar organic solvents.
• whereas aglycones are normally insoluble
or only slightly soluble in water.
 Preparation & extraction
• Polar substances – soluble in polar solvents

• Extraction:
– starting material should be well dried and
carefully stored
• enzymes will hydrolyse glycosides if >10%
water content remaining
– cold extraction procedure (room temp)
• with percolation and maceration
– water, water/alcohol mixture or alcohol
 • Purification:
– solvent/solvent partition
• H2O/hexane or CH3Cl (methyl chloride)to remove
pigments in the non-polar phase
– or adsorption methods
• make column and do chromatography
• or mix with adsorbents (Celite, Fuller’s Earth,
graphite)
• or use heavy metal to precipitate out impurities
– should end up with clear alcoholic extract
– crystallisation – final stage
Purification of Glycosides from Natural Sources:
Alcohol and acetone are not used as solvents for aglycone separation
because they are water-miscible.
The best solvent is ethyl acetate to extract the aglycone part because of the
solvent is immiscible in water and in a separating funnel the solvent is
present in the upper layer
 Classification
• On the basis of aglycone structure
• [1] Saponins
• aglycone = pentacyclic or steroid-triterpenoid
• [2] Cardiac glycosides (poisons)
• from squill, digitalis, lily of the valley
• used as crow poisons through history
• aglycone = steroid
• [3] Anthracene derivatives (purgatives)
• can cause side effects and adverse reactions but
not death
• [4] Flavanoids and Coumarins
• yellow or orange colored
• phenolic compounds with aromatic rings
 – (a) Flavanoids
• mainly anti-inflammatory drugs and antioxidants
– (b) Coumarins
• eg from clover - basis of anticoagulants
• [5] Simple phenols
• from willow and poplar bark
• analgesics – aspirin
• [6] Thioglycosides or Mustard oils
• S-linked compounds
[7] .Cyanogenic compounds
• breakdown liberating CN
• found in Bitter Almond, ‘cherry’ bark and kernel
• also liberate benzaldehyde on breakdown (almond
smell)
[8]. Aldehydye compounds
• Vanilla beans