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Glycosides
Glycosides
Glycosides
Definition:
Glycosides are (usually) non-reducing compounds, on hydrolysis by
reagents or enzymes yield one or more reducing sugars among the
products of hydrolysis.
non-sugar
(genin)
glycosidic
linkage
sugar
(glycone)
CH2OH
O-C6 H11 O5
OH
C6 H12 O6 +
-H2O
Glycosidic linkage
Sugar
Salicin
C 6H12 O6
Sugar
+ CH2
SH
CH
CH2
CH2
N
CH
CH2
OSO3 K
Sinigrin
C6 H11 O5
OSO3 K
2
NH2
OHCH2
NH2
OH
N
N
OH OH
N
N
OHCH2
N
O
Glycosidic linkage
H
OH OH
Adenine
4- C-Glycoside
HO
C6 H12 O6
HO
OH
OH
+
CH2 OH
CH2 OH
Glycosidic
linkage
C6 H11 O5
Barbaloin
Sugars in glycosides:
1- Monosaccharide (glucose in salicin, rhamnose in ouabain)
2- Disaccharides (gentiobiose in amygdalin).
3- Trisaccharides (strophanthotriose).
4- Tetrasaccharides (purpurea glycosides)
5- Rare sugers (deoxy sugers)
6- Sugar linked in one position to the aglycone rarely in 2 positions as
sennosides.
A- 6-deoxy sugars
e.g., 1- methylpentoses
H
H
HO
HO
CHO
C OH
C OH
C H
C H
CH3
2- -L-rhamnose.
HO CH3
O OH
OH OH
2- D.cymarose
3- diginose
6
CHO
CHO
CHO
C H2
C H2
C OH
C OCH3
C H2
OH
OH
OH
OH
CH3
CH3
H3 CO C
HO C
H
OH
CH3
C- 2-deoxy sugars
e.g.,
2-deoxy-D-ribose
HOH2 C
H
O
H
OH
OH H
1- Acid hydrolysis:
a- Acetal linkage between the aglycon and glycone more unstable than
that between two individual sugars within the molecule.
b- all glycosides are hydrolysable by acids non specific (except Cglycosides).
c- Glycosides containing 2-deoxy sugars are more unstable towards acid
hydrolysis even at room temperature.
d- C-glycosides are very stable (need oxidative hydrolysis).
2- Alkali hydrolysis:
1- mild alkali
2- strong alkali
3- Enzyme hydrolysis:
1- Enzymatic hydrolysis is specific for each glycoside there is a specific
enzyme that exerts a hydrolytic action on it.
2- The same enzyme is capable to hydrolyze different glycosides, but
and sterio-isomers of the same glycoside are usually not hydrolysed
by the same enzyme.
acetate.
10
4- Cyanogenetic glycosides give upon hydrolysis hydrocyanic acid
2- Prunasin [Prunase]
glucose + HCN +
H
C
OC 6 H 11 O 5
CN
+ glucose
11
12
13
14
8
10
5
17
13
3
Sugar
CH3
OH
16
15
7
6
14
OH 12
11
1
2
13
9
14
8
10
3
Sugar
CH3
OH
17
16
15
7
6
Cardenolides
Digitalis glycosides
R=CH3
Strophanthus glycosides
R=CHO OR CH2OH
15
O
O
OH 12
11
1
2
13
9
14
8
10
3
Sugar
17
R1
7
16
15
R2
Bufadienolides
Squill glycosides
Bufotoxin
R1=OH, R2=H
R1 & R2 = ester group
16
CHO
CHO
C H2
C H2
C OH
C OCH3
CHO
OH
OH
OH
OH
CH3 O C H
H
OH
OH
CH3
CH3
Cyamarose
Thevetose
CH3
Digitoxose
HC OH
Isolation difficulties:
1- Major difficulty in the isolation of 1 ry glycosides from the
crude drug.. why? because 1ry glycosides are converted
into secondary glycosides by hydrolysable enzymes.
2- Other difficulty is the existence of several closely related
glycosides in the same drug, which are extremely difficult
to separate and purify.
17
O
R1
12
11
1
2
14
8
10
3
Compounds
Digitoxigenin
17
13
16
OH
R2
15
7
6
R1
H
R2
H
Gitoxigenin
OH
Digoxigenin
OH
DX = Digitoxose, DX (AC)=Acetyldigitoxose,G
= Glucose.
18
terminal
acetyldigitoxin,
glucose,
give
acetylgitoxin
the
and
2ry
glycosides
acetyldigoxin
respectively.
2- The deacetyl-lanatosides A, B and C can be obtained by
the alkaline hydrolysis of the corresponding lanatosides.
3- Digitoxin, gitoxin and digoxin are obtained by the action
of alkali on their acetyl-derivatives.
Lanatoside A
purpurea gly. A
Specific
enzyme
Alkaline
hydrolysis
Specific
enzyme
Digitoxin
Acetyldigitoxin
Alkaline
hydrolysis
Acid hydrolysis
Digitoxigenin + 3 digitoxose
19
1- The
glycoside
K-strophanthoside
(a
trioside),
K-
11
1
2
O
Cymarose
B-glucose
a-glucose
CHO 9
10
5
3
4
12 13
OH 6
14
8
OH
7
17
16
15
K- strophanthidin
Cymarin
K- strophanthin B
K- strophanthoside
20
OH
OH
OH
1
11
CH2 9
17
13
14
10
3
Rhamnose
12
OH
16
15
7
6
OH
Ouabain (G-strophanthin)
21
OH
Glucose-Glucose-Rhamnose
Scillaridin A
Proscillaridin A
Scillarin A
Glucoscillarin A
Structure
Glucoscillarin
Scillaridin A ---RHG---G
Scillarin A
Scillaridin A ---RHG
Proscillaridin A
Scillaridin A ---RH
22
Alcohols are good solvents for both the glycosides and the
* pet.ether and ether are used for defatting process of drug, they
do not dissolve CG.
23
12
11
1 R
2
Sugar
13
9
14
8
10
3
CH3
OH
7
CH3
12
17
11
16
-H2O
15
14
8
10
3
Sugar
7
6
17
13
16
15
24
O
12
11
1
2
Sugar
9
8
10
4
14
OH
16
CH3
12
17
13
3
O
CH3
OH
11
-2H2 O
15
7
6
14
8
10
3
Sugar
7
6
17
13
16
15
25
1- Cardiotonics,
CHF,
rheumatic
heart
disease,
atherosclerosis, HTN.
2- Diuretics (capillary of the kidneys are dialated).
26
lanatoside
C,
deslanoside,
strophanthus,
27
Anthraquinone
Anthrone
Anthranol
O
1
OH
2 4H
10
10
H
O
2H
8
7
10
OH
Oxanthrone
1-
O-glycosides
where
the
aglycone
moiety
is
1,8
Gl
OH
1
10
5
Gl
4
O
Aloe-emodin-8-glycoside
OH
1
10
CH2 OH
Gl
4
O
Chrysophanol-8-glycoside
OH
1
10
COOH
Rhein-8-glycoside
CH3
28
Gl
OH
OH
2
3
10
5
4
O
Emodin-oxanthrone-9-glucoside
OH
8
7
6
OH
10
CH2 OH
C6 H11 O5
Barbaloin
O
8
6
5
OH
10
COOH
H
COOH
Gl
OH
29
Cassia
senna
(C.acutifolia),
Tinnevelly
senna
(C.angustifolia).
Constituents:
Dimeric anthracene glycosides derived from two anthrones
moieties which may be:
OH
OH
1
OH
2
10
5
Aloe-emodin anthrone
OH
1
8
CH2 OH
10
5
COOH
Rhein anthrone
30
Gl
7
O
8
6
5
OH
10
COOH
H
COOH
Gl
OH
Sennosides A &B
O
8
6
5
OH
10
CH2 OH
H
COOH
Gl
OH
Sennoside C&D
31
OH
OH
Gl
CH2 OH
Gl
Cascaroside A& B
OH
Gl
CH2 OH
Gl
Barbaloin
OH
OH
Gl
CH3
Chrysaloin
OH
Gl
CH3
Cascaroside C & D
32
C- A number of O- glycosides:
e.g., derived from emodin, emodine oxanthrone, aloe emodin
and chrysophanol.
OH
OH
OH
OH
CH2 OH
CH3
O
O
Aloe emodin
Chrysophanol
E- Free anthraquinones:
Aloe emodin, chysophanol and emodin.
RO
OH
CH3
O
Frangulin
Glucofrangulin
R= Rhamnose
R= Rhamnose-glucose
33
1- Consist
of
glycoside
of
rhein,
rhein
anthrone,
34
OH
Danthrone
Note:
1- The 1ry glycosides are more active than the aloins while
the free anthraquinon have little purgative activity.
2- C-C glycosides, aloins are very resistance to hydrolysis
and are not easily hydrolysed (like other anthrones and
anthranols) to corresponding anthraquinones.
3- Aloin type glycosides are present in aloes and other
anthracene bearing drugs of the family liliaceae.
35
1- Glycosilation:
The purgative action of anthracene bearing drugs is owed to
their anthracene glycosidal content rather than their content
of free anthracene aglycones (i.e., glycosylation is the main
requirement for activity, as the sugar moiety serve to
transport the aglycone to the site of action in the large
intestine).
2- Hydroxylation:
Hydroxylation of C-1, C-8 is essential for activity. Increase
hydroxylation leading to increase solubility.
3-
Oxidation level:
The degree of oxidation at positions C-9 & C-10 plays an
important role in the pharmacological activity. Higher
oxidation level at C-9 & C-10 caused lowering of activity.
i.e., anthrones and anthranols are more potent than their
corresponding oxanthrones, which in turn more active than
their corresponding anthraquinones. Complete reduction of
C-10 &C-9 lead to complete loss of activity.
36
37
38
39
isoflavones,
flavonols,
flavanones,
(true
flavones,
are
2-phenyl
chromones
(2-phenyl
(2-phenylbenzopyran)
(2-phenylbenzopyrone)
40
1'
6
5
10
3'
2'
1
O
4'
6'
5'
Flavan
Flavone
O
OH
O
Flavonol
Isoflavone
O
H
H
O
Flavanone
structure.
Anthocyanidins
and
its
glycosides
41
8
7
6
5
2'
+
O
1'
3
10
3'
4' OH
6'
5'
R
OH
8
7
6
5
Anthocyanidins
10
Cl
+
O
2'
3'
1'
3
OH
OH
4' OH
6'
5'
Cyanidin chloride
OH
phenyl-styryl
ketone,
or
benzylidene
acetophenone.
Aurones are oxidized forms that are obtained by enzymatic
oxidation. Instead of the central pyrone ring of the normal
flavonoidal structure, aurones have five membered ring.
O
CH
Chalcon
Aurone
42
43
Benzoyl
O
A
R
Cinnamoyl
O
I
Band
II
Band
200
Wave length
Hypsochromic shift
400
Bathochromic shift
R=OH
R=O-substitution
Flavones
flavonols
3-sub flavonol
Band I: 304-350 nm
Band I: 352-385
Band I: 328-357
44
A
OH
OCH3
Diosmin
Upon hydrolysis, diosmin yields rhamnose, glucose and
diosmetin.
2- Rutin and quercetrin: are examples of flavonol
glycosides
a- Rutin occurs in the leaves of buckwheat. It is the 3rhamnoglucoside (called rutinose) of the genin quercitin.
It gives on hydrolysis the aglycone (quercitin) beside one
molecule of glucose, and one molecule of rhamnose.
Rutin is used to
45
HO
OH
OR
OH
Quercetin:
Quercetrin:
Rutin:
R=H
R= rhamnosyl
R=rutinosyl
46
OH
A
OH
OCH3
Hesperitin R:H
Hesperidin R:rutinosyl
rhamnose,
47
Isoflavone:
1- Genistein show significant oestrogenic activity.
O
HO
OH
O
OH
Flavono-lignans
Coupling of a flavonoid moiety with hemi-lignan molecule
by oxidative coupling.
48
OH
OR
OH
+
OH
OH
Hemi-lignan moiety
Flavonoid moiety
OH
O
OH
O
OH
OCH3
OH
Flavonolignan
OH
A
OH
OH
OH
OCH3
Silybin
OH
49
O
O
A
CH3
O
Flavoxate
Uses:
To remove pain (anti-spasmodic) and anti-inflammatory of the
genitor urinary tract.
Flavoxate tablets are available under several names: Urispas,
Uronid, Spasurit, Genurin).
50
51
Chemically:
Saponins are classified according to the genin part into:
1- Steroidal type C25.
2- Triterpinoidal type C30.
Both types of saponins have the glycosidic linkage at position 3.
O
COOH
R2
HO
HO
R1
Diosgenin
Quillaic acid: R1=CHO, R=OH
Olianolic acid R1=CH3, R2=H
52
CH3
OH
O
CO
OH
Testosterone
Progesterone
O
CH2 OH
CO
OH
HO
Cortisone
Diosgenin
active
substances
(e.g.,
cardiac
glycosides).
3- Many saponin-containing drugs are used as expectorants
(e.g., Ipeca, Senaga and liquorice) as their contents of
saponins stimulate bronchial secretion and also activate
the ciliary epithelium of the bronchi.
a-The triterpenoidal saponin glycoside, glycyrrhizin, is the
main sweet principle of liquorice. It is calcium and
potassium salts of glycyrrhizic acid, which in tern is the
diglucuronic acid glycoside of glycyrrhitinic acid.
53
COOH
Glucuronic-glucuronic
O
B-Glycyrrhitinic
Glycyrrhizic acid
Glycyrrhizin =Ca, K
54
as
gallic
acid,
catechin,
flavan-3,4-diol
and
55
HO
HO
OH
HO
OH
HO
COOH
COOC6 H11 O5
Gallic acid
Glucogallin
OH
CH=CH-COO
HO
OH
HO
HO
OH
Chlorogenic acid
OH
OH
Flavan-3,4-diol
Hydrolysable tannins
Condensed tannins
OH
56
1- Hydrolysable tannins:
a- These can be hydrolyzed by acids or enzymes to give
phenolic acids (gallic or ellagic) and glucose, so called
phenolic acid glycosides.
b- Tannins of gallic acid are called gallitannins and those of
ellagic acid is called ellagitannins.
c- Dry distillation of hydrolysable tannins gives pyrogallol.
This class is named pyrogallol tannins.
d- Gallitannins and ellagitannins react with ferric salts to give
bluish color precipitate.
2- Condensed tannins:
a- These are more resistant to hydrolysis upon prolonged
heating with acids.
b- They undergo decomposition (not hydrolysis) to give a
red soluble compound (phlobaphane).
c- Condensed tannins are derived from catechin and flavan,
3,4-diol.
d- Dry distillation of condensed tannins gives catechol. This
class is named catechol tannins.
e- Being phenolic, it reacts with ferric salts to give greenish
color precipitate.
57
1- Salicin:
Salicin is classified as:
1- Alcoholic glycoside, as it contains free primary alcoholic
group.
2- A phenolic glycoside, as its aglycone is phenolic in
nature.
CH2 OH
Gl O
Salicin
58
Acid
Enzyme
CH2 OH
CH2 OH
HO
+ Glucose
Saligenin
+ Glucose
CH2 OH
Saliretin
59
OH
OCH3
O-Gl
O-Gl
Arbutin
Methylarbutin
60
CHO
OCH3
OCH3
O-Gl
OH
Glucovanillin
Vanillin
CH=CH-CH2 OH
Hydrolysis
CHO
Oxidation
OCH3
OCH3
OCH3
OH
O-Gl
Coniferin
OH
Coniferyl alcohol
Vanillin
2- From Eugenol
CH2 -CH=CH2
CH=CH-CH3
KOH
Oxidation
OCH3
OH
Eugenol
CHO
OCH3
OH
isoeugenol
OCH3
OH
Vanillin
61
Hydrolysis
coniferyl alcohol
OH
HCN
CH
Mandilonitrile glycosides
CN
Benzaldehyde
Mandilonitrile
CH3
C
Sugars
HCN
CH3
OH
C
Sugars
CN
CH3
CH3
Acetone
Acetone cyanohydrin
O-Gl
CH3
C
CH3
CN
Linamarin
62
D-Mandelonitrile gentiobioside
1- Amygdalin is the most widely distributed cyanophore
glycoside.
2- It occurs in several Prunus species, and is obtained from
bitter almonds (Prunus amygdalus Var. amara Family
Rosaceae).
3- Amygdalin is considered as gentiobioside of Dmandelonitrile. Gentiobioside is a reducing disaccharide
consisting of two molecules of -glucose linked by -1,6
linkage.
63
CN
C
O
O
6
CH2 OH
6
CH2
4
4
Amygdalin
CN
C
O
1
CH2 OH
5
3
4
O
2
Prunasin
64
Amygdalase
Gl-Gl-O
C
H
Amygdalin
Prunase
CN
Emulsin
or acid
Glocose + Prunasin
Prunase
Thioglycosides
1- A number of plants of the family Cruciferae yield glycosides
containing sulphur.
65
S-GL
X
R C
N-OSO3
HO
CH-CH2 -C
N-OSO3 K
Sinigrin
CH2 C
N-OSO3 - Sinapine+
Sinalbin
66
6- Sinigrin
gives
allylisothiocyanate
upon
(volatile
hydrolysis,
oil
of
glucose,
mustard)
and
CH3 O
HO
CH-CH-COO-CH2 -CH2 -N
CH3
CH3
CH3
CH3 O
Sinalpine cation
67
a-pyrone
HO
coumarin
umbelliferone
oleo
gum
resin
galbanum
that
contains