Medicinal Plants
Lecture 21
20/4/2013
The last thing we have discussed was saponins, we have talked about the
characteristics of saponins as well as the structure of saponins and we said that they
occur in the form of their glycosides. We have monodismoside and bisdesmoside. We
have also talked about the common characteristic regardless we have an hydroxyl
group at carbon number three or on other positions. And when we talk about the
pentacyclic triterpene, we have three general types :Lupeol, α- and β- amyrin types.
We will mention few examples of saponin glycoside-containing plants:
Liquorice
Scientific name: Glycyrriza glabra
Family: Fabaceae (Fabaceae is the subfamily of Legumenosa).
This plant is rich in triterpene saponins ; more exactly the β amyrin type
pentacyclic triterpene saponins.
This plant has other constituents; it is rich in coumarins glycosides as well as
flavonoid glycosides.
the plant has yellowish color due to high occurrence of flavonoid glycosides.
Liquorice is common in the temperate regions, it grows widely in the
mediterranean region. It also grows in Jordan.
Uses: widely utilized pharmaceutical aid because of their sweet taste, it
improves the bitter taste of pharmaceutics. It is used in industry as sweetening
agent. It is also used in the convectional industry as the sticks which are taken
from the aqueous extracts of Glycyrriza glabra.
Countries that produce Glycyrriza glabra are: Spain, Mediterranean countries and
Russia.
Used part: root and rhizome (sub-terrestrial organs)
Since saponins occur as glycosides (water soluble secondary metabolites, although
saponin glycosides have large M.wt, the presence of more than one sugar moiety
make it water soluble) we use aqueous extraction to extract saponin glycosides from
root and rhizome.
From medicinal point of view Glycyrriza glabra possess different activities:
-
It is an expectorant.
used as demulcent
softening agent
has laxative properties
As a pharmaceutical aid it possesses surfactant activity; since it decrease
surface tension (but keep in mind that this is not a characteristic property for
this glycoside because all saponins glycoside act as surfactants and as
emulsifying agents).
The aglycone alone is used in the treatment of the gastrointestinal disorders;
especially the duodenal and gastric ulcer.
It also has glucocorticoid and menralocorticoid properties, but it is not strong
properties. In fact we can say that it has approximately 1/10 of the activity of steroidal
substances.
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But the major activity is the inhibition of the steroidal metabolizing enzymes, and it is
somehow stronger than glucocorticoidal activity.
Chemically, we know that here we are talking about triterpene saponins, and we said
that unlike steroids when we talk about triterpenes the we should keep in mind that
they contain 30 carbons; backbone of triterpenes contains 30 carbons unless
something else were mentioned.
There are three critical methyl groups:
- Two angular methyl groups at position number 4
- methyl group at position number 14
These methyl groups should not be removed if we remove them then we will obtain
the 27 carbons backbone of the steroidal substances.
We can see in the structure β-amyrin type while one of the methyl groups is oxidized
into carboxyl group (then the origin of this carboxyl group is oxidized methyl group)
Numbering of the genin
glycyrrhizinic acid
What is the sugar moiety?
Two glucouronic acid moieties attached to carbon number three via a hydroxyl group.
In general in saponins glycosides we do not find only common sugars, but also we
find their derivatives such as –uronic acids and -onic acids.
In case of Glycyrriza glabra carbon number 6 of the sugar is oxidized to carboxyl
group so here we are talking about glucuronic acid.
Be careful! names are a little bit confusing!..
glycyrrhizic acid and glycyrrhizinic acid are synonymous.
But "glycyrrhizin" without "acid" is the sodium or calcium salt of the glycyrrhizic
acid, since we have a carboxyl group we can easily form salts.
As we said before, this glycoside is used as pharmaceutical aid to mask the bitter taste
of the different preparations. in this form as a glycoside it is around 50 or in some
references 100 folds more sweet than sucrose (this property can be considered as
characteristic property).
If we split the sugar part we will obtain the genin.
Note: In cardiac glycosides and saponins glycosides we call the aglycone :"genin".
The genin in Glycyrriza glabra is the glycyrrhetic acid or glycyrrhetinic acid
(synonymous words); since it contains a carboxyl group then it is an acid.
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The genin lost the sweet taste, but pharmacologically it gains many activities for
example:
- it is used as anti-inflammatory compound.
- it is more potent than the glycoside in treatment of ulcer, and more widely
used for this purpose.
Remember: The glycoside is mainly pharmaceutical aid, slightly as emulsifying agent,
as expectorant and diuretic.
By the way many saponins glycosides possess diuretic activity. there is big number of
triterpene with diuretic activity.
We use extract of this plant for sweetening in convectional industry , we said that
glycosides are responsible for the sweet taste, but in fact they are not the only
sweetening agent because extracts of liquorice root contains a lot of free sugars .
And all of these substance are water soluble. We obtain around 10-12% water extract
then it will be purified. then it will be put in boxes or in masses then cut in sticks and
widely used in convectional industry.
It is a model, and it has been used for synthesizing Carbenoxolone Na.
Carbenoxolone Na is a semi-synthetic derivative of glycyrrhetic acid, and it used in
the treatment of gastric & duodenal ulcers .
In our are liquorice root is used as beverage especially in Ramadan. But it should not
be given in high concentrations or high amounts to elderly people because it causes
water retention and this may lead to hypokalemia.
Ginseng
Very well known plant, and one of the most widely sold plant-originated drugs for its
benefits not only for elderly people -to improve longevity (‫)طول العمر‬
and to overcome their physical and psychological illness- but also in young people
for the treatment of different conditions including sexual impotence. It is a universal
remedy.
The first discovery of ginseng was in Chinese and Korean medicine. The
representative species is Panax ginseng this name include all other species; in other
words it is used to refer to extracts of any ginseng roots and rhizomes. Other species
are P. quinquefolium and P. notoginseng
It has been used to treat nearly all diseases in China. The name is coming from two
greek words: Pan=all, akos =remedy
In the slides there is a list of diseases, some of them are pathologic combination like
diabetes , gastritis, insomnia, sexual impotence.
We don not use pure isolated compound ,we use crude extracts form different types
of rhizomes.
Preparation (it is not an exam topic)
It is prepared by peeling or drying. Peeling is done by passing steam through the plant
material. By passing roots to the steam colour changes to reddish color.
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We get either form over seas or most commonly from Korean and western companies,
They use hectares of ground in order to grow ginseng . Roots take 4-6 years to
mature. It is a shrub. The production of the secondary metabolites takes 4-6 years to
contain the highest percentage of the active principles.
In fact, until the late seventies the western medicine was not interested in ginseng, and
it was studied by Russian and Chinese scientists.
Russian introduced the word "Adaptogen" to the scientific literature in combination
with ginseng.
Adaptogen: agent helps the body to adapt to stress (physical/ chemical/ biological
stress).
Ginseng is an adaptogen; it helps you to adapt all types of stress conditions, toxic
compounds or physical stress. So it is unspecific enhancer of body powers, it enhance
body's defence and metabolism somehow to resist the toxic influence .
With the long term use corticosteroid poisoning symptoms appear and it is called
ginseng abuse symptoms:
- Hypotension
- nervousness caused by hypotension
- extra alertness
- sleeplessness
Ginseng preparation should not be used continuously, it should be used for 4 weeks
then stop administration for two weeks at least as an interval between cycles, to
minimize the toxic effects and achieve ginseng benefits.
When ginseng is used for very long time or with high doses ( higher than 600
mg/daily) toxicity appears. It is administered in divided doses usually 150-200 mg
twice daily.
It is recommended to administer 600 mg/day of ginseng in divided doses.
Ginseng products in Jordanian market:
It is found in different forms for example in combination with ginger. Jordanian
market is oversaturated with ginseng products .
What are the compounds found in the ginseng?
Russian and Chinese termed the compound with the biological activity as the
Panaxoside. When Japanese scientists isolated the same compound independently
they termed it as Ginsenosides.
Ginsenosides = Panaxoside
You have to know each kind of Panaxoside with its corresponding Ginsenosides
(since every compound has two names)
• Russians use capital letters with Panaxoside, For example Panaxosides A,
B,G, M,….
• Western scientists write Ginsenosides with subscriptions Rb, Rg, Re,Rf,…
So try to make a table of each Panaxoside with its corresponding Ginsenosides, so
you can understand the articles in the different magazines that is talking about
ginseng. (The Dr. wants that but I am not sure if this table is recommended in the
exam).
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Chemistry:
The backbone of Panaxoside (ginseng saponins) is tetracyclic not like the common
triterpene saponins that is pentacyclic lupeol, α- and β- amyrin types.
In the seventies Dr. Fatima worked on ginseng, she utilized HPLC in identification of
Ginsenosides.
The issue is so complicated with Panax ginseng saponins:
- They are tetraterpenoid triterpene saponins
-
They have two derivatives of ginseng saponins:
1. derivatives of panaxodiols :have two hydroxyl groups in the form of the
glycoside
2. derivatives of panaxatriol: have three hydroxyl groups in the genin to form
the glycoside.
One of the big discoveries in ginseng chemistry is that the isolated genins are
artifacts; the isolated substances are produced during isolation, in another words
isolated genins occur in the plant in another form.
In the isolated forms we have cyclic pyrronucleous, but it has been found that this
panaxodiol which is isolated as a genin is an artifact.
In fact, within the plant the genins occur in form of their proto-derivatives , the
original derivatives are : protopanaxodiols and protopanaxatriol , and they are
tetracyclic triterpene.
With the usage of HPLC and linking HPLC to mass spectroscopy it has been
found that the ginsenosides aglycone in nature occur in form in the
protopanaxodiols and protopanaxatriol.
The only Difference between panaxatriol and panaxodiols:
In case of –diols we do not have an additional hydroxyl group at carbon number 6.
At position 20 and 3 both of them has hydroxyl groups.
Another difference when the two compounds form glycoside is:
-diols form glycosidic linkage using hydroxyl groups at positions 3 and 20
While –triols form glycosidic linkage using hydroxyl groups at positions 6 and
20
There are different species of ginseng:
- Korean ginseng
- Siberian ginseng
- American ginseng
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-
The real ginseng is the Russian Panax ginseng which is produced in china, but
in the market the other types. When we say Panax ginseng then we are talking
about Korean ginseng and American ginseng.
Siberian ginseng:
Latin name is : Eleutherococcus senticosus
Obtained from roots and rhizomes.
Has adaptogen activity, and is nearly identical to Panax ginseng with regard to the
biological activity.
The major difference between Siberian ginseng and Panax ginseng is the chemistry of
their compounds. The compounds isolated from Siberian ginseng are neither
ginsenosides nor panaxoside, it contains eleutherosides; several eleutherosides have
been isolated.
The two plants are completely different plants, but they have similar biological
activities. They differ in potency.
The Siberian ginseng is cheaper and does not need six years to grow; so younger plant
can produce the active secondary metabolites.
But because the potency difference the dose is different; So instead of 400 mg pure
Panax ginseng , they mix it with the Siberian ginseng since it is cheaper.
So in the market they use combinations of both plants to achieve the same activity
with lower cost.
Several eleutherosides have been isolated, again we have the capital letters A,B,C,..
The important ones are:
Eleutheroside E and Eleutheroside B
These glycosides does not belong to saponins, they are alkylated aromatic compounds
linked via its hydroxyl group (phenolic glycosides) derived from shikimik acid
pathway to produce syringin.
OCH 3
Glc-O
OCH 3
Glc-O
H3CO
O
H3CO
OH
Syringin
(Eleurtheroside B)
OCH 3
O
Syringaresinol diglucoside
(Eleutheroside E)
O-Glc
OCH 3
When we look to eleutheroside E, we will see C6 linked to another C6. And we have
two C3 units linked via their beta-carbons (we have alpha- and beta- carbons but C3
units are linked via the beta-carbon). So we are talking about C18 carbon derivatives
which are the lignans.
Despite this complex structure with the two five-membered bi-furan rings, we are
talking about dimeric C6-C3 derivative which is lignan.
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In case of eleutherosid B we are talking about the phenolic glycosides.
Siberian ginseng is used as crude extract –like Panax ginseng- that contains more than
one compound, and the extract is standardized to the two major compounds
Eleutheroside E and Eleutheroside B.
Steroids
Steroids are a huge class of bioactive natural products, we will classify them
according to their occurrence in the mammalian organisms, plants and fungi.
The two precursors of steroids are:
- lanosterol is the precursor in the mammalian organisms.
- cycloartenol is the precursor in the plants.
lanosterol and cycloartenol are 30 carbons compounds. They are converted to their
corresponding steroidal substances like cholesterol (has 27 carbons, and it is found in
the mammalian organisms) , cholesterol can easily lose 6 carbons from its side chain
and be converted to a lower carbon number steroidal substances.
In the steroidal chemistry we are not restricted to a certain carbon number.
Steroids have different activities, like:
Mineralocorticosteroids , glucocorticosteroids, sex hormones or other different
products in the market.
The most commonly used steroidal substances are semisynthetic steroids that is
derived from parent compounds in plant kingdom (around 60% of steroids in the
market).
around 10% are synthetic, the rest are from microorganisms, animals.
Steroidal compounds differ in:
- their carbon number ( 19, 21,27 carbons)
- they also differ in their functional group like oxoderivatives (corticosteroids).
- Stereochemistry( how rings are attached; either all are trans "A-B trans, B-C
trans, C-D trans" like in the case of cholesterol derived. But in the case of
cardiac glycosides we will see different linkage.
Any modification in the above things will change the biological activity.
In steroidal glycoside, the genin part is responsible for the biological activity, and the
sugar part is responsible for the transportation (pharmacokinetics).
Structure:
The backbone contains four rings A,B,C and D. Ring D can be five- or six-membered.
The rings numbering is shown in the underlying structure.
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Numbering of steroidal compounds
We have different methyl groups that is numbered 18 and 19. At position 7 we have
side chain, this side chain has different carbon number (8,9 or 10) depending on the
origin of the steroidal compound (plant, fungal or mammalian).???48
The most important therapeutic steroids are: hormonal substances and cardiac
glycosides.
Steroidal saponins are not important pharmacologically but are important
pharmaceutically because they are the raw material in the production of steroidal
hormones.
In the past, they produced sex hormones using mammalian steroids. But this way
takes hundreds of steps.
Using steroidal we can obtain steroidal hormones by five reactions.
Norgestrel:
One of the synthetic steroids, it has structural characteristics that are not encountered
in the natural compounds.
Synthetic compounds have structural characteristics that is not found in the natural
compounds –until now- like the acetyl triple bond.
The natural steroids are more important in the production of steroidal hormones.
Cardiac glycosides are isolated from the plants. But hormones are modified steroidal
precursors (for example we can not isolate progesterone from plants, it is
semisynthetic and after synthesizing progesterone it can be converted to another
related hormones by minor reaction).
Marker degradation:
A reaction named for the scientist who invented it. It is the most important reaction in
the production of steroidal hormones and it is composed from five steps only .
By: Done
Banan Mohammad Oqilan
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