Download - ISpatula

From sesquiterpenes we will continue to our next group of the
terpenoids substances. We talked about 10C "monoterpenes" , 15C
"sesquiterpenes" , and now we'll talk about 20C "Diterpenes"
substances. We know that the aliphatic compound is the first
compound in the biosynthesis of any subclass of the terpenoid
substances, and we classified it as a regular terpenoid substance
because the chain elongation is achieved by addition of an IPP to the
phosphorilated N of the biosynthesized chain which is Farnesyl
Pyrophosphate -or Farnesyl Diphosphate- with the pyrophosphate
group IPP CH2P group electrophilic attack on the pyrophosphate . and
we obtain the aliphatic chain of the diterpene GGPP, because the GPP
the 10C was the basic unit of monoterpenes and we have 20 carbon
so it's a repetition ten ten GGPP "gerenyle gerenyle pyrophosphate" it's
the basic acyclic compound or acyclic precursor of this big class of
secondary metabolites which termed as the phenityle terpenoids and
not like the FPP and its derivatives, we are restricted with the GPP to
certain plants families. We said FPP primary found in the family
Asteraceae in the case of GGPP as the basic unit of the diterpenoid we
are talking about constituents which are ubiquitous in all green
plants, because the basic unit or the derivative of GGPP "its reduced
derivative phytol one double bond, mono unsaturated alcohol phytol "
is found in the side chain of chlorophyll so presumably " ‫"من المفروض‬
any plant which has chlorophyll in its nucleus we'll find a diterpenoid
compound so presumably the diterpenoid are very very widely
distributed. Therefore we are saying there are ubiquitous broad
occurring secondary metabolites not like the sesquiterpenoid
compounds. So side chain of the chlorophyll is based on phytol as a
mono unsaturated derivative of the GGPP.
We have as a side chain an alkylating agent, because as you
remember when we start with hemeterpenoid we can use it as an
alkylating agent; as newly synthesized terpenoids have the same
terminal group after eliminating the pyrophosphate they can be used
as alkylating agents not only the hemeterpenoid as (meroterpinod or
mixed terpenoid) although they are the only ones that are found as
alkylating agents, also we have the side chain of tocoferol of vit.E and
vit.K.
We have another 20c diterpenoid which is vit.A or retinic acid but
although it is 20 C it is a derivative of tetraterpenes (splitted).
Then another proof that diterpenoids are widely distributed in nature
is the plant growth regulators Gebberellins ,so we have both
chlorophyll and Gibberellins that are very important compounds in
higher plants of 20C or 18c diterpinoid indicate that is widely
distributed in nature.
We also have other potent biological and industrial active compounds
as well as anticancer chemotherapeutic taxol and sweetening agents
and adaptogenic ginkolytes. Unfortunately also there are toxic
cocarcinogenic substances (tumor promoter) especially in long term
1
use and some other toxins like alpha- meta toxin!! , and some are in
the structure of alkaloids.
The first compound of diterpenoids is Phytol:
1- Monounsaturated aliphatic compound (possesses only one
double bond in its structure)
2- It is found as an alkylating agent in Vit.K and Vit.E
3- Also it is a side chain in chlorophylls
So it is the most common simple diterpinoid found with many
important metabolites
The other is Gibberellins
1- It has been isolated 1st time from fungus Gibberella fujikurio by
Japanese scientist
2- It has been found that it stimulates the growth of seed and
elongation of stem, so it is a growth promoting agent ,( opsonin
another promoting agent but it is an alkaloid )
3- A lot of Gebberllins have been isolated, so they are differentiated
by using letters A,B,C… and numbers as subscripts as A13
,C19,, so in different isolated new compounds in order to make
it less complicated in name instead of using the name of the
fungus( Gibberell fujikurio )to name the secondary metabolites
4- It is tetracylic type of cyclic diterpenoid from acyclic so this
complexity due to many steps in their biosynthesis
5- Primarily we have 2 groups have been isolated A13 gibberllin
and C19 gibberellic acid , representative 19c acid in this class of
growth promoting agent in higher plants.
Forskolin is a Compound isolated from Roots of Coleus forskohlii, a
plant used in india , it is possessing +ve inotropic action so it can
be used in treatment of different cardiovascular disorders
(hypertension,..) and for the treatment of bronchial asthma.
Anti-hypertensive activity is based on several studies, and these
studies indicate the responsibility of this compound to treat these
disorders, it is major acting as diterpenoids compounds, it is
completely different from digitalis glycosides in stimulation of
adenylyl cyclase activity.
Diterpenoid cmpds of these substances with regard to the CVS
activity are completely different than digitalis glycosides, it
stimulates adenyl cyclase activity.
Now we will talk about Stevia rebaudiana which contains the
secondary metabolite Stevioside which is 200 times sweeter than
sucrose, and considered as non-calorie sweetening agent, and their
major compounds that are responsible for sweetening such as
Stevioside which is a diterpine tricyclic compound, but it is not used
2
in Jordan because until now it is not accepted by FDA according to its
safety.
And there are a several studies which indicate that Stevioside is
possessing mutagenic activity.
So, due to mutagenicity, Stevioside is not yet accepted by FDA.
It is available in market in japan and in many countries as a non-color
sweetening agent; the producer company is responsible for adverse
rxns if any occur.
Our next biologically active compound is one of the most important
and therapeutically used chemotherapeutic agent is Taxol which has
been isolated early in 1970s by screening program of naturally acting
anticancer in USA that screen 1000s of plants against 6 common
different types of cell lines for anticancer activity so find many
compounds work as broad spectrum anticancer , and it is firstly
isolated from Taxus brevifolia ( Pacific Yew ) in Canada as well as from
Taxus baccata and the difference is that baccata is growing in Europe
The compound isolated (structure not for memorizing) but mention
the important points that are relating to its bioactivity.
It is a diterpenoid compound but it has a N in its side chain can be
considered theoretically as pseudo alkaloid; because any compound
by the definition that contains N considered as alkaloids but here the
N ( the precursor a.a is isoserine ) is not a part of the heterocyclic ring
so it is pseudo , but it is included here in diterpenoid because its
biological activity is due to diterpenoid nucleus and chemistry.
Its complex structure contains rings A, B, C ,, the ring a , and c are
hexacycles linked via central 8 membered ring ( unusual) and
moreover we have the oxetane 4 membered - o -ring attaches ,4,5,and
20 which is necessary for its biological activity plus the presence of
side chain at c13 which is a derivative of 3’ isoserine which prossess
the subtitueted N.
Then we have another benzoyl group at c2 we have 2 acetyl groups,
we have a substitueted tricyclic ring structure with the six membered
ring A, B and C with an oxetane ring.
Several analogs have been prepared, the main modification is
attaching a side chain instead of the hydroxyl group at carbon
number 13. So, different semisynthetic derivatives are prepared by
replacing the side chain substituents and C13.
Taxol is an important compound in the treatment of cancer; its
potency is attributed to the modifications on the side chain attached
to position 13.
3
The first isolation from the Pacific yew (Taxus brevifolia), it was found
that this cmpd occurs in the bark of this plant. These trees are very
slowly growing trees, and taxol occurs in barks in very low
concentrations, in order to obtain 1 Kg taxol we need 7-8 tons of the
bark, large quantities of barks gives very small amounts …. So we
need to find other sources of this taxol and it has been found that
taxus baccata contains not exactly the taxol, and can be converted to
taxol (semisynthetic), but these precursors of the taxol which devoid
the acetyl group at C10 on the side chain, so here we have the two
active compounds which are isolated from the leaves - which are
renewable parts.
- Baccatin: acetyl group on carbon number 10
- OH group on C13 is free.
- We can prepare from these major compounds taxol or other
derivatives using the free OH at C13
- In baccatin we have the acetyl group at C10 which is available
and the side chain can be modified, so baccatin and
deacetylbaccatin both are found in the leaves of T.baccata, and
they are more water soluble than taxol.
- These anticancer agents are used in advanced stages of breast
cancer, cervical cancer, lung cancer, head and neck cancer and
many types of carcinoma
- The major disadvantage of taxol is its low water solubility, and
by using other agents we can improve its solubility and
biological activity.
- These anticancer agents are also considered as anti-mycotic
agents.
We will start our discussion with Ginkgo biloba (G.biloba),
Ginkobiloba is available in different pharmaceutical preparations. In
ginkobiloba we don't isolate the single cmpd, it's a standaradized
crude extract based on flavonoids and terpenoids. It's one of the
exceptions that it's not a pure isolated cmpd but it's a standardized
crude mixture containing 24% flavonoids and 6 % terpenes.
We have two major classes of secondary metabolites:
1. flavonoids (already discussed in chapter of flavonoid such as
Rutin, Quercetin )
2. terpenoids are again subdivide into diterpenoid and
sesquterpeneoid . In both classes we have (lactones) so diterpenoid
lactones and sesqueterpenoid lactones.
Its structure is complex polycyclic, different numbers of the
rings and poly substituted.
4
O
O
OH
O
R2
O
O
R3
O
R1
O
Ginkgolide A
Ginkgolide B
Ginkgolide C
Ginkgolide J
Ginkgolide M
R1
OH
OH
R2
H
OH
R3
H
H
OH
OH
OH
OH
H
H
OH
OH
OH
The characteristic for the diterpenoid is the lactone ring and for
sesqueterpenoid is also lactone ring. Both (diterpenoid and
sesqueterpenoid) have biological activity from lactone ring that means
that the lactone ring is responsible for biological activity of terpenoid.
The Ginkgo is one of the exception class not use purified
secondary metabolite but standardized crude extract : the
standardized crude extract contains 24% flavonoid and 6% terpenes,
so they have the synergistic activity somehow of flavonoid and
terpenoid for observing the biological activity of the substances.
There is another requirement for this ginkgo, because we are
using crude drug while crude drug even go further standardization
then there is different other secondary metabolites and one of them is
Gingolic acid (alkyl derivative).
GINGOLIC ACID:
R
COOH
13
OH
Gingolic acid(s)
R =
15:1 ( 8 )
R =
C 13-17 (0-1 double bond)
It's a free partial phenolic compound with very short R chain (13
– 17 carbons). It is very irritant substance and it causes dermatitis as
well as to a certain degree it is not very highly mutagenic. It has
certain mutagenicity so any preparation containing this gingolic acid
or phenolic derivative must to be nearly free (contain less than 5
P.P.M of this Gingolic acid phenolic derivative, so standardization is
required to determine concentration of this toxic compound), because
it is responsible for irritant and mutagenicity to a certain degree.
MEDICAL VALUE OF GINKGO:
In fact it is used to early management of the senile people
specially elderly people in order to improve cerebrovascular circulation
5
and peripheral circulation, it will improve the mental and physical
performance of senile and elderly people and this substance has
potent and selective activity against PAF(platelet activating factor).
That means it has protective effect or immuno-protective effect.
By experiment we found the Gingolide and Ginkgo extract has
anti-inflammatory activity and improvement in cerebral circulation. It is (not drug) plant which is used in treatment of dementia
(Alzheimer’s symptoms) What is the difference between dementia and senile people ????
Both treated by G.biloba but the senile (age dependent) is impairment
of cerebral circulation because of old age but the cause of dementia is
impairment of transmission of neurotransmitter so it is a disease
(pathological case).
What are the common symptoms of elderly people??
Note: these symptoms treated by G.biloba and its extract. These
symptoms resulted from impairment in cerebral circulation.
There are 12 major symptoms common in elderly people:
1. Difficulty in concentration
2. Difficulty in short term memory (definitely seen when you talk to
your grandparents, they will not remember what just before a
while but they could remember what happened in long 80 year
ago, so there is a decrease in the short term memory and
improvement in long term memory, so senile talking about
childhood in very late age)
3. Absent mindedness
4. Confusion
5. Lack of energy and apathy
6. Tiredness
7. Decreased physical performance
8. Depressive mood
9. Anxiety
10.
Dizziness
11.
Frequent headache is the common
12.
Tinnitus sound in ear
 These symptoms are not considered a pathological condition
because they are signs of getting old or senile.
 Different sign of senility is not exam topic but it is a general
information or knowledge when we are talking about senile
people
6
Note: the term elderly people become delayed, i.e. in the past a
person with 50 years was consider elderly but now a person with 60
or more considered elderly and might develop senility.
G.biloba improves senile condition but it should be considered in
relation to the rest of drugs that taken by the elderly person (it is
contraindicated in different conditions especially patients taking antiepileptic drugs and asthmatic patients, people taking hypo or
hypertensive drugs and spatially anticoagulant drug)
But a HTN is a common disease for elderly people, so if you want to
administer the anti-hypertensive drugs along with G.biloba, this must
be under supervision of the physician.
We have in Jordan tea packs of the G.biloba and most of the
studies indicate that the common drug in tea packs is not very
beneficial so the study indicates that it should be standardized and
should be available in the form of herbal tea mixture containing
among other plant barks also G.biloba.
Until now we talked about terpenoid and diterpenoid substances
with medicinal value but we have also toxic diterpens and these
found in many ornamental plants and it is specially precursor of
allergy (dermatitis) dermatism problem observed in gardeners.
*Note: ornamental plants from family Euphorbiaceae and
Thymelaceae. The Euphorbiaceae is very widely distributed in Jordan
and the milky juice extracted from euphorbiacea will form dermatitis if
it was handled without gloves.
The phorbol ester (which is toxic diterpenes extract from
euphorbiaceae and thymelaceae) classified as carcinogenic
compounds (promoter of tumor formation).
The other class of the toxic diterpenes is Andomedotoxin
(gryanotoxin 1) from family Ericaceae, they are again irritant to the
mucus membranes and they cause vomiting diarrhea dizziness and
GIT disturbances if taken internally.
 If bees used Ericaceae plants for making honey, then we will
obtain toxic honey!
Note: Ericaceae is considered as an ornamental plant.
OH
H3C
OH
OR
HO
OH
CH3
H3C
CH3
OH
O
OH
Phorbol
OH
CH3
Andromedotoxin
(Gryanotoxin I) R=COCH3
7