Transcript D. Sesquiterpenes

Sesquitrpenes and Diterpenes
D. Sesquiterpenes
• Sesquiterpenoids are defined as the
group of 15 carbon compounds
derived by the assembly of 3
isoprenoid units and they are found
mainly in higher plants but also in
invertebrates.
• Sesquiterpene structures present
several acyclic, mono-, bi-, tri-, and
tetracyclic systems.
• The addition of another IPP unit to geranyl
diphosphate (GPP) gives rise to farnesyl
diphosphate (FPP) (C15).
• FPP gives rise to the linear and cyclic
sesquiterpenes.
• Some interesting sesquiterpenes are found in
Feverfew, Cotton seeds and Chamomile.
Some natural sesquiterpenes
Volatile Oil containing terpenoid compounds
Oil
Plant
Constituents
uses
Camphor
Cinnamomum camphora
(Lauraceae)
Camphor, cineole, safrol
Saops
Caraway
Carum carvi
(Umbelliferae)
Carvone, limonene
Carminative, flavour
Cardamom
Elettaria cardamomum
Zingiberaceae
α-Terpinyl acetate, cineole
Carminative, flavour
Citronella
Cymbopogon wineterianus
Graminae
+- citronellal,
geraniol,citronellol
Insect repellent
Coriander
Coriandrum sativum
Umbelliferae
+- linalool, α- pinene, γterpinene
Carminative, flavour
Dill
Anethum graveolens
Umbelliferae
+- carvone
Carminative, flavour
Eucalyptus
Eucalyptus globus
Myrtaceae
Cineole, α- pinene
Antiseptic,
flavour
Juniper
Juniperus communis
Cupressaceae
α- pinene, limonene
borneol, myrcene
Diuretic
Antiseptic
Lavender
Lavandula angustifolia
Labiatae
Linalool, linalyl acetate
Perfumery
Peppermint
Mentha piperita
Labiatae
Menthol, menthone
Menthyl acetate
Carminative,
flavour
Rosemary
Rosmarinus officinalis
Labiatae
Cineole, camphor,
α- pinene
Perfumary
Sage
Salvia officinalis
Labiatae
Thujone, camphor
Cineole, β-caryophylline
Flavouring,
aromatherapy
Thyme
Thymus vulgaris
Labiatae
Thymol, carvacrol
Antiseptic,
flavouring
Tanacetum parthenium
• Feverfew (Family: Asteraceae)
• Also called as Chrysanthemum
parthenium,(‫) حشيشة الملكة‬
• Various forms of feverfew grow to
heights of between 9 inches and 2
feet. The deeply cut leaves are
brightly colored and have a sharp,
unpleasantly bitter taste. The
flowers, which are produced from
summer until mid-fall, are thick
and daisy like with yellow centers.
Traditional Use
• Feverfew was mentioned in Greek medical
literature as a remedy for inflammation and for
menstrual discomforts.
• Traditional herbalists in Great Britain used it
to treat fevers, rheumatism, and other aches
and pains.
• Tablets and tinctures are the safest form of this
herb when used medicinally: It is used for the
relief of migraine, to help prevent blood clots,
as an anti-inflammatory for relief of arthritis,
to relieve some types of menstrual problems,
and as a digestive aid.
Active constituents
• Feverfew contains a range of compounds known as
sesquiterpene lactones. Over 85% of these is a
compound called parthenolide.
• Parthenolide is the active constituent of feverfew leaves
(up to 1%), a natural remedy used in the treatment of
acute migraine attacks.
• In test tube studies, parthenolide prevents excessive
clumping of platelets and inhibits the release of certain
chemicals, including serotonin and some inflammatory
mediators.
Artemisia annua
‫القيصوم‬
• Family: Asteraceae
• Sweet wormwood is an annual herb traditionally
grown in China as a medicinal plant. The wormwood
bush can grow to a height of 2 meters, and produces a
number of bushy stems that are covered with fine,
silky grey-green hairs. Wormwood produces small
yellow-green flowers from Summer through to early
autumn or fall.
• The constituents of wormwood include absinthin,
anabsinthin (both bitter compounds), and a volatile
oil that is 70% thujone. Artemisinin present in leaves
and flower of the plant in 0.01-0.08% dry weight
Artemisinin
• Artemisinin, is a component of the Chinese traditional
antimalarial drug ‘Qinghaosu’ (grey plant). Used for
centuries for the treatment of fever and malaria
• Artemisinin shows antimalarial properties against the
chloroquine resistant strain of Plasmodium falciparum
• The structure is that of a sesquiterpene lactone with a
peroxide link that is important for activity
• Problem is that artemisinin is unstable and insoluble in
practically everything.
• A number of semisynthetic derivative have been
produced, namely artemether and arteether.
• The major metabolite of these molecules is
dihydroartemisnin, which is a more active antimalarial
than artemisinin, rapidly clearing the blood of the
malaria parasite.
(R)
O
(R)
O
O
(R)
(R)
O
(R)
(S)
OR
R= Me artemether
R= Et arteether
Gossypium hirsutum L.
• Family: Malvaceae
Folk Medicine
• Cottonseed and roots have been used in nasal polyps, uterine
fibroids and other types of cancer.
• Gossypol has shown anticancer activity in the new LL, WA
and PS-150 tumor systems.
• Mucilaginous tea of fresh or roasted seeds used for bonchitis,
diarrhea, dysentry, and hemorrhage.
• Flowers diuretic and emollient, used for hypochondriasis.
Often used by early American slaves for abortion; apparently
with no serious side effects.
• Root decoction used for asthma, diarrhea, and dysentery. Root
bark, devoid of tannin, astringent, antihemorrhoidal; used as
an emmenagogue, hemostat, lactagogue, oxytocic, parturient,
and vasoconstrictor.
• Gossypol is being used in China as a male contraceptive
(causes male infertility).
Gossypol
• Gossypol, a dimeric sesquiterpene, is found in cotton
seeds (Gossypium species) in amounts up to 0.6%.
• It acts as a male contraceptive, effective multiple
aspects of sperm quality and function (sperm
maturation, motility, and inactivate sperm enzymes
necessary for fertilization).
• Clinical trials in China have shown that this infertility
can be reversible.
• Gossypol is a chiral molecule.
• Only the (-) isomer is active. Most of the toxic effects
are caused by the (+) isomer.
• Gossypol, like artimisinin is derived from the cadinyl
cation.
Chamomile
Roman chamomile
(Chamaemelum nobile)
German chamomile (Matricaria chamomilla )
Chamomile
• Two types of chamomile (Family: Asteraceae)are used in herbal
medicine:
- Roman chamomile or Chamaemelum nobile (Perennial) and
- German chamomile or Matricaria chamomilla (annual).
• Both plants are cultivated mainly in Europe where the flower heads
are utilized
• Roman chamomile is usually taken as an infusion (tea) to aid
digestion. It is also included in shampoos and mouthwashes due its
mild anti-inflammatory and antiseptic properties.
• The flower heads contain up to 1.5% of volatile oils, consisting of
esters of angelic, tiglic, isovaleric and isobutyric acids, with small
amounts of mono and sesquiterpenes.
• The oil contains α-bisabolol which is responsible for antibacterial
properties and chamazulene which is anti-inflammatory (inhibits
cyclooxygenase enzyme).
• German chamomile is mainly employed for its anti-inflammatory
and antibacterial properties. Used in creams and ointments.
Diterpenes
• C20 compounds derived from geranylgeranyl
diphosphate (GGPP) which is formed by addition of IPP
unit to FPP
Examples of diterpene substances
• Cyclisation of GGPP results in a number diterpenes the more
important of which are Phytol, the Taxanes, and the Ginkolides.
• Phytol is important due its presence in Chlorophyll, Vitamin E,
and Vitamin K
Phylloquinone (Vitamin K1)
Phylloquinone is abundant in:
- Green vegetables (peas: 0.4, lettuce and asparagus: 1,
Brussel sprout: 1.8, brocoli: 2.4, spinach: 5, kale: 8 µg/g).
- Some oils (sunflower: 0.1, olive: 0.8, soybean: 2.4 µg/g).
- But poorly represented in fruits (1 to 30 ng/g) except
avocado (400 ng/g) and kiwi (250 ng/g).
- Grain products have also very low levels of vit. K1 (1 to
70 ng/g).
Taxanes and Taxol
• Taxanes are of the more pharmaceutically significant
diterpenes.
• Over 100 taxanes have been identified being obtained
from the taxus species.
• The anticancer taxane drug paclitaxel is extracted
from the bark (0.02%) of the Pacific yew (Taxus
brevifolia).
• Taxol (paclitaxel) is a complex fuctionalized
diterpene.
• Taxol was first isolated from Yew bark in 1962 as
part of the National Cancer Institute (NCI) program
in search of natural products exhibiting anticancer
activity.
Taxane diterpene nucleus
Taxol
(Paclitaxel)
Docetaxel
Mechanism of action
• Taxol is a potent compound that targets rapidly
dividing cancer cells and prevents them from
replicating.
• Taxol binds to the microtubules and inhibits their
depolymerization into tubulin. This means that Taxol
blocks a cell's ability to break down the mitotic spindle
during mitosis (cell division). With the spindle still in
place the cell can't divide into daughter cells and
therefore the cancer can’t spread .Used to treat breast
cancer.
• Contains a 4-membered oxetane ring and complex ester
side chain, both of which are required for activity
Taxol analogues, in which the oxetane ring is opened such as the Dsecotaxol, were uniformly inactive in both tubulin assembly and
cytotoxicity assays.
Taxus brevifolia Nutt
• Synonym: pacific yew (Family: Taxaceae)
• Historically, native American tribes used yew brews
to treat rheumatism, fever, and arthritis, but it wasn’t
until the 1960’s that the anticancer qualities were
discovered.
• The Japanese used yew leaves to treat diabetes and to
induce abortions
• The bright red fruits of yews are called arils and each
cups a single seed. The seeds are deadly.
• The Pacific yew is a slow growing tree found in
North America. The tree needs to mature (100 years)
in order for it to be large enough for exploitation.
• Three mature trees give approximately 1.0g of drug.
• Content of other taxanes is considerably higher:
Baccatin III and 10-deacetylbaccatin III are present in
quantities up to 0.2%. These are used to semi-synthesis
of paclitaxel (taxol).
• 10-deacetylbaccatin III is also found in the leaves and
twigs of the Common yew (Taxus baccata). A faster
growing tree found in the USA and Europe
Baccatin III
10-deacetyl-baccatin III
ٍ
Semi-synthesis of Taxol
The Ginkolides
• The ginkolides are produced from extensive modification of the
diterpene structure. Derived ultimately from copalyl PP.
• They are the active constituents of Ginkgo biloba (Ginkoacea).
• Standardised exracts of the leaves found in Europe and USA have
been shown to improve peripheral and cerebral circulation.
• Dried leaves contain up to 0.25% of the active constituents
consisting of 5 ginkolides, A,B,C, J and M and bilobolide
(sesquiterpene)
• Ginkgo trees are can live for over 1000 years
• Cultivated in the southern USA, China and Japan
• Use of ginkgo, historically, can be traced back well over 5000
years in Chinese herbal medicine
• The nuts were used to treat respiratory tract ailments such as
asthma and bronchitis
• The leaves are used by the elderly to alleviate memory loss.
Ginkgo biloba (Ginkgo, ‫)الجنكة‬
• It is the only representative species of its family
Ginkgoaceae.
• Ginkgo biloba is dioecious tree. The Ginkgo has been
preserved as a sacred tree in Chinese temple gardens
since ancient times.
• Ginkgo tree was discovered in China in 1690 by
Kaempfer who wrote the first scientific description of
this tree.
• In Chinese pharmacopoeia, Ginkgo seed and leaves
are reported as “good for heart and lungs”. The main
uses are anti-asthma, anti-tussive, expectorant,
analgesic, anthelmintic, etc., and most of these actions
can be described with modem pharmacology and
clinical studies.
• Recently the preparations of Ginkgo biloba extract
(GBE) are widely used in the treatment of cardiac and
cerebral vascular and peripheral circulatory disorders.
• Also used in the treatment of diverse neurological
disorder, such as cerebrovascular insufficiency with
symptoms of vertigo, tinnitus, short-term memory loss,
headache, hearing loss and depression.
• GBE has certainly risen to the forefront of safe and
nontoxic intervention for CNS injury and prevention and
treatment of early senile dementia (Alzheimer's disease).
The clinical efficacy of GBE is mainly due to Ginkgo
terpenes (ginkgolides and bilobalides).
Current uses
• Ginkgo may be of benefit in:
-
Alzheimer's disease
Atherosclerosis
Impotence
Retinopathy
migraine headaches
Raynaud's phenomenon and tinnitus.
constituents
• The constituents of Ginkgo biloba leaf extract,
ginkgolides A, B, C and J are known as
effective antagonists of platelet-activating
factor (PAF).
ginkgolides