PHYTOCHEMISTRY AND NATURAL PRODUCTS CPPH403
Dr. Dima MUHAMMAD 2018-2019
1 -Trease and Evans Pharmacognosy, William C. Evans, Saunders Elsevier, 2009, sixteenth edition., ISBN 978-0 -7020 -2934 9 2- Textbook of pharmacognosy & phytochemistry, Biren Shah & A.K. Seth, Elsevier, 2010, 1st edition, ISBN: 978-81- 312-2298-0 3-Medicinal Natural Products: A Biosynthetic Approach. Paul M Dewick, John Wiley & Sons, 2009,3rd edition, ISBN 978-0-470-74168-9. 4- Pharmacognosy. Phytochemistry, medicinal plants. Bruneton Jean, Lavoisier; 2009 4th edition; ISBN 978- 2743011888.
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PRIMARY AND SECONDARY METABOLISM
All organisms need to transform and interconvert a vast number of organic compounds to enable them to live, grow, and reproduce. They need to provide themselves with energy in the form of ATP, and a supply of building blocks to construct their own tissues.
An integrated network of enzyme-mediated and carefully regulated chemical reactions is used for this purpose, collectively referred to as intermediary metabolism, and the pathways involved are termed metabolic pathways.
Despite the extremely varied characteristics of living organisms, the pathways for generally modifying and synthesizing carbohydrates, proteins, fats, and nucleic acids are found to be essentially the same in all organisms, apart from minor variations. These processes demonstrate the fundamental unity of all living matter, and are collectively described as primary metabolism.
In contrast to these primary metabolic pathways, which synthesize, degrade, and generally interconvert compounds commonly encountered in all organisms, there also exists an area of metabolism concerned with compounds which have a much more limited distribution in nature. Such compounds, called secondary metabolites, are found in only specific organisms, or groups of organisms, and are an expression of the individuality of species. Secondary metabolites are not necessarily produced under all conditions, and in the vast majority of cases the function of these compounds and their benefit to the organism are not yet known. Some are undoubtedly produced for easily
2 Dr. Dima MUHAMMAD PHYTOCHEMISTRY & NATURAL PRODUCTS appreciated reasons, e.g. as toxic materials providing defense against predators, as volatile attractants towards the same or other species, or as colouring agents to attract or warn other species, but it is logical to assume that all do play some vital role for the well-being of the producer. It is this area of secondary metabolism which provides most of the pharmacologically active natural products. It is thus fairly obvious that the human diet could be both unpalatable and remarkably dangerous if all plants, animals, and fungi produced the same range of compounds.
Figure 1.1: Origins of secondary metabolites in relation to the basic metabolic pathways of plants
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THE MEVALONATE AND METHYLERYTHRITOL PHOSPHATE
PATHWAYS
1. TERPENOIDS
Terpenoids comprise the largest group of natural products, with over 35000 known members.
Terpenoids form a large and structurally diverse family of natural products derived from C5 isoprene units (Figure 1.2) joined in a head-to-tail fashion. Typical structures contain carbon skeletons represented by (C5)n, and are classified as hemiterpenes (C5), monoterpenes (C10), sesquiterpenes (C15), diterpenes (C20), sesterterpenes (C25), triterpenes (C30), and tetraterpenes (C40).
Figure 1.2: Isoprene structure.
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Figure 1.3: Terpenoids derivatives.
Isoprene itself was known as a decomposition product from various natural cyclic hydrocarbons, and had been suggested as the fundamental building block for Terpenoids, also referred to as ‘isoprenoids„.
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methyl-erythrol-4-phosphate, MEP -2
Figure 1.4: Isporene bio-origin.
The biochemically active isoprene units were subsequently identified as the diphosphate
(pyrophosphate) esters dimethylallyl diphosphate (DMAPP) and isopentenyl diphosphate
(IPP) (Figure 1.5).
O P P O P P I PP D M A PP
Figure 1.5: active isoprene forms
Isoprenoid synthesis then proceeds by the condensation of isopentenyl pyrophosphate with the isomeric dimethylallyl pyrophosphate to yield geranyl pyrophosphate. Further C5 units are added by the addition of more isopentenyl pyrophosphate.
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Figure 1.6: Preliminary stages in the biosynthesis of isoprenoid compounds.
Figure 1.7: Terpenoid derivatives of linear combination of isoprene units.
Relatively few of the natural terpenoids conform exactly to the simple concept of a linear head-to-tail combination of isoprene units as seen with geraniol (C10), farnesol (C15), and geranylgeraniol (C20) (Figure 1.6). Squalene (C30) andphytoene (C40), although formed entirely of isoprene units, display a tail-to-tail linkage at the centre of the molecules. Most terpenoids are modified further by cyclization reactions.
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Many other natural products contain terpenoid elements in their molecules, in combination with carbon skeletons derived from other sources, such as the acetate and shikimate pathways. Many alkaloids, phenolics, and vitamins are examples of this.
1.1. MONOTERPENES (C10)
Enzyme-catalysed combination of DMAPP and IPP yields geranyl diphosphate (GPP).
Figure 1.8: Geranyl diphosphate synthesis
GPP and its isomers (Linalyl PP and neryl PP), by relatively modest changes, can give
rise to a range of linear monoterpenes found as components of volatile oils used in
flavouring and perfumery. The resulting compounds may be hydrocarbons, alcohols,
aldehydes, or perhaps esters.
Figure 1.9: Simple Monoterpenes formation
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The range of monoterpenes encountered is extended considerably by cyclization
reactions, and monocyclic or bicyclic systems can be created.
Figure 1.10: monocyclic or bicyclic monoterpenes
1.1.1. IRIDOIDS (C10)
The iridane skeleton (Figure 1.11), found in iridoids, is monoterpenoid in origin and
contains a cyclopentane ring which is usually fused to a six-membered oxygen
heterocycle. The iridoid system arises from geraniol by a type of folding.
Iridane Iridoids Geraniol
Figure 1.11: Iridane skeleton and iridoid based structure.
The name derives from Iridomyrmex, a genus of ants which produces these
compounds as a defensive secretion . Most occur as glycosides; some occur free and as
bis compounds; Of pharmaceutical significance is their presence in Valerian, Gentian
and Harpagophytum.
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1.1.1.1. GENTIAN, Gentiana lutea L.
Gentian (Gentian Root BP, EP, BHP) consists of the dried fermented rhizomes and
roots of the yellow gentian, Gentiana lutea L. (Gentianaceae).
- Description: Gentian is a perennial herb about 1m high found in the mountainous
districts of central and southern Europe and Turkey. Important districts for its
collection are the Pyrenees, the Jura and Vosges Mountains, the Black Forest and
former Yugoslavia.
- Collection and preparation: When the plants are 2–5 years old, the turf is carefully
stripped around each and the rhizomes and roots are dug up. This usually takes
place from May to October, collection in the autumn being more difficult on
account of the hardness of the soil, although possibly preferable from the
medicinal point of view.
The commercial drug consisting of ‘red„ or fermented gentian; Usually, the drug is
made into heaps, which are allowed to lie on the hillside for some time and may even
be covered with earth. After it is washed and cut into suitable lengths the drug is dried,
first in the open air and then in sheds. Prepared in this way the drug becomes much
darker in colour, loses some of its bitterness and acquires a very distinctive odour.
- Constituents: Gentian contains bitter glycosides, alkaloids, yellow colouring
matters, sugars, pectin and fixed oil. The secoiridoid gentiopicroside (about 2%,
also known as gentiopicrin and gentiamarin).
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The yellow colour of fermented gentian root is due to xanthones.
- Uses: Gentian is used as a bitter tonic, it is also reported to have choleretic,
antioxidative and hepatoprotective. In traditional medicine it has been employed
to treat various gastrointestinal conditions, as an anti-inflammatory and wound-
healing agent.
Figure 1.12: Gentiana lutea
1.1.1.2. VALERIAN ROOT
Valerian consists of the rhizome, stolons and roots of Valeriana officinalis L.s.l.
(Valerianaceae), collected in the autumn and dried at a temperature below 40°C.
- Description: The plant is a perennial about 1–2 m high. It is obtained from wild
and cultivated plants in The Netherlands, Belgium, France, Germany, eastern
Europe and Japan. It is also cultivated in the USA.
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Figure 1.13: Valeriana officinalis
- Constituents: The drug yields about 0.5–1.0% of volatile oil, sesquiterpen
derivatives (valerenic acid derivatives), in addition to epoxy-iridoid esters called
valepotriates.
Seasonal variations in the constituents of valerian raised in the Netherlands have
been reported. Thus the accumulation of valerenic acid and its derivatives
together with valepotriates reached a maximum in February to March whereas the
volatile oil remained essentially constant during the period of study.
H O, air, 2 tº>41 ºC
Figure 1.14: Valerian roots constituents.
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- Quality control: The pharmacopoeia requires a minimum volatile oil content of
0.5% for the whole drug and 0.3% for the cut drug. There is a minimum
requirement for sesquiterpenic acids of 0.17% calculated as valerenic acid.
- Action and uses: Valerian preparations are widely used as herbal tranquillizers to
relieve nervous tension, anxiety, and as a mild sedative to promote sleep; the drug
was especially popular during the First World War, when it was used to treat shell-
shock. The drug does possess mild sedative and anxiolytic properties.
Considerable quantities of valerian are used by the perfumery industry.
Despite the information given above, many workers believe the sedative activity
of valerian cannot be due to the valepotriates, which are rather unstable and not
water soluble.
Some of the sedative activity is said to arise from sesquiterpene derivatives such as
valerenic acid (about 0.3%) and those found in the volatile oil content (0.5–1.3%);
GABA and glutamine have also been identified in aqueous extracts of valerian, and
these have been suggested to contribute to the sedative properties. The
valepotriates are reported to be cytotoxic in vitro, and this may restrict future use
of valerian. The reactive epoxide group is likely to be responsible for these
cytotoxic properties.
1.1.1.3. DEVIL„S CLAW
Devil„s claw is the common name for Harpagophytum procumbens (Pedaliaceae)
from the appearance of its fruit, which have curved, sharp hooks.
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Devil„s claw BP/EP consists of the cut and dried tuberous secondary roots of H.
procumbens D.C. and/or H. zeyheri L. Decne. It contains not less than 1.2%
harpagoside calculated with reference to the dried drug.
- Description: The plant is a weedy, perennial, tuberous plant with long creeping
stems found in southern Africa (South Africa, Namibia, Botswana); commercial
material is collected from the wild.
Figure 1.15: Devil„s claw, Harpagophytum procumbens.
- Constituents: The main constituents of devil„s claw root are a group of
decarboxylated iridoid glycosides (about 3%), including harpagoside (at least
1.2%) as the main component and smaller amounts of procumbide, and harpagide.
Figure 1.16: Devil„s claw constituents.
- Action and uses: Devil„s claw has a wide reputation for the treatment of rheumatic
disease. Preparations of the secondary roots have gained a reputation as an anti-
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inflammatory and antirheumatic agent to relieve pain and inflammation in people
with arthritis and similar disorders. Clinical studies appear to support its medicinal
value as an anti-inflammatory and analgesic, though some findings are less
positive.
The secondary roots contain significantly higher levels of iridoids than the primary
tubers. Harpagoside and related iridoids have been shown to inhibit thromboxane
biosynthesis, which may relate to the observed anti-inflammatory activity of
devil„s claw.
Gastric and duodenal ulcers are cited as contraindications; Diarrhea may occur
during treatment.
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1.1.2. ESSENTIAL OILS:
Volatile or essential oils, as their name implies, are volatile in steam. They differ
entirely in both chemical and physical properties from fixed oils. They are secreted
in oil cells, in secretion ducts or cavities or in glandular hairs. They are frequently
associated with other substances such as gums and resins and themselves tend to
resinify on exposure to air.
In few cases the volatile oil does not preexist, but is formed by the decomposition
of a glycoside. For example, whole black mustard seeds are odourless, but upon
crushing the seeds and adding water to it a strong odour is evolved.
1.1.2.1. VOLATIL OILS COMPOSITION
With the exception of oils derived from glycosides (e.g. bitter almond oil and
mustard oil) volatile oils are generally mixtures of hydrocarbons and oxygenated
compounds derived from these hydrocarbons (esters, alcohol, aldehyde…..etc).
Many oils are chemically derived from terpenes (mainly mono and sesqui-
terpenes) and their oxygenated derivatives, a smaller number such as those of
cinnamon and clove contain principally aromatic (benzene) derivatives mixed
with the terpenes. A few compounds (e.g. thymol, carvacrol), although aromatic in
structure, are terpenoid in origin.
Figure 1.17: Structures of some volatile oil monoterpens
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Volatile oils are classified on the basis of functional groups present as given in
Table 1.1.
Table 1:1: Classification of volatile oils
Groups Drugs Hydrocarbons Turpentine oil (mono & sesqui terpens) Alcohols Peppermint oil, Pudina, Sandalwood oil, etc. Aldehydes Lemongrass oil, Cinnamon, Cassia, and Saffron Ketones Camphor, Caraway and Dill, Jatamansi, Fennel.. Phenols Clove and Ajowan …. Phenolic ethers Nutmeg….. Oxides Eucalyptus and Cardamom oil Esters Valerian, Rosemary oil, Garlic, etc.
1.1.2.2. PHYSICO-CHEMICAL PROPERTIES VOLATIL OILS
Volatile oils are freely soluble in ether and in chloroform and fairly soluble in
alcohol; they are insoluble in water.
Volatil oils are lighter than water (Clove oil heavier), possess characteristic odour,
have high refraction index, and most of them are optically active. Volatile oils are
colourless liquids, but when exposed to air and direct sunlight these become
darker due to oxidation. Unlike fixed oils, volatile oils neither leave permanent
grease spot on filter paper nor saponified with alkalis.
1.1.2.3. STABILITY OF ESSENTIAL OILS:
As terpenoids tend to be both volatile and thermolabile and may be easily oxidized
or hydrolyzed depending on their respective structure, it is well accepted that the
chemical composition of essential oils is moreover dependent on the conditions
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during processing and storage of the plant material, upon distillation as well as in
the course of subsequent handling of the oil itself.
Essential oils are known to be susceptible to conversion and degradation
reactions. Oxidative and polymerization processes may result in a loss of quality
and pharmacological properties.
Volatile oils should be stored in cool, dry place in tightly sealed containers,
protected from heat and light.
Figure 1.18: Possible conversion reactions in essential oils. 1.1.2.4. EXTRACTION OF VOLATILE OILS:
Pharmacopeal volatile oils, used in aromatherapy must be prepared by distillation
except this of Citrus spp. peels are extracted by water after pressing or
scarification.
Volatile oils are prepared by means of several techniques and those techniques are
discussed below:
1.1.2.4.1. Extraction by Distillation
All the official volatile oils are extracted by distillation with the exception of oil of
lemon and oil of cade. The distillation is carried out either by water or steam. The
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volatile oils from fresh materials and tough material like roots and barks are
separated by hydrodistillation, and volatile oils from air dried parts and fragile
plant tissues like petals are separated by steam distillation.
The distillation of volatile oils by means of water or steam has long been practiced.
Modern volatile oil stills contain the raw material on perforated trays or in
perforated baskets. The still contains water at the base which is heated by steam
coils, and free steam under pressure may also be passed in.
Tough material such as barks, seeds and roots may be mixed to facilitate
extraction but flowers are usually placed in the still without further treatment as
soon as possible after collection. Distillation is frequently performed in the field.
The distillate, which consists of a mixture of oil and water, is condensed and
collected in a suitable receiver which is usually a Florentine flask or a large glass
jar with one outlet near the base and another near the top. The distillate separates
into two layers, the oil being withdrawn through the upper outlet and the water
from the lower outlet, or vice versa in the case of oils, such as oil of cloves, which
are heavier than water. The oil-saturated aqueous layer may be returned to the
still or may form an article of commerce, as in the case of rose water and orange-
flower water.
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Figure 1.19: Extraction by Distillation
1.1.2.4.2. Extraction by Scarification
This method is used for the preparation of oil of lemon, oil of orange, and oil of
bergamot. These oils are found in large oil glands just below the surface in the
peel of the fruit. The peel, been scarified (cut or chopped), is placed in direct
contact with hot water.
The turbid liquid consisting of oil and water is allowed to cool down and stand
for a short time, whereupon the oil separates from water and is collected.
1.1.2.4.3. Extraction by Non-Volatile Solvent
A nonvolatile solvent, for example, a fine quality of either lard or olive oil, is
used in this process. After saturation with the floral oil the lard or olive oil is
sometimes used as a flavouring base for the preparation of pomades, or
converted to a triple extract. In the latter instance the lard or oil is agitated
with two or three successive portions of alcohol, which dissolve the odorous
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substances. The mixed alcoholic solutions so obtained constitute the ‘triple
extract„ of commerce.
There are two chief methods that come under this; they are enfleurage,
maceration and a spraying process.
- Enfleurage: In this a fatty layer is prepared using lard and the flower petals are
spreaded over it, after the imbibitions is over the fatty layer is replaced with fresh
petals. After the saturation of fatty layer the odorous principles are removed by
treating with alcohol and a triple extract then prepared.
Figure 1.20: Extraction by Enfleurage.
- Maceration: This is also used to extract the volatile matters of flowers. The lard or
oil is heated over a water bath, a charge of flowers added and the mixture stirred
continuously for some time.
1.1.2.5. USES OF VOLATILE OILS:
Volatile oils are used for their therapeutic action, for flavouring (e.g. oil of lemon),
in perfumery (e.g. oil of rose) or as starting materials for the synthesis of other
compounds (e.g. oil of turpentine).
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For therapeutic purposes they are administered as dry or wet inhalations (e.g.
eucalyptus oil), orally (e.g. peppermint oil), as gargles and mouthwashes (e.g.
thymol) and transdermally (many essential oils including those of lavender,
rosemary and bergamot are employed in the practice of aromatherapy.
- Essential oils as expectorants, e.g. anise oil and eucalyptus oil, the essential oils
are well absorbed after oral administration and are partially excreted via the lungs.
As the exhaled molecules pass through the bronchial tree, they can act on the
bronchial mucosa to stimulate the serous glandular cells and ciliated epithelium.
- Those oils with a high phenol content, e.g. clove and thyme, have antiseptic
properties, whereas others are used as carminatives.
- Oils showing antispasmodic activity, and much used in popular medicine, are
those of Melissa officinalis, Rosmarinus officinalis, Mentha piperita, Matricaria
chamomilla, Foeniculum vulgare, Carum carvi and Citrus aurantium.
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1.1.2.6. TOXICITY OF VOLATILE OILS:
Just because essential oils are natural does not mean they do not have potential
risks, or hazards if used inappropriately.
The molecular sizes of the essential oils are very tiny and they can easily penetrate
through the skin and get into the blood stream directly. They can cross the blood
brain barrier affecting the central nervous system CNS and may cause convulsions
in large doses.
It takes anything between a few seconds to two hours for the essential oils to enter
the skin, and within four hours, the toxins get out of the body through urine,
perspiration and excreta.
Figure 1.21: Distribution and excretion of essential oils.
Myristicin (nutmeg oil), pinocamphone (Hyssop), Thujone (sage, Artemisia….) and
anethole (anise and star-anise) are toxic to human beings and large doses of
nutmeg or its oil may cause convulsions and psycho.
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Oil of Juniper, traditionally used for its diuretic effect, may cause violent irritations
of the genital and urinary tract.
Menthol: when taken in large dose, menthol can be fatal by renal and respiratory
failure.
Parsley Herb, (Petroselinum crispum, Apiaceae) is routinely contraindicated in
pregnancy in herbal medicine texts. Common symptoms of parsley apiole
poisoning are fever, severe abdominal pain, vaginal bleeding, vomiting and
diarrhea. Apiole-rich essential oils present a high risk of abortion if taken in oral
doses.
Skin irritation: The irritant component is most often a phenol (found in clove,
oregano and thyme) or an aromatic aldehyde (found in cinnamon).
*neurotoxic and convulsant agent
Figure 1.22: LD50 of toxic components of essential oils.
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1.1.2.7. PHARMACOPEIAL ESSENTIAL OILS
1.1.2.7.1. Lamiaceae:
- Peppermint oil: Peppermint Leaf as defined in the BP and EP is the dried leaves of
Mentha piperita L. It is required to contain not less than 1.2% of volatile oil. The
oil is obtained from the same plant by steam distillation using the flowering tops.
The oil of the BP (1993) was required to contain 4.5–10% of esters calculated as
menthyl acetate, not less than 44% of free alcohols calculated as menthol and
15–32% of ketones calculated as menthone, while pulegone les than ≤4.0%.
Action and uses: spasmolytic and carminative agent.
Figure 1.23: Mentha piperita L. and major monoterpens.
- Sage oil: The official drug consists of whole or cut leaves of Salvia officinalis
containing not less than 1.5% (whole leaf) or 1.0% (cut leaf) of essential oil
which is determined by steam distillation.
Constituents: The pharmacopoeia specifies the acceptable concentration limits
for constituents of the oil as follows: α- and β-thujone (less than 0.2%), linalol
(6.5–24.0%), linalyl acetate (50–80%). Action and uses: Sage as an infusion is
used as a mouthwash and gargle for its antiseptic and astringent action.
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Figure 1.24: Salvia officinalis and major monoterpen.
- Rosemary oil: Rosemary oil is steam distilled from the flowering aerial parts of
Rosmarinus officinalis L. The fresh material yields about 1–2% of a colourless to
pale yellow volatile oil with a very characteristic odour. The principal
constituents are 1,8-cineole, borneol, camphor, bornyl acetate and monoterpene
hydrocarbons, principally α-pinene and camphene.
Action and uses: The oil is frequently used in aromatherapy, in the perfumery
industry and for the preparation of spirits and liniments for medical use; it has
antibacterial and antispasmodic properties.
Figure 1.25: Rosmarinus officinalis L. and major monoterpens.
- Thyme oil: Thyme Oil BP/EP is obtained by steam distillation from the fresh
flowering aerial parts of Thymus vulgaris L.
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Major constituents: thymol (36–55%) and carvacrol (1.0 and 4.0%), γ-terpinene
(5–10%), p-cymene (15–28%), linalol (4.0–6.5%), β-myrcene (1–3%), terpinen-
4-ol (0.2–2.5%).
Action and uses: The official drug is required to contain not less than 1.2%
volatile oil. of which not less than 40% consists of thymol and carvacrol. It is
these phenols that are largely responsible for the antiseptic, antitussive and
expectorant properties of the drug.
Figure 1.26: Thymus vulgaris L. and major monoterpens. - Oregano: Two medicinally used species described in the BP/EP are Origanum
onites L. and Origanum. vulgare L.
The BP/EP requires a minimum of 2.5% oil in the drug and a minimum 1.5%
carvacol and thymol.
Action and uses: Although in Britain oregano is not used medicinally to any
extent, its thymol content gives it strong antiseptic properties. Traditionally its
uses include the treatment of digestive disorders, pharnygeal infections and mild
fevers.
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Figure 1.27: Origanum. vulgare L.
- Melissa officinalis L.: Lemon balm BP/EP consists of the dried leaf of Melissa
officinalis L. Lemon balm yields only a small quantity of volatile oil (0.06– 0.4%),
which nonetheless gives the plant, when crushed, its strong lemon-like odour.
Principal components of the oil are the aldehydes citral and citronellal.
Action and uses: For over 2000 years lemon balm has been used for medicinal
and culinary purposes. It is used traditionally for its sedative, spasmolytic and
antibacterial properties.
Figure 1.28: Melissa officinalis L. and major monoterpens. - Lavender oil: The botanical source of lavender oil is the flowers of Lavandula
angustifolia Miller.
It is required (BP) to contain a minimum volatile oil content of 1.3% expressed on
a dry weight basis. The major components of the pharmaceutical oil is given in
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the BP/EP; linalol (20–45%) and linalyl acetate (25–46%) are the principal
constituents with a maximum limit for camphor of 1.2%.
Action and uses: Lavender oil is principally used in the toiletry and perfumery
industries and occasionally in ointments, etc., to mask disagreeable odours. It is
employed pharmaceutically in the anti-arthropod preparation. Lavender flowers
are included in the BHP and are indicated for the treatment of flatulent
dyspepsia and topically, as the oil, for rheumatic pain. The oil is extensively used
in aromatherapy.
Figure 1.29: Thymus vulgaris L. and major monoterpen. 1.1.2.7.2. Apiaceae
- caraway oil: Caraway (Caraway Fruit) consists of the dried, ripe fruits of Carum
carvi; contain 3–7% of volatile oils (BP not less than 3.0%).
Caraway oil the volatile oil (BP/EP) consists largely of the ketone carvone and the
terpene limonene with small quantities of dihydrocarvone, carveol and
dihydrocarveol.
Action and uses: The fruits and oil are used in medicine for flavouring and as
carminatives and antispasmodic agent.
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Figure 1.30: Carum carvi and major monoterpens.
- dill oil: Dill (Dill Fruit) consists of the dried, ripe fruits of Anethum graveolens.
The volatile oil (Dill Oil BP/EP) resembles oil of caraway in containing carvone
and limonene. The European fruits yield about 3–4% of volatile oil which should
contain from 43 to 63% of carvone.
Action and uses: Like caraway, dill is used as a carminative and flavour; it is much
used in infant„s gripe water.
Figure 1.31: Anethum graveolens and major monoterpen.
- bitter fennel and sweet fennel: Bitter Fennel consists of the dried ripe fruits of
Foeniculum vulgare.
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The fruits contain 1–4% of volatile oil with higher yields recorded. The principal
constituents of bitter fennel oil, with BP/EP prescribed limits, are fenchone (12–
25%), trans-anethole (55–75%) together with anisaldehyde (maximum 2.0%).
Action and uses: Fennel and its volatile oil are used as an aromatic and
carminative.
Sweet Fennel is derived from F. vulgare, var. dulce and is also included in the
BP/EP. The fruits resemble those of the bitter variety but have a sweet taste and
lower volatile oil content (not less than 2.0%).
Figure 1.32: Foeniculum vulgare and major monoterpens.
- aniseed oil: Aniseed of the BP and EP consists of the dried, ripe fruits of
Pimpinella anisum. Anise fruits yield 2–3% of volatile oil (BP/EP ≥ 2.0%), which is
almost identical with that obtained from star-anise fruits.
Major constituents: trans-anethole 87–94%; anisaldehyde 1.0–1.4%; maximum
limit of 0.1% for fenchone and 0.01% for foeniculin;; estragole 0.5–5.0%, and
linalol <1.5%.
31 Dr. Dima MUHAMMAD PHYTOCHEMISTRY & NATURAL PRODUCTS
When aniseed oil is stored in bad conditions of temperature and/or sunlight,
trans-anethole may be oxidized to anisaldehyde or isomerized to cis-anethole
(toxic >0.5%).
Figure 1.33: Isomerization of trans-anethole.
Action and uses: Both aniseed oil and star anise oil are used as flavouring agents
and as carminatives.
1.1.2.7.3. Illiciaceae
- star anise oil: The star-anise Illicium verum Hook, f. The fruits consist of eight
(rarely seven or nine) one-seeded follicles. The oil, which is present in both seed
and pericarp, gives the drug an aromatic odour and spicy taste. The fruits of
Illicium verum should yield a minimum of 7.0% volatile oil. The essential oil
should contain 87–94% trans-anethole, 0.5–5.0% of estragole and smaller
amounts of anisaldehyde (0.1–0.5%).
32 Dr. Dima MUHAMMAD PHYTOCHEMISTRY & NATURAL PRODUCTS
Figure 1.34: Illicium verum and major monoterpens.
1.1.2.7.4. Pinaceae
- turpentine oil: Pharmaceutical turpentine oil is obtained by distillation and
rectification from the oleoresin produced by various species of Pinus Oil of
turpentine is a colourless liquid with a characteristic odour and a pungent taste.
Oil of turpentine consists chiefly of the terpenes (+)- and (−)-α-pinene, (−)-β-
pinene and camphene.
Figure 1.35: Major turpentine monoterpenes„ structures.
Action and uses: Oil of turpentine is now rarely given internally. Externally it is
used as a counterirritant and rubefacient. Now, most turpentine is processed to
give its various constituents which find use in the manufacture of fragrances,
flavours, insecticides, etc.
33 Dr. Dima MUHAMMAD PHYTOCHEMISTRY & NATURAL PRODUCTS
1.1.2.7.5. Cupressaceae
- Oil of Juniper BP/EP: This is obtained from the non-fermented berry cones of
Juniperus communis L. by steam distillation.
Principal components and official limits are α-pinene (20–50%), β-myrcene (1–
35%), limonene (2–12%), β-pinene (1–12%), terpinen-4-ol (0.5–10%), sabinene
(≤ 20%) and β-caryophyllene (≤ 7.0%).
Action and uses: Juniper oil is traditionally used for its diuretic, carminative and
antirheumatic properties. Side-effects of some oils have been attributed to a
relatively high proportion of terpene hydrocarbons and a low proportion of
terpinen-4-ol.
Figure 1.36: Juniperus communis L. and major monoterpens.
1.1.2.7.6. Rutaceae
- Orange oil:
Bitter orange flower oil This oil, also known as Oil of Neroli, official in the BP/EP
is prepared by steam distillation from fresh flowers of the bitter orange Citrus
aurantium. Dried bitter orange peel contains not less than 2.0% of volatile oil.
34 Dr. Dima MUHAMMAD PHYTOCHEMISTRY & NATURAL PRODUCTS
The official volatile oil of orange peel in the BP/EP is obtained by mechanical
expression of the fresh peel. The BP/EP permitted ranges α-terpineol (2.0–5.5%),
linalyl acetate (2.0–15.0%), linalol (28.0–44.0%), limonene (9.0–18.0%), β-
pinene (7.0–17.0%).
Action and uses: Bitter orange peel is used as a flavouring agent and as a bitter
tonic.
1.1.2.7.7. Lauraceae
- Cinnamon oil: (Lauraceae)
The BP/EP states that cinnamon is the dried bark of the shoots grown on cut
stock of Cinnamomum zeylanicum Blume. Cinnamon contains volatile oil (BP/EP
not less than 1.2%). Oil of cinnamon contains about 60–75% w/w of trans-
cinnamic aldehyde.
Action and uses: Cinnamon is used as a flavouring agent and mild astringent. The
oil has carminative properties and is a powerful germicide.
Figure 1.37: Cinnamomum zeylanicum and major monoterpen.
- Natural camphor: Natural camphor is a white, dextrorotatory ketone, C10H16O,
obtained from the wood of Cinnamomum camphora. The best yield of camphor is
35 Dr. Dima MUHAMMAD PHYTOCHEMISTRY & NATURAL PRODUCTS
obtained from old trees. The wood is cut into chips and treated with steam, when
a solid sublimate of camphor and liquid volatile oil pass into the receiver.
Camphor oil contains, in addition to camphor, safrole, borneol, heliotropin,
vanillin and terpineol, a number of sesquiterpene alcohols.
Action and uses: Camphor is used externally as a rubefacient, and internally as a
mild antiseptic and carminative.
Figure 1.38: Cinnamomum camphora and major monoterpen.
1.1.2.7.8. Myrtaceae
- Clove oil: Cloves are the dried flower buds of Syzygium aromaticum (Eugenia
caryophyllus), The flower buds are collected when their lower part turns from
green to crimson.
Clove oil contains 84–95% of phenols (eugenol with about 3% of acetyleugenol),
sesquiterpenes (α- and β-caryophyllenes) and small quantities of esters, ketones
and alcohols.
36 Dr. Dima MUHAMMAD PHYTOCHEMISTRY & NATURAL PRODUCTS
Action and uses: Clove stem oil is used mainly in the flavouring and perfumery
industries. The high eugenol content gives the oil antiseptic and anaesthetic
properties.
Figure 1.39: Syzygium aromaticum and major monoterpen.
- Eucalyptus oil: Oil of eucalytus is distilled from the fresh leaves of various species
of Eucalyptus. The leaves are required to contain not less than 2.0% v/w of
essential oil which contain not less than 70.0% of cineole and 1,8-Cineole.
Action and uses: Eucalyptus oil is much used for alleviating the symptoms of
nasopharyngeal infections, for treating coughs and as a decongestant.
Figure 1.40: Eucalyptus globulus and major monoterpen.
37 Dr. Dima MUHAMMAD PHYTOCHEMISTRY & NATURAL PRODUCTS
1.1.2.7.9. Asteraceae
- Matricaria oil: Matricaria oil is that steam-distilled from the fresh or dried flower
heads or flowering tops of Matricaria recutita. The flower-heads are required to
contain not less than 0.4% of a blue volatile oil; this consists mainly of the
sesquiterpenes α-bisabolol, chamazulene and farnesene.
Figure 1.41: Matricaria recutita and major Sesquiterpenes.
Action and uses: Matricaria flowers are mainly used for their anti-inflammatory
and spasmolytic properties. The ulcer-protective properties of German
chamomile have been ascribed to bisabolol-type constituents.
- Chamomile oil: Roman Chamomile Flowers are the expanded flower-heads of
Chamaemelum nobile. Chamomiles contain 0.4–1.0% of volatile oil which is blue
when freshly distilled owing to the presence of azulene. Other components of
the oil are n-butyl angelate (principal), isoamyl angelate. Chamomiles also
contain sesquiterpene lactones.
38 Dr. Dima MUHAMMAD PHYTOCHEMISTRY & NATURAL PRODUCTS
Action and uses: Considerable quantities of chamomiles are used in domestic
medicine in the form of an infusion to aid digestion, curb flatulence.
Figure 1.42: Chamaemelum nobile and azulene structure.
39 Dr. Dima MUHAMMAD PHYTOCHEMISTRY & NATURAL PRODUCTS
1.2. SESQUITERPENES (C15)
Sesquiterpenes are formed from three C5 units; the terminology comes from the
Latin prefix sesqui: ‘one and a half times„.Sesquiterpenes are biogenetically
derived from farnesyl pyrophosphate; by the addition of a further C5 IPP unit to
GPP, and in structure may be linear, monocyclic or bicyclic. They constitute a very
large group of secondary metabolites, some having been shown to be ‘stress
compounds„ formed as a result of disease or injury. For many years their presence
in certain volatile oils and resins has been recognized.
Figure 1.43:Farnesyl biosynthesis. 1.2.1. SESQUITERPENE LACTONES
Over 6000 compounds of this group are known and continue to constitute an active area of research. They are particularly characteristic of the Compositae/Asteraceae but also occur sporadically in other families.
41 Dr. Dima MUHAMMAD PHYTOCHEMISTRY & NATURAL PRODUCTS
Not only have they proved of interest from chemical and chemotaxonomic viewpoints, but also many possess antitumour, antileukaemic, cytotoxic and antimicrobial activities. They can be responsible for skin allergies in humans and they also act as insect-feeding deterrents. Some sesquiterpene lactones cause hepatotoxicity.
The pharmacological or toxic bioactivity may due to binding of the exocyclic methylene group with tissue constituents, such as sulphydril groups (-SH), amine (-NH2) and other nucleophilic components.
Figure 1.44: Sesquiterpene lactone (parthenolide) binding with sulphydril group.
As examples of Compositae/Asteraceae members are ‘Feverfew„, ‘Chicory„ and ‘Arnica„.
Other which are herbal remedies and contain sesquiterpene lactones are Taraxacum officinale (dandelion), Artemisia absinthium, Cichorium spp.,
1.2.1.1. ARNICA FLOWERS:
The drug consists of whole or partially broken dried flower-heads of Arnica montana L.
(Compositae/Asteraceae), a perennial herb with a creeping rhizome. The principal producers are the former Yugoslavia, Spain, Italy and Switzerland where it grows on the lower mountain slopes.
41 Dr. Dima MUHAMMAD PHYTOCHEMISTRY & NATURAL PRODUCTS
Figure 1.45: Arnica Montana and the major active sesquiterpens. Constituents. The flowers contain volatile oil (0.5–1.0%), a range of methylated
flavones and sesquiterpene lactones The principal active constituents
(antirheumatic, antiarthritic, antihyperlipidaemic, respiratory analeptic) are
esters of helenalin.
Uses: the herb arnica is used for pain, never take it orally. It„s meant to be applied
to your skin and is typically used as a gel. Arnica isn„t used very often in internal
medicine, as larger doses of undiluted arnica can be fatal. It is used for the
treatment of sprains and bruises. However, neither should be applied to broken
skin and treatment should be discontinued should dermatitis develop. In some
countries, the use of the drug is subject to legal restrictions.
1.2.1.2. FEVERFEW:
Tanacetum parthenium (L.) Schultz Bip. [Chrysanthemum parthenium (L.)
Bernh.], from Asteraceae/Compositae, The crude drug is the aerial parts. It has a
long history as a medicinal plant. It is probably native in S.E. Europe, Asia Minor
and the Caucasus but is now established throughout Europe and in N. and S.
42 Dr. Dima MUHAMMAD PHYTOCHEMISTRY & NATURAL PRODUCTS
America, where it is found on roadsides and waste areas. The plant is a strongly
aromatic herb. The crude drug is the aerial parts.
- Constituents: Feverfew is phytochemically characterized by the production of
sesquiterpene lactones. Feverfew is standardized on its parthenolide content and
the BP/EP requires a minimum of 0.2% with reference to the dried drug.
Figure 1.46: Tanacetum parthenium (L.) and the major active sesquiterpen.
- Uses
Feverfew has long been used for the treatment of fever, arthritis, migraine, menstrual problems and other disorders.
Parthenolide inhibits the secretion of serotonin, and degranulation of polynuclear leukocytes (thus the release of prostaglandin PL-A2, involved in inflammatory mechanisms).
More recently, it attracted much popular and scientific interest resulting from favourable reports concerning its use for the prophylactic treatment of migraine headaches.
43 Dr. Dima MUHAMMAD PHYTOCHEMISTRY & NATURAL PRODUCTS
1.2.1.3. ARTEMISIA:
Artemisia annua (Compositae/Asteraceae) is known as qinghao in Chinese traditional
medicine, where it has been used for centuries in the treatment of fevers and malaria.
The crude drug is the aerial parts.
- Chemical constituents: Artemisinin occurs in the herb Artemisia annua This
unusual sesquiterpene lactone possesses an endoperoxide moiety which appears
to be essential for activity. It has been successful in treating cases of chloroquine-
resistant Plasmodium falciparum and particularly cerebral malaria.
Some plants of A. annua have been found to produce as much as 1.4%
artemisinin. Fortunately, the artemisinic acid content may be converted
chemically into artemisinin by a relatively straightforward and efficient process.
Artemisinin and artemisinic acid have been used for the semi-synthesis of a range
of analogues.
Figure 1.47: Artemisia annua and the major sesquiterpens.
Malaria is caused by protozoa of the genus Plasmodium, especially P. falciparum,
entering the blood system from the salivary glands of mosquitoes, and worldwide
44 Dr. Dima MUHAMMAD PHYTOCHEMISTRY & NATURAL PRODUCTS
is responsible for 2–3 million deaths each year. Established antimalarial drugs,
such as chloroquine, are proving less effective in the treatment of malaria due to
the appearance of drug-resistant strains of P. falciparum.
Artemisinin is currently effective against these drug-resistant strains. Currently,
there is no shortage of Artemisia for drug use. However, as artemisinin derivatives
become more widely used, the longer term supply of artemisinin for drug
manufacture may need addressing. A significant development then is the use of
genetic engineering to produce artemisinic acid in culture based on the
biosynthetic pathway deduced for artemisinin.
45 Dr. Dima MUHAMMAD PHYTOCHEMISTRY & NATURAL PRODUCTS
1.3. DITERPENES (C20)
The origin of the C20 diterpenoids, involving the mevalonate pathway; The
diterpenes arise from geranylgeranyl diphosphate (GGPP), which is formed by
addition of a further IPP molecule to FPP.
The group comprises a structurally diverse range involving hundreds of
compounds which may be acyclic or possess 1–5 ring systems. Diterpenoids
constitute the active constituents of a number of medicinal plants and are of
current interest for their potential as future drugs, either, as isolated from the
plant, or as modified derivatives.
Figure 1.48: Geranylgeranyl biosynthesis.
46 Dr. Dima MUHAMMAD PHYTOCHEMISTRY & NATURAL PRODUCTS
1.3.1. Taxus baccata Nutt. (Taxaceae)
The common yew (European yew / English yew) , produces valuable wood. The fruit
has a fleshy red aril. All parts of the plant are very poisonous. Cattle and horses can
die very rapidly after eating the leaves and stems (cyanogenetic glycoside).
Figure 1.49: Taxus baccata Nutt
- Chemical constituents:
The potent anticancer drug taxol, a nitrogenous diterpene, was first reported in
the bark of Taxus brevifolia. Low yields from the bark and the lack of raw material
leading to damage to forests by, often illegal, over-collection hampered the
development of the drug.
A promising development involving a renewable source has been the isolation of
10-deacetylbaccatin III from the fresh needles of Taxus baccata in up to 0.1%
yield, and its chemical conversion to taxol.
47 Dr. Dima MUHAMMAD PHYTOCHEMISTRY & NATURAL PRODUCTS
Figure 1.50: diterpene derivatives from Taxus baccata.
- Uses:
Taxol® (paclitaxel) is being used clinically in the treatment of ovarian cancers,
breast cancers and non-small cell lung cancer. It may also have potential value
against other cancers. Taxotere® (docetaxel) is a side-chain analogue of taxol. It
has improved water-solubility and is used in treatment of breast cancers.
1.3.2. Ginkgo biloba L. (Ginkgoaceae)
Ginkgo (Maidenhair-tree) is a primitive member of the gymnosperms and the only
survivor of the Ginkgoaceae, also called the living fossil. Native to China and Japan
but cultivated ornamentally in many temperate regions. The leaves of ginkgo are
official in the BHP 1996 and the BP/EP.
Figure1.51: Gikkgo biloba (Maidenhair-tree).
48 Dr. Dima MUHAMMAD PHYTOCHEMISTRY & NATURAL PRODUCTS
- Chemical composition:
From among the many groups of compounds isolated from ginkgo it is the
diterpene lactones and flavonoids which have been shown to possess therapeutic
activity.
Five diterpene lactones (ginkgolides A, B, C, J, M) have been characterized as
highly oxidized diterpene trilactones.
Some 33 flavonoids have now been isolated from the leaves and involve mono-, di-
and tri-glycosides of kaempferol, quercetin, myricetin and isorhamnetin
derivatives. The tree also synthesizes a number of biflavonoids (ginkgetin).
Figure 1.52: Flavonoids derivatives from Gikkgo biloba.
Figure 1.53: diterpene derivatives from Gikkgo biloba.
49 Dr. Dima MUHAMMAD PHYTOCHEMISTRY & NATURAL PRODUCTS
- Uses:
Ginkgolides, the diterpene lactones, are platelet-activating factor (PAF)
antagonists. The later (PAF) is an important mediator involved in both allergic
and nonallergic inflammatory diseases as well as thrombotic disorders.
Flavonoids: have vitamin P and radical-scavenging properties.
Ginkgo has a traditional use as an antiasthmatic, bronchodilator, and for the
treatment of chilblains. Extracts of the leaf containing selected constituents are
used especially for improving peripheral and cerebral circulation in those elderly
with symptoms of loss of short-term memory, hearing and concentration; it is
also claimed that vertigo, headaches, anxiety and apathy are alleviated and
positive results have been obtained in trials involving the treatment of dementia
and Alzheimer„s disease.
1.3.3. White horehound:
White horehound consists of the dried leaves and flowering tops of Marrubium
vulgare L., family Labiatae/Lamiaceae. It is described in the BP/EP, BHP and the
Complete German Commission E monographs. The plant is common throughout
Europe, including the UK.
- Chemical constituents:
The active principals appear to be diterpenes. Marrubiin is one such, which, on the
opening of its lactone ring, gives marrubinic acid, to which is ascribed the
choleretic property of the drug
51 Dr. Dima MUHAMMAD PHYTOCHEMISTRY & NATURAL PRODUCTS
- Uses:
Its principal use is as an expectorant and antispamodic in the treatment of
bronchitis and whooping cough; it also possesses choleretic properties.
Figure 1.54 : Marrubium vulgare L.
1.3.4. Black horehound
The dried aerial parts of Ballota nigra L. family Lamiaceae / Labiatae collected
during the flowering period are included in the BP/EP and BHP 1996. Dispersed
throughout Europe, N. Africa, western Asia, the USA and Australia, the plant is
common to roadsides, hedges, etc. and is often regarded as a weed.
Figure 1.55 : Ballota nigra L.
- Chemical constituents:
51 Dr. Dima MUHAMMAD PHYTOCHEMISTRY & NATURAL PRODUCTS
Marrubiin a lactone diterpen, recognized as a constituent of white horehound, is
present in very small amounts, its derivates ballotinone, ballonigrine and
ballotenol form the major representatives of the group.
- Uses: Its principal use is as an expectorant.
1.3.5. Stevia rebaudiana (Bertoni)
Stevia rebaudiana (Asteraceae), a herb indigenous to North Eastern Paraguay, is
the source of stevioside, an ent-kaurene glycoside used as a sweetener for soft
drinks.
- Chemical constituents and uses:
Stevioside. A group of ent-kaurane glycosides, derivatives of steviol, have
sweetening properties some three hundred times that of sucrose. Although first
isolated in 1931 its structure was not elucidated until 1963 and then some 10 years
later it was produced commercially in Japan.
Figure 1.56 : Stevia rebaudiana and its glycosides.
52 Dr. Dima MUHAMMAD PHYTOCHEMISTRY & NATURAL PRODUCTS
1.4. TRITERPENES (C30)
Triterpenes are formed by addition of two molecules of FPP joined tail-to-tail to yield
squalene. Squalene is a hydrocarbon originally isolated from the liver oil of shark,
yeast and seed oils; it is recognized as a precursor of triterpenes and steroids.
Figure 1.57 : Squalene biosynthesis.
Cyclization of squalene is via the intermediate 2,3-oxidosqualene; If oxidosqualene is
suitably positioned and folded on the enzyme surface, then the polycyclic triterpene
structures can be formed. Most natural triterpenoids and steroids contain a 3-hydroxyl
group, the original epoxide oxygen from oxidosqualene.
53 Dr. Dima MUHAMMAD PHYTOCHEMISTRY & NATURAL PRODUCTS
Figure 1.58 : Triterpenes biosynthesis.
1.4.1. TRITERPENOID SAPONINS
The name comes from the Latin sapo, meaning soap, and plant materials containing saponins were originally used for cleansing clothes, e.g. soapwort (Saponaria officinalis;
Caryophyllaceae) and quillaia or soapbark (Quillaja saponaria; Rosaceae).
Saponins are glycosides which, even at low concentrations, produce a frothing in aqueous solution, because they have surfactant and soap-like properties.
These materials also cause haemolysis, lysing red blood cells by increasing the permeability of the plasma membrane, and thus they are highly toxic when injected into the bloodstream. Toxicity is minimized during ingestion by low absorption, and by hydrolysis.
54 Dr. Dima MUHAMMAD PHYTOCHEMISTRY & NATURAL PRODUCTS
Some saponin-containing plant extracts have been used as arrow poisons. However, saponins are relatively harmless when taken orally, and some of our valuable food materials, e.g. beans, lentils, soybeans, spinach, and oats, contain significant amounts.
Acid-catalysed hydrolysis of saponins liberates sugar(s) and an aglycone (sapogenin) which can be either triterpenoid or steroidal in nature.
1.4.1.1. STEROIDS C27
The steroids are modified triterpenoids containing the tetracyclic ring system of lanosterol, but lacking the three methyl groups at C-4 and C-14. Cholesterol typifies the fundamental structure, but further modifications, especially to the side-chain, help to create a wide range of biologically important natural products, e.g. sterols, steroidal saponins, cardioactive glycosides, bile acids, corticosteroids, and mammalian sex hormones.
The steroidal saponins are less widely distributed in nature than the pentacyclic triterpenoid type. Phytochemical surveys have shown their presence in many monocotyledonous families, particularly the Dioscoreaceae (e.g. Dioscorea spp.),
Agavaceae (e.g. Agave and Yucca spp.) and Smilacaceae (Smilax spp.).
55 Dr. Dima MUHAMMAD PHYTOCHEMISTRY & NATURAL PRODUCTS
Figure 1.59 : Steroidal derivatives biosynthesis.
Steroidal saponins are of great pharmaceutical importance because of their relationship to compounds such as the sex hormones, cortisone, diuretic steroids, vitamin D and the cardiac glycosides; So many natural steroids and a considerable number of synthetic and semi-synthetic steroidal compounds are routinely employed in medicine.
1.4.1.1.1. Natural steroids for the production of pharaceuticals
1.4.1.1.1.1. Dioscorea species
Tubers of many of the dioscoreas (yams) have long been used for food, as they are rich in starch. In addition to starch, some species contain steroidal saponins, others alkaloids.
From a suitable source the sapogenins are isolated by acid hydrolysis of the saponin. The water•insoluble sapogenin is then extracted with a suitable organic solvent.
56 Dr. Dima MUHAMMAD PHYTOCHEMISTRY & NATURAL PRODUCTS
Figure 1.60 : dioscoreas (yams) and diosgenin.
Until 1970 diosgenin isolated from the Mexican yam was the sole source for steroidal contraceptive manufacture. Total synthesis also became economically feasible and is now much used. More recently, the economics of steroid production have again changed in that China is now exporting large quantities of diosgenin of high quality.
1.4.1.1.1.2. Sisal species
Hecogenin is obtained commercially as the acetate in about 0.01% yield from sisal leaves
(Agave sisalana). In East Africa, from leaf ‘waste„ stripped from the leaves during removal of the fibre, a hecogenincontaining ‘sisal concentrate„ is produced. From this the ‘juice„ is separated and allowed to ferment for 7 days. The sludge produced is undergone a hydrolysis process by high pressure; Then after filtration and drying a concentrate containing about 12% hecogenin and other sapogenins is produced. This crude material is shipped for further processing and cortisone manufacture.
57 Dr. Dima MUHAMMAD PHYTOCHEMISTRY & NATURAL PRODUCTS
Figure 1.61 : Agave sisalana and hecogenin.
1.4.1.1.1.3. Fenugreek
Although included in this section as a potential industrial source of diosgenin, the seeds of
Trigonella foenum-graecum L. (Leguminosae/ Fabaceae) are also described in the BP and
EP.
Pharmaceutical manufacturing interest lies in a number of steroidal sapogenins, particularly diosgenin (0.8–2.2%) which is contained in the oily embryo. Although the diosgenin yield is lower than that of the dioscoreas, fenugreek is an annual plant which will also give fixed oil, mucilage, flavouring extracts and high•protein fodder as side•products.
Uses: In addition to its use as a spice and potential source of diosgenin fenugreek is widely employed in traditional systems of medicine. Its antidiabetic, cholesterol•lowering, anti•inflammatory, antipyretic, antiulcer and anticancer properties have been demonstrated.
58 Dr. Dima MUHAMMAD PHYTOCHEMISTRY & NATURAL PRODUCTS
Figure 1.62 : Trigonella foenum-graecum.
Figure 1.63 :Semi-synthesis approach of human hormones.
1.4.1.1.1.4. Sarsaparilla root
Sarsaparilla consists of the dried roots and sometimes also of the rhizomes of species of
Smilax (Liliaceae, modern authors, Smilacaceae).
59 Dr. Dima MUHAMMAD PHYTOCHEMISTRY & NATURAL PRODUCTS
Different species contain one or more steroidal saponins; Two isomeric genins are known: smilagenin and sarsasapogenin.
Figure 1.64 : Sarsaparilla and Sarsapogenin.
Uses: Sarsaparilla formerly enjoyed a high reputation in the treatment of syphilis, rheumatism and certain skin diseases. It is included in the BHP (1960) where it is indicated in the treatment of psoriasis and eczema, and for rheumatism and rheumatoid arthritis. Its action would appear to arise from the steroid content of the roots. Sarsaparilla is widely used as a vehicle, and large quantities are employed in the manufacture of non•alcoholic drinks. The genins are used in the partial synthesis of cortisone and other steroids.
1.4.1.1.2. Cardioactive glycosides
Steroidal glycosides (C23 or C24) which exert on the failing heart a slowing and strengthening effect. The cardioactive glycosides increase the force of contractions in the heart, thus increasing cardiac output and allowing more rest between contractions.
Many of the plants known to contain cardiac or cardiotonic glycosides have long been used as arrow poisons (e.g. Strophanthus) or as heart drugs (e.g. Digitalis). They are used
61 Dr. Dima MUHAMMAD PHYTOCHEMISTRY & NATURAL PRODUCTS medicinally to strengthen a weakened heart and allow it to function more efficiently, though the dosage must be controlled very carefully, since the therapeutic dose is so close to the toxic dose. The cardioactive effects of Digitalis were discovered as a result of its application in the treatment of dropsy, an accumulation of water in the body tissues.
Digitalis alleviated dropsy indirectly by its effect on the heart, improving the blood supply to the kidneys and so removing excess fluid.
The fundamental pharmacological activity of the cardioactive glycosides resides in the aglycone portion, but is considerably modified by the nature of the sugar at C-3. This increases water solubility and binding to heart muscle.
The primary effect on the heart appears to be inhibition of the ion transport activity of the enzyme Na+/K+-ATPase in the cell membranes of heart muscle, specifically inhibiting the
Na+ pump, thereby raising the intracellular Na+ concentration. The resultant decrease in the Na+ gradient across the cell membrane reduces the energy available for transport of
Ca2+ out of the cell, leads to an increase in intracellular Ca2+ concentration, and provides the positive ionotropic effect and increased force of contractions resulting in a complete emptying of the ventricles. As a result of depression of conduction in the bundle of His, the atrioventricular conduction time is increased, resulting in an extended P–R interval on the electrocardiogram. The improved blood circulation also tends to improve kidney function, leading to diuresis and loss of oedema fluid often associated with heart disease.
61 Dr. Dima MUHAMMAD PHYTOCHEMISTRY & NATURAL PRODUCTS
1.4.1.1.2.1. Distribution in nature
In plants, cardiac glycosides are confined to the angiosperms, but are found in both monocotyledons and dicotyledons. The cardenolides are more common, and the plant families the Apocynaceae (e.g. Strophanthus), Liliaceae (e.g. Convallaria), and
Scrophulariaceae (e.g. Digitalis) yield medicinal agents. The rarer bufadienolides are found in some members of the Liliaceae (e.g. Urginea) and Ranunculaceae (e.g.
Helleborus), as well as in toads. Monarch butterflies and their larvae are known to accumulate in their bodies a range of cardenolides which they ingest from their food plant, the common milkweed (Asclepias syriaca; Asclepiadaceae). This makes them unpalatable to predators such as birds.
Figure 1.65 : (a) cane toad, (b,c) Monarch butterflies and its larvae on milkweed
1.4.1.1.2.2. Structure of glycosides
Two types of genin may be distinguished according to whether there is a five•or six•membered lactone ring. These types are known respectively as cardenolides(C23) (e.g. digitoxigenin) and bufanolides or bufadienolides (C24) (e.g. scillarenin). The following formulae indicate their structure and ring numbering:
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Figure 1.66: Structure of cardiac glycosides
The sugar moieties, attached to the aglycone by a C•3,β•linkage, are composed of up to four sugar units which may include glucose or rhamnose together with other deoxy•sugars whose natural occurrence is, to date, known only in association with cardiac glycosides.
The sugar unit may have one to four monosaccharides; many (e.g. D-digitoxose and d- digitalose) are unique to this group of compounds. About 20 different sugars have been characterized, and with the exception of d-glucose, they are 6-deoxy- (e.g. l-rhamnose, d- digitalose) or 2,6-dideoxy- (e.g. d-digitoxose, d-cymarose) hexoses, some of which are also
3-methyl ethers (e.g. d-digitalose and d-cymarose.
Figure 1.67 : Structures of 2,6-deoxy•sugars.
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Figure 1.68 : Structures of 6-deoxy•sugars.
1.4.1.1.2.3. Biosynthesis of Cardioactive Glycosides
Aglycones of the cardiac glycosides are derived from mevalonic acid but the final molecules arise from a condensation of a C21 steroid with a C2 unit (Cardenolides C23).
Bufadienolides are condensation products of a C21 steroid and a C3 unit.
Figure 1.69 : Biosynthesis of Cardioactive Glycosides
1.4.1.1.2.4. Physico-chemical properties
Fairly soluble in water, freely soluble in alcohol. The lactone ring is fragile and open easily once treated with heat or alkaline.
64 Dr. Dima MUHAMMAD PHYTOCHEMISTRY & NATURAL PRODUCTS
1.4.1.1.2.5. Tests and assays
- Identification of deoxy•sugars (Keller-Killiani): the extract of cardio-glycosides
is dissolved in glacial acetic acid, then two drops of 5% ferric chloride solution
are added; Then Carefully transfer this solution to the surface of 2 ml of
concentrated sulphuric acid; a reddish•brown layer forms at the junction of the
two liquids and the upper layer slowly becomes bluish•green, darkening with
standing.
- Identification of steroidal genines: After the cardio-glycosides being
hydrolyzed (liberating the genines), the genines are extracted with organic
solvent; The addition of anhydrous acetic acid and concentrated sulphuric acid
leads to the formation of bluish-green coulour in the presence of steroidal
genines.
- Identification of lactone ring (Cardinolides)
Nitro-substituted aromatic derivatives in alkaline solution (KOH) reacts with
the unsaturated lactone six-membered ring of cardenolides and gives strong
coloration.
Kedde test: using the 3, 5 dinitrobenzoic acid gives blue or violet colour; while
in Baljet test we use picric acid and if the cardio-glycosides is present yellow to
orange colour will be seen.
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1.4.1.1.2.6. CARDENOLIDES
1.4.1.1.2.6.1. Digitalis purpurea
Digitalis (Purple Foxglove Leaves) consists of the dried leaves of Digitalis purpurea L.
(Scrophulariaceae). It is required to contain not less than 0.3% of total cardenolides calculated as digitoxin.
It is a perennial herb which is very common in the UK and most of Europe, including some Mediterranean regions of Italy.
Figure 1.70 : Digitalis purpurea L. (Scrophulariaceae)
Collection:
Either first• or second•year leaves are permitted by the pharmacopoeias. After collection the leaves should be dried as rapidly as possible at a temperature of about
60°C and subsequently stored in airtight containers protected from light. Their moisture content should not be more than about 6%.
Chemical constituents:
- The primary (tetra) glycosides: constitute the principal active constituents of
the fresh leaves: Purpurea glycoside A, purpurea glycoside B and E, all possess
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at C•3 of the genin a linear chain of three digitoxose sugar moieties terminated
by glucose.
- The secondary glycoside: On drying, enzyme degradation takes place with the
loss of the terminal glucose to give digitoxin, gitoxin and gitaloxin, form
Purpurea glycoside A, purpurea glycoside B and E respectively.
Figure 1.71 : Structure of Purpurea glycosides.
1.4.1.1.2.6.2. Digitalis lanata
The plant, Digitalis lanata (Scrophulariaceae), the leaves of which are used as a
source of the glycosides digoxin and Lanatoside C, is a perennial or biennial
herb about 1 m high, indigenous to central and south•eastern Europe.
67 Dr. Dima MUHAMMAD PHYTOCHEMISTRY & NATURAL PRODUCTS
Figure 1.72 : Digitalis lanata (Scrophulariaceae)
- Collection:
Total glycoside levels are higher in first•year leaves but the important
medicinal glycosides (e.g. lanatoside C) attain their highest levels in the
second•year plants.
- Chemical constituents:
The primary glycosides (Lanatoside A, B and E) resemble those of D. purpurea
but are acetylated at the digitoxose moiety next to the terminal glucose. This
confers crystalline properties on the compounds, making them more amenable
to isolation.
Partial hydrolysis of the glycosides occurs during the drying and storage of
leaves, and deacetylation will produce products the same as in D. purpurea. In
addition to the above series of glycosides, two others (Lanatosides C and D),
involving respectively digoxigenin and diginatigenin are found in the leaves.
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Figure 1.73 : Structure of Lanatosides A, B and E.
Figure 1.74 : Structure of Lanatosides C and D.
Enzymic hydrolysis of the lanatosides generally involves loss of the terminal glucose
prior to removal of the acetyl function, so that compounds like acetyldigitoxin and
acetyldigoxin, as well as digitoxin and digoxin, are present in the dried leaf as
decomposition products from lanatosides A and C respectively.
69 Dr. Dima MUHAMMAD PHYTOCHEMISTRY & NATURAL PRODUCTS
Figure 1.75 : Preparation of Digoxin from Lanatoside C
Digoxin, prepared from Lanatoside C, has a rapid action and is more quickly
eliminated from the body than digitoxin; therefore, it is the most widely used of the
cardioactive glycosides. It is more hydrophilic than digitoxin, binds less strongly to
plasma proteins, and is mainly eliminated by the kidneys.
Digoxin is used in congestive heart failure and atrial fibrillation. Because of the
extreme toxicity associated with these compounds (the therapeutic level is 50–60%
of the toxic dose; a typical daily dose is only about 1mg), dosage must be controlled
very carefully.
1.4.1.1.2.6.3. Strophanthus
Strophanthus comprises the dried ripe seeds of Strophanthus kombe or S.
gratus (Apocynaceae), which are tall vines from equatorial Africa.
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Figure 1.76 : (a,b) Strophanthus komb, (c,d) Strophanthus gratus.
- Chemical constituents:
S. kombe has a history of use by African tribes as an arrow poison, the seeds
contain 5–10% cardenolides, a mixture known as K-strophanthin. This has little
drug use today, though was formerly used medicinally as a cardiac stimulant.
The main glycoside (about 80%) is K-strophanthoside with smaller amounts of K-
strophanthin-β and cymarin, related to K-strophanthoside as shown. These are
derivatives of the aglycone strophanthidin.
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Figure 1.77 : Glycosides of the aglycone strophanthidin.
S. gratus contains 4–8% of Ouabain (G-strophanthin), the rhamnoside of
ouabigenin. Ouabain is a potent cardiac glycoside, acts quickly, but wears off
rapidly. It is very polar, with rapid renal elimination and must be injected because
it is so poorly absorbed orally. It has been used for emergency treatment in cases
of acute heart failure.
Figure 1.78 : Ouabain (G-strophanthin).
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1.4.1.1.2.6.4. Nerium oleander
Nerium oleander (Apocynaceae), the oleander plant, and related species
contain glycosides having a similar action to that of digitalis. Of Mediterranean
origin, this evergreen flowering tree is widely cultivated in Japan and other
countries as a garden and roadside ornamental.
The principal constituent of the leaves is the oleandrin, a monoside comprising
oleandrigenin and oleandrose. The leaves also contain gitoxigenin and
digitoxigenin glycosides.
Oleander ingestion causes many cases of poisoning world•wide; in 1994, 303
cases were reported in Texas, and in Australia during 1972–8 it was responsible
for 27% of paediatric plant poisonings. Fatal cases have been reported
elsewhere and in Sri Lanka the use of the seeds in suicide attempts, particularly
among teenagers, poses a problem.
Figure 1.79 : Nerium oleander and oleandrine.
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1.4.1.1.2.6.5. Thevetia
The seeds of Thevetia peruviana (T. neriifolia) (Apocynaceae), the yellow
oleander, are a rich source of the glycoside thevetin A, which by partial
hydrolysis and the loss of two glucose units yields peruvoside, the therapeutic
cardioactive properties of which are well•known.
Thevetin has found use in continental Europe, and is considered particularly
useful in cases of mild myocardial insufficiency and where digitalis intolerance
exists.
Figure 1.80 : Thevetia peruviana and Thevetosides.
1.4.1.1.2.6.6. Convallaria
The dried roots and tops of lily of the valley Convallaria majalis
(Liliaceae/Convallariaceae) contain cardioactive glycosides (0.2–0.3%) and in
the past have been used in some European countries rather than digitalis. The
effects are similar, but the drug is less cumulative. This plant is widely
cultivated as an ornamental, particularly for its intensely perfumed small white
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flowers, and must be considered potentially toxic. The major glycoside (40–
50%) is convallatoxin, the rhamnoside of strophanthidin.
Figure 1.81 : Convallaria majalis and convallatoxine.
1.4.1.1.2.7. BUFADIENOLIDES
The bufadienolides are less widely distributed in nature than are the
cardenolides; they are found in some Liliaceae and Ranunculaceae, and in the
toad venoms.
Therapeutically they find little use as cardioactive drugs because of their low
therapeutic index and their production of side-effects. However squill has a
time•honoured place as an expectorant and has been widely used in the
treatment of cough.
1.4.1.1.2.7.1. Helleborus niger
Black hellebore rhizome is obtained from Helleborus niger (Ranunculaceae), a
perennial herb indigenous to Central Europe.
It contains three crystalline cardiac glycosides: helleborin, helleborein and
hellebrin. Of these, the last two have a digitalis•like action, hellebrin being
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approximately 20 times more powerful than helleborein. The aglycone
hellebrigenin is the bufadienolide analogue of strophanthidin.
The drug which has abortifacient as well as cardiotonic properties is considered
dangerous and is now obsolete in ordinary medicine.
Figure 1.82 : Helleborus niger and hellebrigenin. 1.4.1.1.2.7.2. Urginea maritime
Squill (white squill) consists of the dried sliced bulbs of the white variety of
Urginea maritima (formerly Scilla maritima; also known as Drimia maritima)
(Liliaceae/Hyacinthaceae) which grows on seashores around the
Mediterranean. The plant contains bufadienolides (up to 4%), principally
scillaren A and proscillaridin A.
Squill is not usually used for its cardiac properties, as the glycosides have a
short duration of action. Instead, squill is employed for its expectorant action in
preparations such as Gee„s linctus. Large doses cause vomiting and a digitalis-
like action on the heart.
76 Dr. Dima MUHAMMAD PHYTOCHEMISTRY & NATURAL PRODUCTS
Action and uses: The glycosides are poorly absorbed from the gastrointestinal
tract, they are of short•action duration and they are not cumulative. In small
doses the drug promotes mild gastric irritation causing a reflex secretion from
the bronchioles. It is for this expectorant action that it is widely used; in larger
doses it causes vomiting.
Red squill is a variety of U. maritima which contains an anthocyanin pigment
and bufadienolides which are different from those of the white squill. The main
glycosides are glucoscilliroside and scilliroside.
It has mainly been employed as a rodenticide. Rodents lack a vomiting reflex
and are poisoned by the cardiac effects, whilst vomiting will occur in other
animals and humans due to the emetic properties of the drug.
Figure 1.83 : Urginea maritime and scillaenine.
77 Dr. Dima MUHAMMAD PHYTOCHEMISTRY & NATURAL PRODUCTS
1.4.1.2. TRITERPENOID SAPONINS C30
As seen with the biosynthesis of steroids, the 2,3-epoxysqualene should be folded giving the transient dammarenyl cation; If no further cyclization occurs the tetracyclic triterpenoid “dammarane” is formed as found in Ginseng (Panax ginseng; Araliaceae).
Generally the dammarenyl cation undergoes further carbocation-promoted cyclizations and a pentacyclic ring system can now be formed by cyclization onto the double bond giving a new five-membered ring and the tertiary lupenyl cation; Ring expansion in the lupanyl cation by bond migration gives the oleanyl system, the widely distributed β- amyrin (Oleanans); While the formation of the isomeric α-amyrin (Ursans) involves first the migration of a methyl in the oleanyl cation.
O dammarane epoxydation HO squalene 2,3-epoxysqualene
H H H
H HO H -amyrine HO -amyrine LUPANS HO H URSANS OLEANANS H Figure 1.84 : Triterpenoid saponin structures.
The pentacyclic triterpenoid skeletons exemplified by lupeol, α-amyrin, and β-amyrin are frequently encountered in the form of triterpenoid saponin structures. Triterpenoid saponins are rare in monocotyledons, but abundant in many dicotyledonous families.
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1.4.1.2.1. Anti-inflammatory saponin containing drugs:
1.4.1.2.1.1. Liquorice
Licorice; glycyrrhiza is the dried unpeeled rhizome and root of the perennial herb
Glycyrrhiza glabra (Leguminosae/Fabaceae).
Most of the liquorice produced is used in confectionery and for flavouring, including tobacco and beers. Its pleasant sweet taste and foaming properties are due to saponins.
Figure 1.85: Glycyrrhiza glabra.
- Chemical constituents:
Liquorice root contains 3–5% of the root, (up to 12% in some varieties), is comprised of glycyrrhizin, a diglucuronide of the aglycone glycyrrhetic acid. The bright yellow colour of liquorice root is provided by flavonoids (1–1.5%) liquiritigenin and isoliquiritigenin and their corresponding glucosides.
79 Dr. Dima MUHAMMAD PHYTOCHEMISTRY & NATURAL PRODUCTS
Figure 1.86 : Liquorice (Glycyrrhiza glabra) chemical derivatives.
- Uses:
Liquorice has long been employed in pharmacy as a flavouring agent, demulcent and mild expectorant. The recognition of the corticosteroid-like activity (anti-inflammatory and mineralocorticoid activities) of liquorice extracts and glycyrrhetinic acid has led to its use for the treatment of rheumatoid arthritis, Addison„s disease (chronic adrenocortical insufficiency) and various inflammatory conditions.
The flavonoid component of the root, which possesses antimicrobial properties, also exerts spasmolytic and antiulcerogenic activity.
Because of the mineralocorticoid like action of glycyrrhizin, a higher dosage or longer use could lead to adverse effects consisting of sodium and water retention, blood pressure elevation, potassium loss, and edema.
1.4.1.2.1.2. Horse chestnut seed
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Horse chestnut seeds and the tree Aesculus hippocastanum (Hippocastanaceae); native to western Asia the species is now widely distributed over the world as an ornamental.
Figure 1.87 : Aesculus hippocastanum and chemical derivatives.
- Chemical constituents:
Medicinally the seeds have long been used for their saponin content, the principal component being aescin, a mixture of many closely related compounds (protoescigenine), which occurs in concentrations of up to 20% in the dried seeds. The seeds also contain flavones, coumarins and tannins.
- Uses:
Extracts of horse chestnut have been traditionally employed for the treatment of peripheral vascular disorders including haemorrhoids, varicose veins, leg ulcers and bruises.
Thus some of the escins are anti•inflammatory agents, inhibiting the activity of lysosomal enzymes that damage capillary walls; tannins tone the blood vessel walls and flavonoids are anti•inflammatory agents.
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Horse chestnut is contraindicated with anticoagulants such as warfarin because of the presence of coumarins.
1.4.1.2.2. Expectorant saponin containing drugs:
1.4.1.2.2.1. Senega root
Senega of the BP and EP consists of the dried root crown and root of Polygala senega L.
(Polygalaceae). Formerly abundant in eastern Canada and eastern USA it is now collected further westward.
Figure 1.88 : Polygala senega and chemical derivatives.
- Chemical constituents:
Senega contains 6–12% of triterpenoid saponins (senegin)
- Uses:
Senega is used as a stimulant expectorant in chronic bronchitis. It is often prescribed with other expectorants.
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1.4.1.2.2.2. Primula root
Primula root BP/EP consists of the dried rhizome and root of Primula veris (L.) (cowslip) from Primulaceae. These species occur wild throughout Europe with Bulgaria and Turkey the principal commercial sources.
Figure 1.89 : Primula veris and chemical derivatives.
- Chemical constituents:
Constituents include a mixture of triterpenoid saponins of the oleane type (5–10%), protoprimulagenine and primulic acid, and phenolic glycosides such as primulaverin
(primulaveroside).
Figure 1.90 : Chemical derivatives of Primula veris.
83 Dr. Dima MUHAMMAD PHYTOCHEMISTRY & NATURAL PRODUCTS
- Uses:
Primula root, like senega, is used as an expectorant for the treatment of bronchial conditions.
1.4.1.2.2.3. Ivy
The drug consists of the whole or cut aerial leaves of Hedera helix L., family Araliaceae, collected in the spring. This familiar climber and creeper is widely distributed throughout
Europe and Asia.
Figure 1.91 : Hedera helix.
- Chemical constituents:
Important constituents of ivy are saponins involving the pentacyclic triterpenoid genins hederagenin, bayogenin and oleanolic acid. The BP/EP requires the presence of α•hederin and heteracoside C; a minimum concentration of 3.0% heteracoside C.
84 Dr. Dima MUHAMMAD PHYTOCHEMISTRY & NATURAL PRODUCTS
Figure 1.92 : Hedera helix saponins.
- Uses:
Ivy•leaf extracts have been traditionally used as an expectorant for the treatment of various chest conditions, such as bronchitis and whooping cough; also for gout and rheumatic pains. Like most saponins, those of ivy are toxic in excess causing diarrhoea, vomiting and allergy. Externally, ivy is used cosmetically and for a variety of skin conditions.
Hedera helix (Araliaceae) contain acetylenic derivatives (Falcarinol), a potent fungicidal, which is a constituent known to cause contact dermatitis in certain individuals when the plants are handled.
These molecules containing triple bonds tend to possess conjugated unsaturation; This gives the compounds intense and highly characteristic UV spectra, which aids their detection and isolation.
The saponins extract doesn„t contain dangerous concentration of acetylenic derivatives, due to the drying process of ivy leaves and the non-polar properties of these compounds.
85 Dr. Dima MUHAMMAD PHYTOCHEMISTRY & NATURAL PRODUCTS
Figure 1.93 : Acetylenic derivative (Falcarinol)of Hedera helix.
1.4.1.2.3. Adaptogenic saponins containing drugs
Adaptogenic drug: is an agent that helps the body to adapt to stress, improving stamina and concentration, and providing a normalizing and restorative effect.
1.4.1.2.3.1. Ginseng
For some 2000 years the roots of Panax ginseng C. A. Meyer (Araliaceae) have held an honored place in Chinese medicine. Today it is a product of world•wide usage. Production is principally confined to China, Korea and Siberia, although it is cultivated commercially on a small scale in Holland, England, Germany and France.
The most expensive ginseng is that derived from Korean root. Panax quinquefolium root is produced in the eastern USA and Canada. The plant, about 50 cm tall with a crown of dark green whorled leaves and small green flowers giving rise to clusters of bright red berries, is cultivated under thatched covers and harvested when 6 years old.
Sun-drying of the root, after removal of the outer layers, produces white ginseng, whereas the red ginseng is obtained by first steaming the root, followed by artificial drying and then sun•drying. The BP/EP recognizes both red and white ginseng.
86 Dr. Dima MUHAMMAD PHYTOCHEMISTRY & NATURAL PRODUCTS
Figure 1.94: Panax spp. & white and red ginseng.
- Chemical constituents:
The medicinal activity appears to reside largely in a number of dammarane•type saponins termed ginsenosides by Japanese workers and panaxosides by Russian workers. These two series of compounds, all now generally termed ginsenosides, are glycosides respectively derived from the diol 20(S)•protopanaxadiol and the triol 20(S)•protopanaxatriol.
Two other groups of compounds present in the root which have known therapeutic activity are high molecular weight polysaccharides (glycans) and acetylenic compounds.
Figure 1.95: dammarane•type saponins from Panax spp.
87 Dr. Dima MUHAMMAD PHYTOCHEMISTRY & NATURAL PRODUCTS
- Uses:
In Asia the drug is held in esteem for the treatment of anaemia, diabetes, gastritis, sexual impotence and the many conditions arising from the onset of old age. In the West, too, it has in recent years become an extremely popular remedy particularly for the improvement of stamina, concentration, resistance to stress and to disease; in this sense the action of the drug is described as ‘adaptogenic„.
Long-term use of ginseng can lead to symptoms similar to those of corticosteroid poisoning, including hypertension, nervousness, and sleeplessness in some subjects, yet hypotension and tranquillizing effects in others.
1.4.1.2.4. Emulsifying saponins containing drugs
1.4.1.2.4.1. Quillaia bark
Quillaia bark or soapbark is derived from the tree Quillaja saponaria (Rosaceae) and other
Quillaja species found in Chile, Peru, and Bolivia. The generic name is derived from the
Chilean word quillean, to wash, from the use made of the bark.
Figure 1.96: Quillaja saponaria and quillaic acid.
88 Dr. Dima MUHAMMAD PHYTOCHEMISTRY & NATURAL PRODUCTS
- Chemical constituents:
The bark contains up to 10% saponins, a mixture known as ‘commercial saponin„ which on hydrolysis yield the principal sapogenin quillaic acid.
- Uses:
Quillaia saponins are used as a foaming agent in beverages and emulsifier in foods. They are occasionally exploited in pharmaceutical preparations, where in the form of quillaia tincture it is used as an emulsifying agent, particularly for fats, tars, and volatile oils.
Saponins from quillaia are also showing great promise as immunoadjuvants, substances added to vaccines and other immunotherapies designed to enhance the body„s immune response to the antigen.
1.4.1.2.5. Other drugs containing saponins
1.4.1.2.5.1. CENTELLA
Centella (Indian pennywort, gotu kola, Indian water navelwort, tiger grass) consists of the dried fragmented aerial parts of Centella asiatica (L.) Urban, family Umbelliferae/
Apeaceae syn. Hydrocotyle asiatica.
It has important traditional uses in India and Africa for the treatment of leprosy, and in the former for meditation purposes under the name brahmi.
89 Dr. Dima MUHAMMAD PHYTOCHEMISTRY & NATURAL PRODUCTS
Figure 1.97: Centella asiatica and triterpenic derivative.
- Chemical constituents:
Among the most active are triterpenoid saponins, principally asiaticoside together with brahmoside, centelloside and medecasside, flavonoids and sesquiterpenic volatile oil.
- Uses:
The BHP (1983) lists centella as a mild diuretic, antirheumatic, dermatological agent and peripheral vasodilator; topically as vulnerary (wound healer). As such, it is used for rheumatic conditions and as a skin tonic in wound healing. It is included in some creams and cosmetics preparation to prevent the development of stretch marks in pregnancy.
These uses have been largely supported by pharmacological data.
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1.5. TETRATRPENES (C40)
Important among these compounds are the C40 yellow or orange-red carotenoid pigments, formed by the tail to tail union of two molecules of the C20 geranylgeranyl diphosphate to give an acylic intermediate with a cis-configuration of the central double bond. By a change of configuration from cis to trans and further desaturation of the isoprenoid chain, lycopene, the all-trans pigment of the ripe tomato fruit is formed.
The various carotenes and derivatives can be envisaged by cyclization of one or both ends of the lycopene molecules.
Figure 1.98: Tetratrpenes derivatives. The most significant dietary carotenoid in this respect is lycopene, with tomatoes and processed tomato products featuring as the predominant source. Crocetin, in the form of esters with gentiobiose, is the major pigment in stigmas of Crocus sativus (Iridaceae) which comprise the extremely expensive spice saffron. The striking pigments of the red peppers, capsanthin and capsorubin; Fucoxanthin in brown algae (Fucus species;
Fucaceae); Astaxanthin is commonly found in marine animals and is responsible for the pink/red coloration of crustaceans, shellfish, and fish such as salmon; These animals are
91 Dr. Dima MUHAMMAD PHYTOCHEMISTRY & NATURAL PRODUCTS unable to synthesize carotenoids, and astaxanthin is produced by modification of plant carotenoids, e.g. β-carotene, obtained in the diet.
In association with chlorophyll, carotenes participate in photosynthesis, but also occur in other non-photosynthetic plant organs such as the carrot and in fungi and bacteria. They also serve as important protectants for plants and algae against photo-oxidative damage, quenching toxic oxygen species.
Recent research also suggests that carotenoids are important antioxidant molecules in humans, quenching singlet oxygen and scavenging peroxyl radicals, thus minimizing cell damage and affording protection against some forms of cancer.
Vitamin A, was recognized to be present in materials such as butter and cod-liver oil and was subsequently shown to be a diterpenoid produced in the livers of animals by enzymic hydrolysis from β-carotene.
In addition to the pro-vitamin A activity of β-carotene, the carotenoids have more recently come to be recognized as essential for human health not only as antioxidants but also for specific functions such as normal vision and actions favouring the immune system.
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Figure 1.99: Pro-vitamin A activity of β-carotene.
It was showed that the lutein of the ‘macula lutea„ of the retina of the eye is chemically identical to that giving the colour of marigold flowers (Tagetes erecta, Compositae). This accords with the use of lutein in nutritional supplements as preventatives of age-related macular degeneration and for other health benefits.
Figure 1.100: Marigold flowers and lutein.
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Second Chapter
CYANOGENETIC GLYCOSIDES &
GLUCOSINOLATE
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CYANOGENETIC GLYCOSIDES & GLUCOSINOLATE
They are important groups of glycosides with medicinal interest; The cyanogenetic glycosides and the glucosinolate compounds, are characteristic of certain groups of plants and have similarities in their biosynthetic origins.
1. CYANOGENETIC GLYCOSIDES
Cyanogenic glycosides, hydroxynitrile glycosides, are a group of mainly plant-derived materials which liberate hydrocyanic acid (HCN) on hydrolysis, and are thus of concern as natural toxicants.
Figure 2.1: General structure of cyanogenic glycosides.
1.1. Biosynthesis :
Cyanogenic glycosides are produced from a range of amino acids by a common pathway.
The main amino acids utilized in the biosynthesis of cyanogenic glycosides are:
- phenylalanine (e.g. prunasin, sambunigrin, and amygdalin)
- tyrosine (e.g. dhurrin and taxiphyllin)
- valine (e.g. linamarin from flax (Linum usitatissimum; Linaceae)
- isoleucine (e.g. lotaustralin, also from flax)
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- leucine (heterodendrin from Acacia species (Leguminosae/Fabaceae).
Figure 2.2: Cyanogenic glycosides and the Amino acids precursors
glycosides are produced from a range of amino acids by a common pathway, the amino
acid is N-hydroxylated and then converted into the aldehyde oxime (aldoxime), by a
sequence which involves further N-hydroxylation and subsequent decarboxylation–
elimination. The nitrile is formed by dehydration of the oxime; Finally, the
glycosylation occurs after a hydroxylation reaction.
Figure 2.3: Biosynthesis of cyanogenic glycosides.
1.2. Hydrolysis:
Enzymes present in the plant may bring about hydrolysis in two stages; When plant tissue containing a cyanogenic glycoside is crushed, glycosidase enzymes (β-glucosidase-
96 Dr. Dima MUHAMMAD PHYTOCHEMISTRY & NATURAL PRODUCTS type) also in the plant, but usually located in different cells, are brought into contact with the glycoside and begin to hydrolyse. Thus, cyanogenic glycoside is hydrolysed sequentially by β-glucosidase-type enzymes to hydroxynitrile, the latter is then hydrolysed, to its component parts, the corresponding aldehyde and toxic HCN, by the action of a further enzyme (hydroxyl-nitrylase).
Figure 2.4: Hydrolysis of cyanogenic glycoside.
1.3. Tests:
To test for a cyanogenetic glycoside qualitatively the material is well broken and placed in a small flask with sufficient water to moisten. In the neck of the flask a suitably impregnated strip of filter•paper is suspended by means of a cork. The paper may be treated in either of the following ways to give a colour reaction with free hydrocyanic acid.
- sodium picrate (yellow), which is converted to sodium isopurpurate (brick•red).
- or a freshly prepared solution of guaiacum resin in absolute alcohol which is
allowed to dry on the paper and treated with very dilute copper sulphate solution.
The latter testpaper turns blue with prussic acid.
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If the enzymes usually present in the material have not been destroyed or inactivated, the hydrolysis takes place within about an hour when the flask is kept in a warm place.
More rapid hydrolysis will result if a little dilute sulphuric acid is added and the flask gently heated.
Quantitative essay: For materials containing a fairly high percentage of cyanogenetic
glycosides (e.g. bitter almonds) the amount may be determined quantitatively by
placing the plant in a flask with water and tartaric acid and passing steam through
until all the hydrocyanic acid has distilled into a receiver. The distillate is then
adjusted to a definite volume and aliquots titrated with standard silver nitrate
solution.
1.4. Risk from Hydrogen Cyanide:
Drug containing cyanogenic glycosides are long considered a potential source of dietary hydrogen cyanide (HCN) poisoning. The lethal dose of HCN for humans is approximately 50-100 mg (0.5-3.5mg/kg). But while HCN is absorbed in minutes through the gastric mucosa when administered in, say, cyanogenic salts such as potassium cyanide, only very low blood levels of HCN were found after the ingestion of 100 g linseed. Similarly low levels were detected after the consumption of 10 bitter almonds, but eating 50 bitter almonds produced blood levels that were life-threatening in one test subject.
One reason for the nonlinear absorption and elimination kinetics of HCN in the body lies in the enzyme-dependency of the release of HCN from its glycosidic bond. In the case of
98 Dr. Dima MUHAMMAD PHYTOCHEMISTRY & NATURAL PRODUCTS linseed, this cleavage is catalyzed by the plant enzyme linamarase; the acidic gastric juice partially inactivates this enzyme, slowing the release of HCN. Once it is absorbed, HCN is subject to transformation by the enzyme rhodanase, which is present in the mitochondria of all somatic cells and rapidly converts small amounts of HCN into the harmless compound thiocyanate. The rhodanase detoxification system has a limited capacity, however. The sudden ingestion of large amounts of HCN can easily overwhelm this system, leading to swift and fatal poisoning.
1.4.1. Cyanide intoxication treatment and management:
Gastric lavage, oxygenation and activated charcoal should be given after oral exposure;
Antidotes like hydroxocobalamin (chelating agent), sodium nitrite and sodium thiosulfate, are administered intravenously in combination or alone.
1.5. Distribution in nature:
Although cyanogenic glycosides are widespread, they are particularly found in the families
Rosaceae, Leguminosae/Fabaceae, Graminae/Poaceae, Araceae, Compositae/Asteraceae,
Euphorbiaceae, and Passifloraceae.
It is highly likely that plants synthesize these compounds as protecting agents against herbivores. Some insects also accumulate cyanogenic glycosides in their bodies, again as a protective device. Whilst many insects obtain these compounds by feeding on suitable plant sources.
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1.5.1. Rosaceae
Amygdalin (amygdaloside of bitter almonds Prunus amygdalus var. amara; Rosaceae); itself is not especially toxic to animals; toxicity depends on the co-ingestion of the hydrolytic enzymes. Although formed by the hydrolysis of amygdalin, prunasin is also a natural cyanogenic glycoside and may be found in seeds of black cherry (Prunus serotina) and in the seeds and leaves of cherry laurel (Prunus laurocerasus).
Figure 2.5: Rosaceae cyanogenic glycosides hydrolysis.
Uses: Wild cherry bark in the form of a syrup or tincture is mainly used in cough preparations, to which it gives mild sedative properties and a pleasant taste. It was regarded as particularly useful for irritable and persistent coughs.
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Figure 2.6: Cyanogenic glycosides of Rosaceae (a & b: P. serotina c & d: P. amygdalus).
1.5.1.1. Cherry-laurel leaves:
Cherry•laurel leaves are obtained from Prunus laurocerasus (Rosaceae), an evergreen shrub common in Europe. They were formerly official in the fresh state.
The cyanide content of small young leaves is reported as 5%, rapidly dropping to about
0.4–1.0% of prunaside as leaf•size increases.
Figure 2.7: Cherry-laurel leaves and prunasin structure.
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2. GLUCOSINOLATE COMPOUNDS
Glucosinolates have several features in common with the cyanogenic glycosides. They, too, are glycosides, in this case S-glycosides containing sulphate groupe. They are enzymically hydrolysed in damaged plant tissues, giving rise to potentially toxic materials.
Figure 2.8: Glucosinolate basic structure.
2.1. Biosynthesis pathway:
They share the early stages of the cyanogenic glycoside biosynthetic pathway for their formation in plants.
The sinalbin is synthetized from tyrosine. The aldoxime is produced from the amino acid by the early part of the cyanogenic glycoside pathway. This aldoxime incorporates sulfur from cysteine to give the thiohydroximic acid, most likely by attack of the thiolate ion onto the imine system. The S-alkylthiohydroximate undergoes bond cleavage via a C–S lyase and the thiol group is then S-glucosylated. Sulfation features as the last step in the pathway.
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Figure 2.9: Biosynthesis of glucosinolates. 2.2. Glucosinolates hydrolysis:
A typical structure is sinalbin, found in seeds of white mustard (Sinapis alba;
Cruciferae/Brassicaceae). Addition of water to the crushed or powdered seeds results in hydrolysis of the S-glucoside bond via the enzyme thioglucosidase to give a thiohydroximate sulfonate. This compound usually yields the isothiocyanate.
Figure 2.10: Hydrolysis of glucosinolates.
Under certain conditions, dependent on pH, or the presence of metal ions or other enzymes, related compounds such as thiocyanates (RSCN) or nitriles (RCN) may be formed from glucosinolates.
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Figure 2.11: Different resulting compounds of glucosinolates hydrolysis. 2.3. Glucosinolates biological properties:
Many glucosinolates have an antithyroid and goitre•inducing effect in man. There is evidence that consumption of the hydrolysis products from glucosinolates in food crops may induce goitre, an enlargement of the thyroid gland, by inhibiting iodine incorporation and thyroxine formation. The goitrogenic effects of glucosinolates cannot be alleviated merely by the administration of iodine. This severely limits economic utilization for animal foodstuffs of these crops.
On the other hand, sulforaphane, formed from the glucosinolate glucoraphanin in broccoli
(Brassica oleracea italica; Cruciferae/Brassicaceae), has been shown to have beneficial medicinal properties, in that it induces carcinogen-detoxifying enzyme systems and accelerates the removal of xenobiotics.
Figure 2.12: Glucosinolate derivatives of broccoli.
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2.4. Distribution in nature:
Glucosinolates are found in many plants of the Cruciferae/Brassicaceae, Capparidaceae,
Euphorbiacae, Phytolaccaceae, Resedaceae, and Tropaeolaceae.
They are responsible of the pungent-taste (mustard oil) typical of many plants in the
Cruciferae/Brassicaceae that are used as vegetables (e.g. cabbage, radish) and condiments
(e.g. mustard, horseradish).
2.4.1. Mustard seeds:
Black or brown mustard (Sinapis) is the dried ripe seed of Brassica nigra or of B. juncea
(Cruciferae/Brassicaceae) and their varieties. The former species is cultivated in Europe and the USA, while B. juncea is grown in India and the former USSR.
- Chemical constituents of Black mustard:
Black mustard seeds contain sinigrin and myrosin and yield after maceration with water
0.7–1.3% of volatile oil. The latter contains over 90% of allylisothiocyanate (pungent odour). The seeds also contain about 27% of fixed oil, 30% of proteins, mucilage and traces of sinapine hydrogen sulphate.
- Chemical constituents of White mustard Sinapis alba:
White mustard seeds contain the glucoside sinalbin and myrosin. In the presence of moisture decomposition takes place with the formation of isothiocyanate (non-volatile, pungent odour is absent), sinapine hydrogen sulphate and glucose (salt of an unstable alkaloid),The seeds also contain about 30% of fixed oil, 25% of proteins and mucilage.
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- Uses:
The mustards have been traditionally used, particularly in the form of plasters, as rubefacients and counterirritants. In large doses they have an emetic action. Both varieties are used as condiments.
Figure 2.13: Glucosinolate derivatives of White and black moustard (a and b respectively).
3. CYSTEINE DERIVATIVES
Derivatives of the amino acid cysteine occur as sulphoxides in the genus Allium and are responsible for the lachrymatory factor of onions, garlic etc. The
S•(trans•propen•1•yl)•cysteine sulphoxide is the active component of the onion and the
S•allyl derivative of garlic. As well as its considerable culinary interest, the latter also has medicinal usage.
Figure 2.14: cysteine derivatives of garlic.
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The cysteine sulfoxides themselves are odourless and non-volatile, with smell and taste developing only upon hydrolytic and other reactions.
3.1. Garlic:
Garlic (Allium sativum; Liliaceae/Alliaceae) has a long history of culinary and medicinal use. The compound bulb is composed of several smaller sections termed cloves.
- Chemical constituents:
The major flavour component of garlic is a thiosulfinate called allicin. Allicin is formed when garlic tissue is damaged as a hydrolysis product of S-allyl cysteine sulfoxide (alliin).
Under these conditions, alliin is cleaved by an elimination reaction and two molecules of the sulfenic acid combine to form allicin.
Figure 2.15: Allicin formation.
Under dry conditions both alliin and allicin are relatively stable but the latter when formed is readily converted during processing of the powder to other sulphur compounds
(diallyldisulphide, diallyltrisulphide and ajoene).
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Figure 2.16: Allicin related compounds.
- Uses:
Allicin has considerable antibacterial and antifungal properties.
Ajoene has been shown to be a potent antithrombotic agent through inhibition of platelet aggregation.
Garlic is used for a variety of reasons, and some of the attributes associated with it, e.g. for cancer prevention or to reduce heart attacks, may not be confirmed. Other properties, such as antimicrobial activity, effects on lipid metabolism (to lower cholesterol levels), and platelet aggregation inhibitory action, have been demonstrated.
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Third Chapter
ALKALOIDS
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1. History
The first isolations of alkaloids in the nineteenth century followed the re-introduction
into medicine of a number of alkaloid-containing drugs and were coincidental with the
advent of the percolation process for the extraction of drugs. The French pharmacist
Derosne probably isolated the alkaloid afterwards known as narcotine in 1803 and the
Hanoverian pharmacist Sertürner further investigated opium and isolated morphine
(1806, 1816). Isolation of other alkaloids, particularly by Pelletier and Caventou,
rapidly followed; strychnine (1817), emetine (1817), brucine (1819), piperine (1819),
caffeine (1819), quinine (1820), colchicine (1820) and coniine (1826). Coniine was the
first alkaloid to have its structure established (Schiff, 1870) and to be synthesized
(Ladenburg, 1889), but for others, such as colchicine, it was well over a century before
the structures were finally elucidated.
In the second half of the twentieth century alkaloids featured strongly in the search
for plant drugs with anticancer activity. A notable success was the introduction of
Catharanthus alkaloids and paclitaxel into medicine and there is much current
interest in other alkaloids having anticancer properties as well as those exhibiting
antiaging and antiviral possibilities.
2. Definition:
The alkaloids are derived from amino acids with low molecular weight nitrogen
containing compounds found mainly in plants, but also to a lesser extent in
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microorganisms and animals; They contain one or more nitrogen atoms, typically as
primary, secondary, or tertiary amines, and this usually confers basicity on the
alkaloid, facilitating isolation and purification, since water-soluble salts can be formed
in the presence of mineral acids.
The biological activity of many alkaloids is often dependent on the amine function
being transformed into a quaternary system by protonation at physiological pH
values.
The name alkaloid is in fact derived from alkali. However, the degree of basicity varies
greatly, depending on the structure of the alkaloid molecule and on the presence and
location of other functional groups. Indeed, some alkaloids, e.g. where the nitrogen is
part of an amide function, are essentially neutral. Alkaloids containing quaternary
amines are also found in nature. Over 27000 different structures have been
characterized, with 21000 from plants.
3. Distribution:
True alkaloids are of rare occurrence in lower plants. In the fungi the lysergic acid
derivatives and the sulphur-containing alkaloids, e.g. the gliotoxins, are the best
known. Among the pteridophytes and gymnosperms the lycopodium, ephedra and
Taxus alkaloids have medicinal interest. Alkaloids are commonly found in the
dicotyledon orders such as Magnoliales (Lauraceae, Magnoliaceae), Ranunculales
(Berberidaceae, Menispermaceae, Ranunculaceae), Papaverales (Papaveraceae,
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Fumariaceae), Rosales (Leguminosae, subfamily Papilionaceae), Rutales (Rutaceae),
Gentiales (Apocynaceae, Loganiaceae, Rubiaceae) and Tubiflorae (Boraginaceae,
Convolvulaceae, Solanaceae). They have limited distribution in monocotyledon such
as Liliaceae and Amaryllidaceae.
Animal alkaloids are rare; They include the potent neurotoxic alkaloids of frogs of the
genus Phyllobates, which are among some of the most poisonous substances known,
other reptilian alkaloids are strongly antimicrobial; other occur in the skins of
amphibians along with other toxins; Chemical defense against predators secreted
from leg joints of ladybirds beetles (Coccinella: coccinelline); The Catoramine,
secreted by the scent gland of the Canadian beaver, is used in perfumery. 4. Physico-chemical properties:
All true alkaloids have a bitter taste and appear as a white solid, with the exception of
nicotine which has a brown liquid. True alkaloids form water-soluble salts. Moreover,
most of them are well-defined crystalline substances which unite with acids to form
salts. True alkaloids may occur in plants (1) in the free state, (2) as salts and (3) as N-
oxides.
Generally free bases of alkaloids are soluble in organic solvents and insoluble in water,
whereas alkaloidal salts are soluble in water and partially soluble in organic solvents.
For example, strychnine hydrochloride is much more soluble in water than strychnine
as a base.
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5. Chemical Tests:
The chemical tests are performed from neutral or slightly acidic solution of drug,
giving precipitants with the following reagents:
Dragendorff„s Test Drug solution + Dragendroff„s reagent (Potassium Bismuth Iodide),
formation of Orangish red colour.
Mayer„s Test Drug solution + few drops of Mayer„s reagent (potassium mercuric
iodide), formation of creamy-white precipitant.
Wagner„s Test Drug solution + few drops of Wagner„s reagent (dilute Iodine solution),
formulation of reddish-brown precipitate. 6. Extraction:
The extraction of alkaloids is based on their basic character and solubility profiles.
Generally alkaloids are extracted mainly using two methods:
Process A: The powdered material that contains alkaloidal salts is moistened with
alkaline substances like sodium bicarbonate, ammonia, calcium hydroxide, etc., which
combines with acids, tannins and other phenolic substances and sets free the alkaloids
bases. Extraction is then carried out with organic solvents such as ether or petroleum
spirit. The concentrated organic liquid is then shaken with aqueous acid and allowed
to separate. Alkaloid salts will be present in aqueous liquid, while many impurities
remain behind in the organic liquid.
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Figure 3.1: Alkaloids extraction with alkaline solution.
Process B: The collected powdered material is extracted with water or aqueous alcohol
containing dilute acid. Chloroform or other organic solvents are added and shaken to
remove the pigments and other unwanted materials. The free alkaloids are then
precipitated by the addition of excess alkalis like, sodium bicarbonate or ammonia and
separated by filtration or by extraction with organic solvents.
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Figure 3.2: Alkaloids extraction with acidic solution.
Volatile liquid alkaloids such as nicotine and coniine are most conveniently isolated by
distillation. An aqueous extract is made alkaline with caustic soda or sodium
carbonate and the alkaloid distilled off in steam. Nicotine is an important insecticide,
and large quantities of it are prepared from those parts of the tobacco plant which
cannot be used for tobacco manufacture.
7. Classification:
For practical purposes it is useful, therefore, to maintain the well-established
classifications based on chemical structures; There are three broad divisions:
I. Heterocyclic or typical alkaloids, derived from amino acids, are divided into 14
groups according to their ring structure.
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II. Non-heterocyclic or atypical alkaloids, sometimes called ‘protoalkaloids„ or
biological amines. Protoalkaloids are compounds, in which the N atom derived
from an amino acid is not a part of the heterocyclic.
III. Pseudoalkaloids are compounds, the basic carbon skeletons of which are not
derived from amino acids. The N atom is inserted into the molecule at a
relatively late stage, for example, in the case of steroidal or terpenoid
skeletons. Certainly, the N atom can also be donated by an amino acid source
across a trans-amination reaction.
Alkaloids are often classified according to the nature of the nitrogen-containing
structure (pyrrolidine, piperidine, quinoline, isoquinoline, indole). As the carbon
skeleton of the particular amino acid precursor is also largely retained intact in the
alkaloid structure, though the carboxylic acid carbon is often lost through
decarboxylation.
Figure 3.3: Amino-acid derived Alkaloids.
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7.1. Ornithine-derived Alkaloids
7.1.1. Tropane Alkaloids biosynthesis:
The bicyclic structure of the tropane skeleton is formed initially by the methylation of
pyrrolinium cation, Then with the addition of two acetyl-CoA units the second ring is
formed.
Figure 3.4: Biosynthesis of Tropane skeletone.
The principal alkaloids of medicinal interest in this group are (−)-hyoscyamine; its
more stable racemate atropine, and hyoscine (scopolamine). The compounds are
tropanol esters and are hydrolysed by heating at 60°C or pH modifying (acid or base).
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Figure 3.5: Tropane derivatives.
These three specific alkaloids are confined to the Solanaceae, including Atropa
belladonna (deadly nightshade), Datura stramonium (thornapple) and Hyoscyamus
niger (henbane); These alkaloids are also responsible for the pronounced toxic
properties of these plants. They constitute an interesting chemotaxonomic study
within the family.
Other tropane bases occur in the Erythroxylaceae (cocaine in coca leaves),
Convolvulaceae, Dioscoreaceae, Rhizophoraceae, Cruciferae and Euphorbiaceae.
Figure 3.6: Tropane Alkaloids from Solanaceae plants.
Hyoscyamine appears to be much more easily racemized than hyoscine (scopolamine);
The racemic form of hyoscyamine is called atropine.
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The chiral center in the tropic acid portion is adjacent to a carbonyl and the aromatic
ring, and racemization can be achieved under mild conditions by heating or treating
with base; this will involve an intermediate enol (or enolate).
Figure 3.7: Hyoscyamine racemization.
7.1.1.1. Biological activity of Tropane Alkaloids:
These alkaloids, competitive antagonists, compete with acetylcholine for the
muscarinic site of the parasympathetic nervous system, thus preventing the passage
of nerve impulses, and are classified as anticholinergics.
Acetylcholine binds to two types of receptor site, described as muscarinic or nicotinic.
These are triggered specifically by the alkaloid muscarine (fly agaric fungus Amanita
muscaria) or by the tobacco alkaloid nicotine respectively.
The structural similarity between acetylcholine and muscarine can readily be
appreciated, and hyoscyamine is able to occupy the same receptor site.
Figure 3.8: Structural similarity between acetylcholine, muscarine and hyoscyamine.
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The agonist properties of hyoscyamine and hyoscine give rise to a number of useful
effects, including antispasmodic action on the gastrointestinal tract (hyoscine:
scopolamine), antisecretory effect controlling salivary secretions before the induction
of anaesthesia during surgical operations, and as mydriatics to dilate the pupil of the
eye. Hyoscine has a depressant action on the central nervous system CNS and finds
particular use as a sedative to control motion sickness.
The potent bronchodilator ipratropium bromide, synthesized from nor-atropine, is
used in inhalers for the treatment of chronic bronchitis.
Figure 3.9: Semi-synthesis of ipratropium bromide
One of the side-effects from oral administration of tropane alkaloids is dry mouth (the
antisecretory effect), but this can be much reduced by transdermal administration
(impregnated patch). Initial toxicity symptoms include skin flushing with raised body
temperature, mouth dryness, dilated pupils, and blurred vision.
Atropine also has useful antidote action in cases of poisoning caused by
acetylcholinesterase inhibitors e.g. physostigmine and neostigmine and
organophosphate insecticides.
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7.1.1.2. Drugs containing tropane alkaloids:
7.1.1.2.1. Belladonna
The deadly nightshade Atropa belladonna (Solanaceae) has a long history as a highly
poisonous plant. The generic name is derived from Atropos, in Greek mythology the
Fate who cut the thread of life. The berries are particularly dangerous, but all parts of
the plant contain toxic alkaloids, and even handling of the plant can lead to toxic
effects, since the alkaloids are readily absorbed through the skin.
Atropa belladonna is indigenous to central and southern Europe, It is cultivated for
drug use in Europe and the United States. The tops of the plant are harvested two or
three times per year and dried to give belladonna herb.
Belladonna herb typically contains 0.3–0.6% of alkaloids, mainly (−)-hyoscyamine.
Figure 3.10: Atropa belladonna. 7.1.1.2.2. Stramonium
Datura stramonium (Solanaceae) is commonly referred to as thornapple on account of
its spikey fruit, the name is originated from dhat an Indian poison. It is a tall bushy
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annual plant widely distributed in Europe and North America, and because of its
alkaloid content is potentially very toxic.
The leaves and tops are harvested when the plant is in flower. Stramonium leaf usually
contains 0.2–0.45% of alkaloids, principally (−)-hyosycamine and (−)-hyoscine in a
ratio of about 2:1. In young plants, (−)-hyoscine can predominate.
Figure 3.11: Datura stramonium. 7.1.1.2.3. Hyoscyamus
Hyoscyamus niger (Solanaceae), or henbane, is a European native with a long history
as a medicinal plant. The alkaloid content of hyoscyamus is relatively low at 0.045–
0.14%, but this can be composed of similar proportions of (−)-hyoscine and (−)-
hyosycamine.
Egyptian henbane, Hyoscyamus muticus, The alkaloid content of the leaf is from 0.35
to 1.4%, of which about 90% is (−)-hyoscyamine.
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Figure 3.12: Hyoscyamus niger. 7.1.1.2.4. Coca
Coca leaves are obtained from two species Erythroxylum coca and Erythroxylum
novogranatense (Erythroxylaceae), small shrubs native to the Andes region of South
America; Peru is the only producer of medicinal coca; illicit supplies originate from
Colombia, Peru, and Bolivia.
Figure 3.13: Erythroxylum coca. Coca-leaf chewing has been practiced by South American Indians for many years and
has been an integral part of the native culture pattern. Leaf is mixed with lime, thus
liberating the principal alkaloid cocaine as the free base, and the combination is then
chewed. Cocaine acts as a potent antifatigue agent, and allows laborers to ignore
hunger, fatigue, and cold, enhancing physical activity and endurance. Originally, the
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practice was limited to the Inca high priests and favoured individuals, but it became
widespread after the Spanish conquest of South America.
In the 1800s, coca drinks were fashionable, and one in particular, Coca-Cola®, became
very popular. This was originally based on extracts of coca (providing cocaine) and
cola (supplying caffeine), but although the coca content was omitted from 1906
onwards, the name and popularity continue.
- Chemical constituents:
Coca leaf contains 0.7–2.5% of alkaloids, the chief component (typically 40–50%) of
which is (−)-cocaine.
Figure 3.14: Cocaine structure.
- Uses:
Medicinally, cocaine is of value as a local anaesthetic for topical application. It is
rapidly absorbed by mucous membranes and paralyses peripheral ends of sensory
nerves. This is achieved by blocking ion channels in neural membranes. It was widely
used in dentistry, but has been replaced by safer drugs.
Cocaine, once absorbed, gives stimulation and short-lived euphoria through inhibiting
reuptake of neurotransmitters dopamine, noradrenaline, and serotonin, so prolonging
and augmenting their effects. Regular usage induces depression, dependence, and
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damage to the nasal membranes when usually sniffed. Cocaine has proved highly
addictive and dangerous.
The essential functionalities of cocaine required for activity were eventually assessed
to be the aromatic carboxylic acid ester and the basic amino group, separated by a
lipophilic hydrocarbon chain. Synthetic drugs developed from the cocaine structure
have been introduced to provide safer, less toxic local anaesthetics.
Lidocaine (lignocaine) is an example of an amino amide analogue and is perhaps the
most widely used local anesthetic, having rapid action, effective absorption, good
stability, and may be used by injection or topically. Lidocaine was found to be a potent
antiarrhythmic agent, and it now finds further use as an antiarrhythmic drug, for
treatment of ventricular arrhythmias especially after myocardial infarction.
Figure 3.15: Cocaine related anesthetic compounds.
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7.2. Lysine-derived Piperidine Alkaloids
7.2.1. Tobacco alkaloids:
7.2.1.1. Biosynthesis :
Figure 3.16: Tobacco alkaloids biosynthesis pathway.
The principal alkaloids of the genus Nicotiana have a pyridine moiety associated with
either a pyrrolidine ring (ornithine-derived) or a piperidine ring (lysine-derived). The
former group is represented by nicotine and the latter by anabasine.
A pharmaceutical introduction is that of nicotine chewing-gum, nasal spray or patch,
intended to help smokers who want to give up smoking but who experience great
difficulty in so doing because of their nicotine dependence.
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Figure 3.17: Nicotiana tabacum and related alkaloids.
- Chemical constituents:
Tobacco is the dried leaves of Nicotiana tabacum (Solanaceae). Tobacco leaves may
contain from 0.6 to 9% of (−)-nicotine , anabasine (about 0.5%).
- Uses:
Powdered tobacco leaves have long been used as an insecticide, and nicotine from
Nicotiana tabacum or Nicotiana rustica has been formulated for agricultural and
horticultural use. The free base is considerably more toxic than salts, and soaps may be
included in the formulations to ensure a basic pH and to provide a surfactant.
Nicotine in small doses can act as a respiratory stimulant, though in larger doses it
causes respiratory depression. Tobacco smoke contains over 4000 compounds,
including more than 60 known carcinogens formed by incomplete combustion.
Tobacco smoking also contributes to atherosclerosis, chronic bronchitis, and
emphysema and is regarded as the single most preventable cause of death in modern
society.
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Nicotine is toxic to man due to its effect on the nervous system, interacting with the
nicotinic acetylcholine receptors, though the tight binding observed is only partially
accounted for by the structural similarity between acetylcholine and nicotine. Recent
studies suggest that nicotine can improve memory by stimulating the transmission of
nerve impulses, and this finding may account for the lower incidence of Alzheimer„s
disease in smokers. Any health benefits conferred by smoking are more than
outweighed by the increased risk of heart, lung, and respiratory diseases.
7.2.2. Broom alkaloids:
Cytisus scoparius (Leguminasea/Fabaceae) is a perennial shrub about 1–2 m high. The
lower part is woody but the long, straight branches are green and glabrous. The upper
leaves are sessile and usually reduced to a single leaflet; The flowers are typical of the
subfamily Papilionaceae. The fruit is a black, hairy pod.
Figure 3.18: Cytisus scoparius.
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- Biosynthesis:
Figure 3.19: Sparteine biosynthesis pathway.
- Chemical constituents:
Their chief constituents of the aerial parts are quinolizidine alkaloids, including the
volatile liquid alkaloid sparteine a yellow isoflavone scoparin, and flavonoids.
Figure 3.20: Cytisus scoparius related compounds.
- Uses:
The drug has diuretic and cathartic actions but is now little used. Sparteine has been
found to exhibit antiarrhythmic activity, to reduce the incidences of ventricular
tachycardia and fibrillation, and to reduce heart rate and blood pressure.
7.2.3. Pomegranate alkaloids:
The pomegranate, Punica granatum L. Punicaceae, is cultivated thoughout subtropical
and tropical regions of the world; some 800 000 metric tons are produced annually,
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principally for dietary purposes. However, the barks, fruit-rind, flowers and seeds all
find medicinal use.
- Chemical constituents:
The barks are smooth and yellowish on their inner surfaces and break with a short
granular fracture. They contain about 0.5–0.9% of volatile liquid alkaloids, the chief of
which are pelletierine and pseudopelletierine, together with about 22% of tannin.
Figure 3.21: Punica granatum and pelletierine structure.
- Uses:
Pelletierine tannate, a mixture of the tannates of the alkaloids, was included in the BP
1948 and was used as an anthelminthic with a specific action on tapeworms.
7.3. Reduced pyridine Alkaloids
7.3.1. Areca alkaloids:
Areca nuts (betel-nuts) are the seeds of Areca catechu (Palmae/Arecaceae), a tall palm
cultivated in the Indian and Asian continents.
These nuts are mixed with lime (Calcium hydroxide Ca(OH)2), wrapped in leaves of
the betel pepper (Piper betle) and then chewed for their stimulant effect, and
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subsequent feeling of well-being and mild intoxication. The teeth and saliva of
chewers stain bright red.
The major stimulant alkaloid is arecoline (up to 0.2%); it has been employed in
veterinary practice as a vermicide to eradicate worms.
Figure 3.22: Areca catechu and arecoline structure.
7.3.2. Hemlock fruit alkaloids:
The drug consists of the dried unripe fruits of Conium maculatum (Umbelliferae/
Apiaceae). The spotted hemlock, a poisonous biennial plant with a purple spotted
stems, is indigenous to Europe. The dried unripe fruits were formerly used as a pain
reliever and sedative, but have no medicinal use now. The ancient Greeks are said to
have executed condemned prisoners, including Socrates, using poison hemlock.
All parts of the plant are poisonous due to the alkaloid content, though the highest
concentration of alkaloids is found in the green fruit (up to 1.6%). The major alkaloid
(about 90%) is the volatile liquid coniine and γ-coniceine.
This alkaloid is not derived from lysine but from polyacetate pathway and the N atom
is inserted by transamination reaction.
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Figure 3.23: Biosynthesis pathway of Hemlock alkaloids.
The poison causes gradual muscular paralysis followed by convulsions and death from
respiratory paralysis. γ-coniceine and coniine act as nicotinic acetylcholine receptor
agonists. The most serious effect occurs at the neuromuscular junction, where they act
as non-depolarizing blockers like curare
Figure 3.24: Conium maculatum and coniine structure.
7.4. Phenylalanine and tyrosine derived Alkaloids
The title compounds and their corresponding decarboxylation products are the
precursors of a large number of alkaloids which include simple protoalkaloids, and the
isoquinoline dervatives.
Figure 3.25: Phenylalanine and tyrosine derived Alkaloids.
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7.4.1. Protoalkaloids:
Those alkaloid-like amines which do not have the nitrogen as part of a heterocyclic
ring system are often termed protoalkaloids. They are not restricted to any particular
class of alkaloids and are often classified according to the amino acids from which they
are derived.
7.4.1.1. Ephedra alkaloids:
It consists of the entire plant or tops of various Ephedra spp. (Ephedraceae).
Figure 3.26: Ephedra spp.
- Chemical constituents:
The plants contain 0.5–2.0% of alkaloids, according to species; Typically, from 30 to
90% of the total alkaloids is (−)-ephedrine. These alkaloids present in pairs of optically
active diastereomeric alkaloids: (−)-ephedrine and (+)-pseudoephedrine.
Figure 3.27: Ephedrine major alkaloids.
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- Uses and action:
Ephedrine: It has bronchodilator activity, giving relief in asthma and hay fever, plus a vasoconstrictor action on mucous membranes, making it an effective nasal decongestant. Pseudoephedrine: is also widely used in compound cough and cold preparations and as a decongestant.
Pseudoephedrine is preferred because it has less side-effect than ephedrine. The ephedrine and pseudoephedrine used medicinally are usually synthetic.
The herbal drug ephedra is currently being traded as ‘herbal ecstasy„. Consumption gives central nervous system stimulation, but in high amounts it can lead to hallucinations, paranoia, and psychosis. Dietary supplements containing Ephedra are sold as an appetite suppressant for weight loss and endurance enhancement; but, because of misuse and abuse, these have been regulated or even banned in some countries.
Ephedrine has repeatedly been implicated in adverse and sometimes fatal outcomes despite compliance with recommended dosages. The FDA cited significant cardiovascular risk of ephedrine like elevated blood pressure and tachycardia, in addition to psychosis and hallucinations.
The FDA bans over-the-counter sales of cold medicines that contain the ephedrine and the pseudoephedrine, so they are only available with a prescription.
7.4.1.2. Khat alkaloids:
This consists of the fresh leaves of Catha edulis Forsk. (Celastraceae). The plant is
cultivated in Abyssinia, in parts of east and southern Africa, and in southern Arabia.
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- Chemical constituents:
Cathinone was isolated at UN laboratories and is considered the principal CNS
stimulant of the fresh plant. (−)-Cathinone has pharmacological properties analogous
to those of (+)-amphetamine, possessing a similar potency and the same mechanism
of action; Both compounds act by inducing release of catecholamines.
Figure 3.28: Catha edulis and cathinone structure.
- Uses:
Khat is widely employed in African and Arab countries, particularly in the Yemen, for
chewing, and its misuse has been surveyed by the WHO. Its traditional use is similar to
that of coca in that the fresh leaves, when chewed, have a stimulatory effect with the
alleviation of depression and of the sensations of hunger and fatigue.
Users become cheerful and talkative, and khat has become a social drug. Prolonged
usage can lead to hypertension, insomnia, or even mania. Khat consumption may lead
to pyschological dependence, but not normally physical dependence.
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7.4.2. Isoquinoline related alkaloids:
A number of important drugs come within this heading. Phytochemically the group is
often subdivided.
Figure 3.29: Isoquinoline related alkaloids.
7.4.2.1. Simple tetrahydroisoquinoline alkaloids:
7.4.2.1.1. Lophophora
Lophophora or peyote consists of the dried sliced tops of Lophophora williamsii
(Cactaceae), a small cactus from Mexico and the southwestern United States. The
plant has been used by the Aztecs and then by the Mexican Indians for many years,
especially in religious ceremonies to produce hallucinations and establish contact
with the gods. The plant is still used by people seeking drug-induced experiences.
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The most active of the range of alkaloids found in lophophora (total 8–9% alkaloids in
the dried mescal buttons) is mescaline , a simple phenylethylamine derivative. Other
constituents include anhalamine, anhalonidine, and anhalonine.
Mescaline has been used as a hallucinogen in experimental psychiatry.
Figure 3.30: Lophophora williamsii and related alkaloids.
7.4.2.1.2. Goldenseal root
Goldenseal root BP/EP, BHP 1990 consists of the dried rhizome and roots of Hydrastis
canadensis (Berberidaceae), a small perennial plant indigenous to the woods of
eastern Canada and the eastern USA.
- Chemical constituents:
Hydrastis contains the alkaloids hydrastine and berberine. Commercial samples yield
1.5–4% of hydrastine and 0.5–6.0% of berberine. The latter, as a constituent of an
extract of the root, is responsible for activity against multiple drug resistant
Mycobacterium tuberculosis.
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Figure 3.31: Hydrastis Canadensis and hydrastine structure.
- Uses:
The use of hydrastis to check uterine haemorrhage, as a bitter stomachic and locally in
the treatment of catarrhal conditions of the genito-urinary tract is largely based on
empirical observations. Hydrastine hydrochloride has been used in various forms to
control uterine haemorrhage.
7.4.2.2. Benzyl-tetrahydroisoquinoline alkaloids:
7.4.2.2.1. Curare
Curare is the arrow poison of the South American Indians, and it may contain as many
as 30 different plant ingredients, which may vary widely from tribe to tribe according
to local custom.
Curare is prepared in the rain forests of the Amazon and represents the crude dried
extract from the bark and stems of various plants.
In the 1880s, it was found that the traditional container used for curare was fairly
indicative of the main ingredients that had gone into its preparation. Three main types
were distinguished:
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- Tube curare was packed in hollow bamboo canes, and its principal ingredient was
the climbing plant Chondrodendron tomentosum (Menispermaceae).
- Calabash curare was packed in gourds, and was derived from Strychnos toxifera
(Loganiaceae).
- Pot curare was almost always derived from a mixture of loganiaceous and
menispermaceous plants, and was packed in small earthenware pots.
Current supplies of curare are mainly of the menispermaceous type, i.e. derived from
Chondrodendron.
Figure 3.32: Curare types (a: Tube curare; b: Calabash curare; c: Pot curare).
- Chemical constituents:
The alkaloid content of curare is from 4 to 7%. The most important constituent in
menispermaceous curare is the bis-benzyltetrahydroisoquinoline alkaloid (+)-
tubocurarine; This is a monoquaternary ammonium salt, and is water-soluble.
139 Dr. Dima MUHAMMAD PHYTOCHEMISTRY & NATURAL PRODUCTS
Figure 3.33: Chondrodendron tomentosum and related alkaloids.
The constituents in loganiaceous curare (from calabash curare, i.e. Strychnos toxifera)
are even more complex, and a series of 12 quaternary dimeric strychnine-like alkaloids
has been identified, e.g. toxiferine-1.
Figure 3.34: Strychnos toxifera and toxiferine -1 structure.
- Action and toxicity:
Curare kills by producing paralysis, a limp relaxation of voluntary muscles. It achieves
this by competing with acetylcholine at nicotinic receptor sites, thus blocking nerve
impulses at the neuromuscular junction. Death occurs because the muscles of
respiration cease to operate.
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Management and treatment: artificial respiration is required until the drug has been
inactivated by normal metabolism (about 30 min) or antagonized by anti-
acetylcholinesterase drugs, such as physostigmine and neostigmine, which are specific
antidotes for moderate curare poisoning.
- Uses:
Curare is now little used except as a source of alkaloids. Tubocurarine chloride, official
in the BP/EP, is used to secure muscular relaxation in surgical operations, such as
abdominal surgery, and in certain neurological conditions, e.g. multiple sclerosis,
tetanus, and Parkinson„s disease, to temporarily relax rigid muscles and control
convulsions, but was not a curative.
7.4.2.3. Modified Benzyltetrahydroisoquinoline Alkaloids
The concept of phenolic oxidative coupling is a crucial theme in modifying the basic
benzyltetrahydroisoquinoline skeleton to many other types of alkaloids. For example
the principal opium alkaloids are formed by intramolecular carbon–carbon bonding
between aromatic rings.
7.4.2.3.1. Opium Alkaloids:
Opium is the air-dried milky exudate, or latex, obtained by incising the unripe
capsules of the opium poppy Papaver somniferum.
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Figure 3.35: Papaver somniferum.
- Chemical Constituents:
Although the ripe poppy capsule can contain up to 0.5% total alkaloids, opium
represents a much concentrated form, and up to 25% of its mass is composed of
alkaloids. Of the many (>40) alkaloids identified, some six represent almost all of the
total alkaloid content: morphine (4–21%); codeine (0.8–2.5%); thebaine (0.5–2.0%);
papaverine (0.5–2.5%); noscapine (narcotine 4–8%); narceine (0.1–2%).
The alkaloids are largely combined in salt form with meconic acid (poppy acid: it gives
a deep red-coloured complex with ferric chloride); In the past, the urine of suspected
opium smokers could also be tested in this way.
Of the main opium alkaloids only morphine and narceine display acidic properties as
well as the basic properties due to the tertiary amine. Narceine has a carboxylic acid
function, whilst morphine is acidic due to its phenolic hydroxyl. This acidity can be
exploited for the preferential extraction of these alkaloids.
142 Dr. Dima MUHAMMAD PHYTOCHEMISTRY & NATURAL PRODUCTS
Figure 3.36: Opium major alkaloids.
- Uses:
Crude opium has been used since antiquity as an analgesic, sleep-inducer (narcotic),
and for the treatment of coughs. It has been formulated in a number of simple
preparations for general use. Opium has traditionally been smoked for pleasure, but
habitual users developed a craving for the drug followed by addiction. An unpleasant
abstinence syndrome was experienced if the drug was withdrawn.
In modern medicine, only the purified opium alkaloids and their derivatives are
commonly employed. Indeed, the analgesic preparation ‘papaveretum„ is now
formulated from selected purified alkaloids, in the proportions likely to be found in
opium.
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- Morphine is a powerful analgesic and narcotic, and remains one of the most
valuable analgesics for relief of severe pain. It also induces a state of euphoria and
mental detachment, together with nausea, vomiting, constipation, tolerance, and
addiction. Regular users experience withdrawal symptoms, including agitation,
severe abdominal cramps, diarrhoea, nausea, and vomiting, which may last for 10–
14 days unless a further dose of morphine is taken. This leads to physical
dependence. Which is difficult to overcome, so that the major current use of
morphine is thus in the relief of terminal pain. Although orally active, to obtain
rapid relief of acute pain it is usually injected.
- Morphine is metabolized in the body to glucuronides which are readily excreted.
Whilst morphine 3-O-glucuronide is antagonistic to the analgesic effects of
morphine, morphine 6-O-glucuronide is actually a more effective and longer
lasting analgesic than morphine, with fewer side-effects, such as nausea and
vomiting. This agent is in clinical trials for the treatment of cancer-related pain.
Since it is significantly hydrolysed in the gut, it is much less effective taken orally
than when administered by injection.
Figure 3.37: morphine 6-O-glucuronide.
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- Codeine: is the 3-O-methyl ether of morphine and is the most widely used of the
opium alkaloids. Because of the relatively small amounts found in opium, almost
all of the material prescribed is manufactured by semi-synthesis from morphine.
Its action is dependent on partial demethylation in the liver to produce morphine,
so it produces morphine-like analgesic effects, but little if any euphoria. As an
analgesic, codeine has about one-tenth the potency of morphine. Codeine is
almost always taken orally and is a component of many compound analgesic
preparations. It is a relatively safe non-addictive medium analgesic, but is still too
constipating for long-term use. Codeine also has valuable antitussive action,
helping to relieve and prevent coughing. It effectively depresses the cough center,
raising the threshold for sensory cough impulses.
- Thebaine: It is almost devoid of analgesic activity, but may be used as a morphine
antagonist. Its main value is as substrate for the semi-synthesis of other drugs.
- Papaverine: is structurally different from the morphine; It has no analgesic or
hypnotic properties, but it relaxes smooth muscle in blood vessels. It was
administered by injection as an effective treatment for male impotence; now is
replaced by orally active agents such as sildenafil (Viagra®).
- Noscapine: Noscapine has good antitussive and cough suppressant activity
comparable to that of codeine, but no analgesic or narcotic action. Despite many
years of use as a cough suppressant, the finding that noscapine may have
teratogenic properties (i.e. may deform a fetus) has resulted in noscapine
preparations being deleted.
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- Papaveretum: is a mixture of purified opium alkaloids, and is now formulated to
contain only morphine (85.5%), codeine (7.8%) and papaverine (6.7%). It is used
for pain relief during operations.
- Semi-synthetic or totally synthetic morphine-like derivatives:
Figure 3.38: Semi-synthetic morphine-like derivatives.
- Heroin: is merely the diacetate of morphine; it is a highly addictive analgesic and
hypnotic. The increased lipophilic character of heroin over morphine results in
improved solubility, with better transport and absorption, though the active agent
is probably the 6-acetate, the 3-acetate group being hydrolysed by esterases in the
brain. Heroin was synthesized originally as a cough suppressant; and though most
effective in this role, it has unpleasant addictive properties, with users developing
a psychological craving for the drug. It is widely used for terminal care, e.g. cancer
146 Dr. Dima MUHAMMAD PHYTOCHEMISTRY & NATURAL PRODUCTS
sufferers, both as an analgesic and cough suppressant. The euphoria induced by
injection of heroin has resulted in much abuse of the drug and creation of a
worldwide major drug problem.
- Apomorphine has no analgesic properties, but morphine„s side-effects of nausea
and vomiting are highly emphasized. Apomorphine is a powerful emetic and can
be injected for emergency treatment of poisoning.
- Dextromethorphan: totally synthetic opioid drug modeled on morphine, possess
the antitussive activity of codeine.
- Dextropropoxyphene is a total synthetic opioid with analgesic and antitussive
activity. It was taken off the market (2010 FDA) because it has effects on the
heart's electrical activity, increasing the risk of serious arrhythmias in addition to
other safety concerns include serious adverse drug reactions (e.g. hepatic
reactions, hallucinations…).
- Tramadol, Pethidine. Methadone all are central analgesic modeled on morphine.
Figure 3.39: Synthetic drug modeled on morphine.
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7.4.2.4. Modified Phentylisoquinoline Alkaloids
They represent analogues of the benzyltetrahydroisoquinoline alkaloids and are found
in a number of genera of the Liliaceae.
7.4.2.4.1. Colchicum seed and corm
Colchicum seed and corm are derived from the autumn crocus or meadow saffron,
Colchicum autumnale (Liliaceae /Colchicaceae).
- Chemical constituents:
Colchicum seeds contain 0.6–1.2% of colchicine, number of other colchicine-type
alkaloids, a resin, fixed oil and reducing sugars.
Colchicine: an alkaloid containing an unusual tropolone ring, thus the nitrogen atom
is no longer in a ring system; the nitrogen of colchicine is part of an amide function, so
colchicine does not display any significant basicity and does not form well-defined
salt.
Figure 3.40: Colchicum autumnale and related alkaloids.
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- Uses:
Colchicine has been used in the treatment of gout, a painful condition in which
impaired purine metabolism leads to a build-up of uric acid crystals in the joints.
Colchicine is an effective treatment for acute attacks, but it is very toxic, and this
restricts its general use. It appears to act primarily as an anti-inflammatory agent and
does not itself affect uric acid metabolism, which needs to be treated with other
agents, e.g. a xanthine oxidase inhibitor such as allopurinol.
Since 1972 colchicine has become the drug of choice for prophylaxis against FMF
(Familial Mediterranean Fever) attacks and amyloidosis FMF-associated.
The cytotoxic properties of colchicine and related alkaloid structures from Colchicum
autumnale led to their being tested as potential anticancer agents. Colchicine binds to
tubulin in the mitotic spindle, preventing polymerization and assembly into
microtubules, as do podophyllotoxin and vincristine.
7.4.2.5. Terpenoid Tetrahydroisoquinoline Alkaloids:
The alkaloids found in ipecacuanha, they provide unusual examples of
tetrahydroisoquinoline structures.
7.4.2.5.1. Ipecacuanha
The dried rhizome and roots of Cephaelis ipecacuanha (Rubiaceae), have a long
history of use, by the South American Indians, in the treatment of amoebic dysentery.
These are low, straggling shrubs possessing horizontal rhizomes with ridged roots.
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Cephaelis ipecacuanha yields what is termed Rio or Brazilian ipecac, and is cultivated
mainly in Brazil.
- Chemical Constituents:
Ipecac contains 2–2.5% of alkaloids, the principal ones being emetine and cephaeline.
Typically, in Cephaelis ipecacuanha the emetine to cephaeline ratio might be about
2:1.
Figure 3.41: Cephaelis ipecacuanha and related alkaloids.
- Uses and action:
Both emetine and the synthetic dehydroemetine have been useful as anti-amoebics,
particularly in the treatment of amoebic dysentery. However, they also cause nausea,
and this has now made other drugs preferable. The emetic action of the alkaloids is
particularly valuable though, and the crude drug extract in the form of ipecacuanha
emetic mixture is an important preparation used for drug overdose or poisoning. The
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emetic mixture is often a standard component in poison antidote kits. Ipecacuanha
also has expectorant activity.
Emetine and cephaeline are both potent inhibitors of protein synthesis, inhibiting at
the translocation stage. They display antitumour, antiviral, and antiamoebic activity,
but they are too toxic for therapeutic use.
7.4.2.6. Amaryllidaceae alkaloids:
The bulbs of this family are well-known for their toxic properties, at least one fatality
in the UK being recorded in 1999 as a result of mistaken consumption of daffodil bulbs
for onions.
The active secondary metabolites are alkaloids especially the Galanthamine, as it is
shown to be a metabolite of many species of different genera of the family, like
Narcissus spp. (Daffodil), Leucojum spp.(snowflakes) and Galanthus spp.(snowdrop);
Where typical content varies from about 0.05 to 0.2% in the bulbs.
Figure 3.42: a: Narcissus (Daffodil), b:Leucojum .(snowflakes) & c: Galanthus (snowdrop).
151 Dr. Dima MUHAMMAD PHYTOCHEMISTRY & NATURAL PRODUCTS
- Uses:
Galantamine acts as a centrally acting competitive and reversible inhibitor of
acetylcholinesterase, and significantly enhances cognitive function in the treatment of
Alzheimer„s disease by raising acetylcholine levels in brain areas lacking cholinergic
neurones.
It is less toxic than other acetylcholinesterase inhibitors, such as physostigmine.
Figure 3.43: Galanthamine structure.
There is also evidence that galantamine displays an increased beneficial effect due to a
sensitizing action on nicotinic acetylcholine receptors in the central nervous system.
In common with other treatments for Alzheimer„s disease, it does not cure the
condition, but merely slows the rate of cognitive decline.
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7.5. TRYPTOPHANE DERIVED ALKALOIDS
L-Tryptophan is an aromatic amino acid containing an indole ring system, having its
origins in the shikimate pathway. With a few minor exceptions, tryptophan and its
decarboxylation product, tryptamine, give rise to the large class of indole alkaloids.
These bases usually contain two nitrogen atoms; one is the indolic nitrogen and the
second is generally two carbons removed from the β-position of the indole ring.
Rearrangment reactions can convert the indole ring system into a quinoline ring
giving the diverse chemical structures.
Figure 3.44: Tryptophane alkaloids dervivatives.
7.5.1. QUINOLIN ALKALOIDS:
7.5.1.1. Cinchona
Cinchona bark is the dried bark from the stem and root of species of Cinchona
(Rubiaceae), which are large trees indigenous to South America. Trees are cultivated
in many parts of the world, including Bolivia, Guatemala, India, Indonesia, Zaire,
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Tanzania, and Kenya. About a dozen different Cinchona species have been used as
commercial sources. Cinchona succirubra provides what is called ‘red„ bark (alkaloid
content 5–7%). and Cinchona calisaya ‘yellow„ bark with an alkaloid content of 4–7%.
The former importance of cinchona bark and its alkaloids in the treatment of malaria
has been reduced by the introduction of synthetic drugs, but it remains of great
economic importance, and salts of quinine and quinidine are included in most
pharmacopoeias.
Figure 3.45: Cinchona succirubra (a & b) and Cinchona calisaya (c & d).
For many years, the bark was obtained from South America, but cultivation was
eventually established by the English in India, and by the Dutch in Java, until just
before the Second World War, when almost all the world„s supply came from Java.
When this source was cut off by Japan in the Second World War, a range of synthetic
antimalarial drugs was hastily produced as alternatives to quinine.
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- Chemical constituents:
Cinchona bark contains quinoline alkaloids. The principal alkaloids are the
stereoisomers quinine and quinidine and their respective 6′-demethoxy derivatives,
cinchonidine and cinchonine. The quinine series has the configuration 8S, 9R and the
quinidine 8R, 9S. The alkaloids are often present in salt combination with quinic acid.
Figure 3.46: Cinchona alkaloids and quinic acid structures.
- Chemical Test:
1. Thalleioquin test: To the extract of cinchona powder add one drop of dilute
sulphuric acid and 1 ml of water. Add bromine water drop wise till the
solution acquires permanent yellow colour and add 1 ml of dilute ammonia
solution, emerald green colour is produced.
2. The powdered drug when heated with glacial acetic acid in dry test tube,
evolves red fumes, which condense in the top portion of the tube.
3. Cinchona bark, when moistened with sulphuric acid and observed under
ultraviolet light shows a blue fluorescence due to the methoxy group of
Quinine and quinidine.
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- Uses and Action:
Galenicals of cinchona have long been used as bitter tonics and stomachics. On
account of the astringent action, a decoction and acid infusion are sometimes used as
gargles.
Before World War II, quinine was the drug of choice for the treatment of malaria but
became largely superseded by the advent of synthetic antimalarials developed during
that period. Many of these compounds were based on the quinine structure. Of the
wide range of compounds produced, chloroquine and mefloquine are important
antimalarials.
Figure 3.47: Synthetic antimalarials.
Until recently, quinidine was used to treat cardiac arrhymias. It inhibits fibrillation,
the uncoordinated contraction of muscle fibres in the heart. However, it is rapidly
absorbed by the gastrointestinal tract and overdose can be dangerous, leading to
diastolic arrest. This has effectively limited its use.
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Quinidine, cinchonine, and cinchonidine also have antimalarial properties, but these
alkaloids are not as effective as quinine. The cardiac effect makes quinidine
unsuitable as an antimalarial.
7.5.1.2. Camptothecin
Camptotheca acuminata is found only in Tibet and west China. Camptothecin and
derivatives are obtained from the Chinese tree Camptotheca acuminata (Nyssaceae).
- Chemical constituents:
Camptothecin is an example of a quinoline-containing structure that is derived in
nature by skeletal modification of an indole system. The Seeds yield about 0.3%
camptothecin, bark about 2%, and leaves up to 0.4%.
Figure 3.48: Camptotheca acuminate.
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- Uses:
In limited clinical trials, camptothecin showed broad-spectrum anticancer activity,
but toxicity and poor solubility were problems.
The natural 10-hydroxycamptothecin (about 0.05% in the bark of Camptotheca
acuminata) is more active than camptothecin, and is used in China against cancers of
the neck and head. Semi-synthetic analogues 9-aminocamptothecin and the water-
soluble derivatives topotecan and irinotecan showed good responses in a number of
cancers; topotecan and irinotecan are now available for the treatment of ovarian
cancer and colorectal cancer respectively. These drugs are currently made from
natural camptothecin.
These agents act by inhibition of the enzyme topoisomerase I, which is involved in
DNA replication and reassembly, by binding to and stabilizing a covalent DNA–
topoisomerase complex.
Figure 3.49: Camptothecin structure and its anticancer derivatives.
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7.5.2. INDOL ALKALOIDS
7.5.2.1. Rauwalfia serpentina
Rauwolfia is the dried rhizome and roots of Rauwolfia (sometimes Rauvolfia) serpentina
(Apocynaceae) or snakeroot, a small shrub from India, Pakistan, Burma, and Thailand.
Other species used in commerce include Rauwolfia vomitoria from tropical Africa.
Rauwolfia has been used in Africa for hundreds of years, and in India for at least 3000 years. It was used as an antidote to snake-bite, to remove white spots in the eyes, against stomach pains, fever, vomiting, and headache, and to treat insanity. It appeared to be a universal panacea, and was not considered seriously by Western scientists until the late
1940s/early 1950s.
Figure 3.50: Rauwolfia serpentine (a, b & c) and : Rauwolfia vomitoria (d, e & f).
- Chemical constituents:
Rauwolfia contains at least 40 alkaloids, which total some 0.7–2.4%; The chief therapeutically important alkaloid is reserpine; Other alkaloids of note are serpentine, ajmalicine, ajmaline and yohimbine drivatives. The alkaloids can be fractionated according to basicity; Thus, serpentine and similar structures are strongly basic, whilst
159 Dr. Dima MUHAMMAD PHYTOCHEMISTRY & NATURAL PRODUCTS reserpine and ajmalicine are weak bases. Ajmaline and related compounds have intermediate basicity.
Figure 3.51: Reserpine structure.
African rauwolfia (Rauwolfia vomitoria) contains reserpine and alkaloids of the same type;
Many other alkaloids such as ajmaline and yohimbine are also present; Yohimbine was first isolated from Yohimbe bark is derived from Pausinystalia yohimbe (Rubiaceae).
Figure 3.52: Rauwolfia Alkaloids.
- Uses:
Clinical tests showed the drug to have excellent antihypertensive and sedative activity. It was then rapidly and extensively employed in treating high blood pressure and to help mental conditions, relieving anxiety and restlessness, and thus initiated the tranquillizer era.
Reserpine has been widely used as antihypertensives and mild tranquillizers. They act by interfering with catecholamine storage, depleting levels of available neurotransmitters.
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Both ajmalicine and ajmaline are used clinically in Europe, though not in the UK.
Ajmalicine is employed as an antihypertensive, whilst ajmaline is of value in the treatment of cardiac arrhythmias. Ajmalicine is also extracted commercially from Catharanthus roseus.
Yohimbine does have some pharmacological activity and is known to dilate blood vessels, thus it is commonly used for the treatment of erectile dysfunction.
7.5.2.2. Catharantus roesus
The Madagascar periwinkle Catharanthus roseus (= Vinca rosea) (Apocynaceae) is a small herb or shrub originating in Madagascar, but now common in the tropics and widely cultivated as an ornamental for its shiny dark green leaves and pleasant five-lobed flowers. Drug material is now cultivated in many parts of the world, including the USA,
Europe, India, Australia, and South America.
The plant was originally investigated for potential hypoglycaemic activity because of folklore usage as a tea for diabetics. Although plant extracts had no effects on blood sugar levels in rabbits, test animals succumbed to bacterial infection due to depleted white blood cell levels (leukopenia), though no other adverse effects were apparent. The selective action suggested anticancer potential for the plant, and an exhaustive study of the constituents was initiated.
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Figure 3.53: Catharanthus roseus.
- Chemical constituents:
The activity was found in the alkaloid fraction, and more than 150 alkaloids have since been characterized in the plant. These are principally terpenoid indole alkaloids. Useful antitumour activity was demonstrated in a number of dimeric indole alkaloid structures
(more correctly, bisindole alkaloids, since the ‘monomers„ are different); These compounds are known as vinblastine and vincristine respectively, the vin- prefix being a consequence of the earlier botanical nomenclature Vinca rosea, in common use at that time. The alkaloids vinblastine and vincristine were introduced into cancer chemotherapy and have proved to be extremely valuable drugs.
A major problem associated with the clinical use of vinblastine and vincristine is that only very small amounts of these desirable alkaloids are present in the plant. Although the total alkaloid content of the leaf can reach 1% or more, over 500 kg. Fortunately, it is
162 Dr. Dima MUHAMMAD PHYTOCHEMISTRY & NATURAL PRODUCTS possible to prepare these alkaloids, from other derivatives produced in much larger amounts, by semi-synthesis approach via a microbiological enzyme activity.
Figure 3.54: Catharanthus roseus anticancer alkaloids.
- Uses:
Despite the minor difference in structure between vinblastine and vincristine, a significant difference exists in the spectrum of human cancers which respond to the drugs.
Vinblastine is used mainly in the treatment of Hodgkin„s disease, a cancer affecting the lymph glands, spleen, and liver.
Vincristine has superior antitumour activity compared with vinblastine but is more neurotoxic. It is clinically more important than vinblastine, and is especially useful in the treatment of childhood leukaemia, giving a high rate of remission. Some other cancer conditions, including lymphomas, small-cell lung cancer, cervical and breast cancers, also respond favourably.
The alkaloids need to be injected, and both generally form part of a combination regimen with other anticancer drugs.
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Vindesine is a semi-synthetic amide derivative of vinblastine which has been introduced for the treatment of acute lymphoid leukaemia in children.
Vinorelbine is a newer semi-synthetic modification obtained from anhydrovinblastine, the indole C2N bridge has been shortened by one carbon .It is orally active and has a broader anticancer activity, yet with lower neurotoxic side-effects than either vinblastine or vincristine.
Figure 3.55: Semi-synthetic derivatives of vinblastine.
These compounds all inhibit cell mitosis, acting by binding to the protein tubulin in the mitotic spindle, preventing polymerization into microtubules, a mode of action shared with other natural agents like colchicine and podophyllotoxin.
7.5.2.3. Strychnus/nux-vomica
Nux-vomica consists of the dried ripe seeds of Strychnos nux-vomica (Loganiaceae), a
small tree found in a wide area of East Asia extending from India to northern Australia.
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Figure 3.56: Strychnos nux-vomica.
- Chemical constituents:
These seeds contain 1.5–5% of alkaloids, chiefly strychnine (about 1.2%) and brucine
(about 1.6%).
Figure 3.57: Strychnos nux-vomica derivatives.
- Uses:
Strychnine is very toxic, affecting the central nervous system and causing convulsions.
This is a result of binding to receptor sites in the spinal cord which normally accommodate glycine. Fatal poisoning (consumption of about 100 mg by an adult) would lead to asphyxia following contraction of the diaphragm. Brucine is considerably less toxic. The drug was used mainly for poisoning animals.
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7.5.2.4. Physostigma venenosum
Physostigma venenosum (Leguminosae/Fabaceae) is a perennial woody climbing plant found on the banks of streams in West Africa.
The seeds are known as Calabar beans (from Calabar, now part of Nigeria) and have an interesting history in the native culture as an ordeal poison. The accused was forced to swallow a portion of the ground seeds, and if the mixture was subsequently vomited, they were judged innocent and set free. If the poison took effect, the prisoner suffered progressive paralysis and died from cardiac and respiratory failure. It is said that slow consumption allows the poison to take effect, whilst emesis is induced by a rapid ingestion of the dose.
Figure 3.58: Physostigma venenosum.
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- Chemical constituents:
The seeds contain several alkaloids (alkaloid content about 1.5%), the major one (up to
0.3%) being physostigmine (eserine) with unusual pyrroloindole ring system. Another alkaloid, geneserine, is an artefact produced by oxidation of physostigmine.
Figure 3.59: physostigmine (eserine) and geneserine structure.
- Uses:
Physostigmine (eserine) is a reversible inhibitor of acetylcholinesterase, preventing normal destruction of acetylcholine and, thus, enhancing cholinergic activity. Its major use has been as a miotic, to contract the pupil of the eye, often to combat the effect of mydriatics such as atropine. It also reduces intraocular pressure in the eye by increasing outflow of the aqueous humour, and provided a valuable treatment for glaucoma, often in combination with pilocarpine.
Because it prolongs the effect of endogenous acetylcholine, physostigmine can be used as an antidote to anticholinergic poisons such as hyoscyamine/atropine, and it also reverses the effects of competitive muscle relaxants such as curare and tubocurarine.
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Acetylcholinesterase-inhibiting drugs are also of value in the treatment of Alzheimer„s disease, which is characterized by a dramatic decrease in functionality of the central cholinergic system. Use of acetylcholinesterase inhibitors can result in significant memory enhancement in patients, and analogues of physostigmine are presently in use (e.g. rivastigmine) or have been tested in clinical trials (e.g. phenserine; These analogues have a longer duration of action, less toxicity, and better bioavailability than physostigmine.
Rivastigmine is also used to treat mild to moderate dementia associated with Parkinson„s disease.
Neostigmine and pyridostigmine are examples of synthetic anticholinesterase drugs used primarily for enhancing neuromuscular transmission in the rare autoimmune condition myasthenia gravis, in which muscle weakness is caused by faulty transmission of nerve impulses.
Figure 3.60: Physostigmine and synthetic derivatives.
7.5.2.5. Ergot
Medicinal ergot is the dried sclerotium of the fungus Claviceps purpurea (Clavicipitaceae) developed on the ovary of rye, Secale cereale (Graminae/Poaceae). Ergot is a fungal disease of wild and cultivated grasses, and initially affects the flowers. In due course, a dark sclerotium, the resting stage of the fungus, is developed instead of the normal seed.
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Figure 3.61: Claviceps purpurea (Clavicipitaceae).
There are three broad clinical features of ergot poisoning which are due to the alkaloids present and the relative proportions of each component:
- Alimentary upsets, e.g. diarrhoea, abdominal pains, and vomiting.
- Circulatory changes, e.g. coldness of hands and feet due to a vasoconstrictor
effect, a decrease in the diameter of blood vessels, especially those supplying the
extremities.
- Neurological symptoms, e.g. headache, vertigo, convulsions, psychotic
disturbances, and hallucinations.
These effects usually disappear on removal of the source of poisoning, but much more serious problems develop with continued ingestion, or with doses of heavily contaminated food. The vasoconstrictor effect leads to restricted blood flow in small terminal arteries, death of the tissue, the development of gangrene, and even the shedding of hands, feet, or limbs. Gangrenous ergotism was known as St Anthony„s Fire, the Order of St Anthony traditionally caring for sufferers in the Middle Ages.
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- Chemical constituents:
The ergot sclerotia contain from 0.15–0.5% alkaloids, and more than 50 have been characterized. The medicinally useful compounds are derivatives of (+)-lysergic acid and can be separated into two groups:
- Water-soluble amino alcohol derivatives (up to 20% of the total alkaloids):
Ergometrine is an amide of lysergic acid and 2-aminopropanol, and is the only significant member of this group.
Figure 3.62:Lysergic acid (a) Ergometrine (b) structures.
- Water-insoluble peptide derivatives (up to 80% of total alkaloids):
The peptide derivatives contain a cyclized tripeptide fragment bonded to lysergic acid via an amide linkage. these structures can be subdivided into three groups: the ergotamine group, the ergoxine group and the ergotoxine group.
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Figure 3.63: Peptide derivatives of lysergic acid.
Medicinal ergot is cultivated in the Czech Republic, Germany, Hungary, Switzerland,
Austria, and Poland, where fields of rye are infected artificially with spore cultures of
Claviceps purpurea. Culturing the fungus in fermentors did not give the typical alkaloids associated with the sclerotia, e.g. ergometrine and ergotamine. Useful derivatives based on lysergic acid can be obtained by fermentation and pharmaceutical alkaloids can be produced semi-synthetically.
- Uses:
The ergot alkaloids owe their pharmacological activity to their ability to act at α- adrenergic, dopaminergic, and serotonergic receptors.
The pharmacological response may be complex. It depends on the preferred receptor to which the compound binds, though all may be at least partially involved, and on whether the alkaloid is an agonist or antagonist.
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Since 16th century the drug have been used to induce uterine contractions during childbirth and to reduce haemorrhage following the birth.
Ergometrine (ergonovine) is used as an oxytocic and is injected during the final stages of labour and immediately following childbirth, especially if haemorrhage occurs. Bleeding is reduced because of its vasoconstrictor effects, and it is valuable after Caesarian operations. It is sometimes administered in combination with oxytocin itself. Ergometrine is also orally active. It produces faster stimulation of uterine muscle than do the other ergot alkaloids, and probably exerts its effect by acting on α-adrenergic receptors, though it may also stimulate 5-HT receptors.
Ergotamine is a partial agonist of α-adrenoceptors and 5-HT receptors. It is not suitable for obstetric use because it also produces a pronounced peripheral vasoconstrictor action.
This property is exploited in the treatment of acute attacks of migraine, where it reverses the dilatation of cranial blood vessels. Ergotamine is effective orally, or by inhalation in aerosol form, and may be combined with caffeine, which is believed to enhance its action.
A number of semi-synthetic lysergic acid derivatives such as bromocriptine (2-bromo-α- ergocryptine) and cabergoline find wider use, in that they also inhibit release of prolactin by the pituitary and can thus suppress lactation and be used in the treatment of breast tumours.
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Figure 3.64: Bromocriptine, Cabergoline and Ergotamine structures.
7.6. Histidine derived Alkaloids
The amino acid L-histidine contains an imidazole ring, and is thus the likely presursor of alkaloids containing this ring system. There are relatively few examples, however, and definite evidence linking them to histidine is often lacking.
The imidazole alkaloids found in Jaborandi leaves (Pilocarpus microphyllus and Pilocarpus jaborandi; Rutaceae) are also probably derived from histidine.
Figure 3.65:Imidazole alkaloids biosynthesis.
7.6.1. JAPORANDI
Pilocarpus or jaborandi consists of the dried leaflets of Pilocarpus jaborandi or Pilocarpus microphyllus (Rutaceae), small shrubs from Brazil and Paraguay. Pilocarpus microphyllus is currently the main source.
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Figure 3.66: Pilocarpine isomerization.
- Chemical constituents:
The alkaloid content (0.5–1.0%) consists principally of the imidazole alkaloid pilocarpine together with small amounts of pilosine and related structures.
Figure 3.67: Pilocarpine and related compounds structures.
Isomers such as isopilocarpine and isopilosine are readily formed if base or heat is applied during extraction of the alkaloids. This is a result of enolization in the lactone ring, followed by adoption of the more favourable trans configuration rather than the natural cis. However, the iso alkaloids lack biological activity. The alkaloid content of the leaf rapidly deteriorates on storage.
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- Uses:
Pilocarpine salts are valuable in ophthalmic practice and are used in eyedrops as miotics and for the treatment of glaucoma.
Pilocarpine is a cholinergic agent and stimulates the muscarinic receptors in the eye, causing constriction of the pupil and enhancement of outflow of aqueous humour.
Pilocarpine gives relief for both narrow-angle and wide-angle glaucoma. However, the ocular bioavailability of pilocarpine is low and it is rapidly eliminated, thus resulting in a rather short duration of action. Pilocarpine is antagonistic to atropine.
Pilocarpine gives relief for dryness of the mouth that is very common in patients undergoing radiotherapy for mouth and throat cancers, and is now prescribed for this purpose.
Figure 3.68: Structural similarity between pilocarpine, acetylcholine and muscarine. 7.7. Xanthine derived Alkaloids (Purine alkaloids)
The purine alkaloids caffeine, theobromine, and theophylline are all methyl
derivatives of xanthine and they commonly co-occur in a particular plant Caffeine, in
the form of beverages such as tea, coffee, and cola, is one of the most widely consumed
and socially accepted natural stimulants. It is also used medicinally, but theophylline
is more important as a drug compound because of its muscle relaxant properties,
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utilized in the relief of bronchial asthma. Theobromine is a major constituent of cocoa
and related chocolate products.
Figure 3.69: Xanthine structure and related Alkaloids.
7.7.1. Biological activity:
They competitively inhibit the phosphodiesterase that degrades cyclic AMP (cAMP).
The resultant increase in cAMP levels thus mimics the action of catecholamines and
leads to a stimulation of the central nervous system, a relaxation of bronchial smooth
muscle, and induction of diuresis, as major effects. These effects vary in the three
compounds:
- Caffeine is the best central nervous system stimulant, and has weak diuretic
action; It is used medicinally as a central nervous system stimulant, usually
combined with another therapeutic agent as in compound analgesic
preparations(paracetamol and codeine). The biological effects produced from
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the caffeine ingested via the different drinks can vary, since its bioavailability
is known to be modified by the other constituents present, especially the
amount and nature of polyphenolic tannins.
- Theobromine has little stimulant action, but has more diuretic activity and
also muscle relaxant properties.
- Theophylline also has low stimulant action and is an effective diuretic, but it
relaxes smooth muscle better than caffeine or theobromine. It is an important
smooth muscle relaxant for relief of bronchospasm; it is frequently dispensed
in slow-release formulations to reduce side-effects. It is also available as
aminophylline, a more soluble preparation containing theophylline with
ethylenediamine in a 2:1 ratio. Aminophylline is less potent and shorter-acting
than theophylline.
7.7.2. Drug containing purine alkaloids
7.7.2.1. Coffeae
Coffee consists of the dried ripe seed of Coffea arabica, Coffea canephora, Coffea liberica, or other Coffea species (Rubiaceae).
The plants are small evergreen trees, widely cultivated in various parts of the world, Brazil and other South American countries and Kenya.
The fruit is deprived of its seed coat, then dried and roasted to develop its characteristic colour, odour, and taste. Coffee seeds contain 1–2% of caffeine and traces of theophylline and theobromine.
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Coffee seeds contain 1–2% of caffeine, combined in the green seed with chlorogenic acid; roasting releases the caffeine and also causes some decomposition of chlorogenic;
Meanwhile tea contains 1–4% caffeine co-occurred with the polyphenolic tannins which may reduce the bioavailability of the caffeine consumed from the tea.
Figure 3.70: Coffea species (Rubiaceae).
7.7.2.2. Tea
Tea is the prepared leaves and leaf buds of Camellia sinensis (Thea sinensis) (Theaceae), an evergreen shrub cultivated in China, India, Japan, and Sri Lanka.
Figure 3.71: Camellia sinensis (Theaceae).
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- Chemical constituents:
Tea contains 1–4% caffeine and small amounts (up to 0.05%) of both theophylline and theobromine. Astringency and flavor come from tannins and volatile oils, the latter containing monoterpene alcohols (geraniol, linalool) and aromatic alcohols (benzyl alcohol, 2-phenylethanol).
For black tea, the leaves are allowed to ferment, allowing enzymic oxidation of the polyphenols, whilst green tea is produced by steaming and drying the leaves to prevent oxidation. During oxidation, colourless catechins (up to 44% in dried leaf) are converted into intensely coloured theaflavins and thearubigins. Oolong tea is semi-fermented.
Theaflavins are believed to act as radical scavengers/antioxidants, and to provide beneficial effects against cardiovascular disease, cancers, and the ageing process generally. Green tea, in particular, contains significant amounts of epigallocatechin gallate, a very effective antioxidant regarded as one of the more desirable dietary components. Tea leaf dust and waste is a major source of caffeine.
7.7.2.3. Cola
Cola, or kola, is the dried cotyledon from seeds of various species of Cola (Sterculiaceae),
Cola nitida and Cola acuminata, trees cultivated principally in West Africa and the West
Indies. Seeds are prepared by splitting them open and drying.
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Figure 3.72: Cola nitida seeds.
- Chemical constituents:
Cola seeds contain up to 3% caffeine and about 0.1% theobromine, partly bound to tannin materials. Drying allows some oxidation of polyphenols, formation of a red pigment, and liberation of free caffeine. Fresh cola seeds are chewed in tropical countries as a stimulant, and vast quantities of dried seeds are processed for the preparation of cola drinks, Coca-
Cola® and Pepsi-Cola.®
7.7.2.4. Cocoa
Although cocoa (or cacao) as a drink is now rather unfashionable, it provides the raw material for the manufacture of chocolate and is commercially very important.
Cocoa (or cacao) is derived from the roasted seeds of Theobroma cacao (Sterculiaceae), a tree widely cultivated in South America and West Africa. The fruits develop on the trunk of the tree; the seeds from them are separated, allowed to ferment, and are then roasted to develop the characteristic chocolate flavour. The kernels are then separated from the husks, ground up, and processed in various ways to give chocolate, cocoa, and cocoa butter.
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Figure 3.73: Theobroma cacao (Sterculiaceae)
- Chemical constituents:
Cocoa seeds contain 35–50% of oil (cocoa butter or theobroma oil), 1–4% theobromine and 0.2–0.5% caffeine, plus tannins and volatile oils. During fermentation and roasting, most of the theobromine from the kernel passes into the husk, which thus provides a convenient source of the alkaloid.
Theobroma oil or cocoa butter is obtained by hot expression from the ground seeds as a whitish solid with a mild chocolate taste. It is a valuable formulation aid in pharmacy, where it is used as a suppository base.
7.7.2.5. Mat´e Tea Mat´e tea is consumed in South America as a stimulant drink. Mat´e or Paraguay tea consists of the leaves of Ilex paraguensis (Aquifoliaceae), South American shrubs of the holly genus.
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Figure 3.74: Ilex paraguensis (Aquifoliaceae)
- Chemical constituents:
The dried leaf contains 0.8–1.7% caffeine and smaller amounts of theobromine (0.3–
0.9%) with little or no theophylline. Considerable amounts (10–16%) of chlorogenic acid are also present.
7.8. Terpenoid alkaloids
A variety of alkaloids based on mono-, sesqui-, di-, and tri-terpenoid skeletons have been characterized, but information about their formation in nature is still somewhat sparse.
Examples of diterpenes alkaloids are the alkaloids of Aconitum, Delphinium and Taxus spp.
7.8.1. Aconite root
Aconite (Wolfsbane Root) consists of the dried roots of Aconitum napellus
(Ranunculaceae), collected from wild or cultivated plants. A. napellus is a polymorphic aggregate extending from Western Europe to the Himalayas.
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Figure 3.75: Aconitum napellus (Ranunculaceae) and aconitine structure.
- Chemical constituents
Aconite contains terpene ester alkaloids, of which the most important is aconitine. The percentage of total alkaloid in the drug is about 0.3–1.2%; About 30% of the total is ether- soluble aconitine.
- Uses
Aconite is a very potent and quick-acting poison which is now rarely used internally in the
UK, except in homeopathic doses. The drug was included in the BPC (1973) and was formerly used for the preparation of an antineuralgic liniment.
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