Download - ISpatula

Pharmacognosy is a very old term which has been used for hundreds of years to
describe the study of the starting materials which are used for diagnosis, prevention
and treatment of diseases. These materials are of natural origin.
This term originates from 2 greek words:
- pharmakon: drug.
- gnosis: knowledge.
- In the past, the term Pharmacognosy was more commonly used than
nowadays; because it was a very incomprehensive term which dealt with the chemistry
or the preparation or how to obtain the drug. However, nowadays we have new terms.
- Phytochemistry: started to be used in the late 1950s, specifically referring to
the natural products which are obtained from the plants. Pharmacognosy was more
incomprehensive it referred to anything natural. Phytochemistry is referring only to the
substances and the chemistry of these substances (which were obtained from the
plants).
-Phyto= plants
- Of course Phytochemistry, as we will see today, isn’t only concerned with the
important primary metabolites, which are common form of the plants, but also the
physiologically active secondary metabolites.
- We are dealing in Phytochemistry primarly with this bioactive substances, and
to obtain these bioactive substances we need different methods of chromatography and
spectroscopy in order to determine, isolate, and identify the structure of these
substances.
- We said that the term Phytochemistry has been introduced in the second half
of the 20th century, because when chromatography and spectroscopy method's, and
equipments were available then we started discovering new chemical entities from the
plant kingdom to isolate then to determine their structure.
So, we need complicated equipment (like: UV, IR, MS, LC-MC), in addition to classical
chromatography methods.
- In fact, the term Phytochemistry refers to the chemistry of plant-originating
products. But in the last lecture we mentioned generally that we are dealing with
"natural products".
1
- We will not restrict our self only to the plant kingdom. We will include the
different bioactive substances which are obtained from the Insect kingdom, animal
kingdom, and marine organisms.
The term Phytochemistry has been replaced more and more with the term
natural products.
(We are enlarging our scope, not restricting ourselves just to the plants, but including
all natural products coming from the nature)
* There is confusion or overlapping in terminology.
- Natural products: here we are not dealing with isolated products.
The plants are just collected and dried." Not anymore extracted and purified "
The broad sense in natural compounds ; anything coming from the nature, which just
collected and dried.
" obtained by simple methods"
For e.g.: Olive oil
It is a natural product, because it is not re-modified; just collected.
- Crude drugs: primarily applied to plant materials, that just collected and dried
by simple procedures, simple exudates.
- Ethnopharmacology: it is a new science concerned with the use of these natural
drugs in different traditional medicine, folk medicine; which varies according to the
environment.
So, this term is dealing with study of materials or natural medicine which are
used in different cultures .
It gives us an idea about the medication methods in different cultures.
Talking about different cultures can interfere with the social status, so it is very
comprehensive term.
In drug discovery, they are based on the traditional medicine; they are getting
these information from the population in certain area:
By asking how to treat this disease, how are preparing the formulation from this plant
; in boiling, drying ...etc.
2
So, ethnopharmacology is a very important backbone in the new drug discovery.
- How drugs of natural origin can be used?
The most elegant form to use the drug us the pure form; when the constituents
of a plant, or of an insect , or animal has been isolated in a pure form.
- Crude drugs are used only for: oral administration
Because it is a mixture of several constituents, so cannot be used by parentral route.
When we isolate the pure (active) compounds, we can determine the dose and
amount we can administer these substances in a parental route.
Several plant-based pure compounds can be isolated, and because of different
reasons, either economically less expensive to be isolated from the plants than to be
synthesized, or their structures are too complicated to be synthesized.
Still there is huge number of pure compounds isolated from the plant kingdom and
used in the modern pharmacology like: Cardiac glycosides ( digitalin) , morphine and
antibiotics.
So, there are pure compounds based on the plants until now that we need.
- There are a big number of substances like different steroidal hormones, which
are obtained from plants but modified to formulate drugs; like the different
corticosteroids or the sex hormones.
“Obtained ,then semi synthetically modifying them in the laboratory to other
substances" . - Derivatization- Several natural products can be synthesized; ex: caffeine.
For the synthetic production of these substances, it is definitely easier for the smaller
molecule, because of the less complicated the structure.
We have substances like tubocurarine which is synthesized, but nowadays there
is more advanced similar compounds available in order to be utilized for the same
purpose of tubocurarine.
3
- Modifications are also obtained from partial synthesis; like different anticancer
drugs (vinblastine, taxol … etc)
Hundreds of derivatives have been prepared by semi synthetic methods.
Sometimes it is convenient to take the natural compound as a model, and
synthesizing small molecule analogs to these larger molecules. Several new
synthesized compounds are using bioactive originally natural compounds as a model.
In this case, we are not anymore taking the natural products, but product-like
compounds are taking it as a model.
How can they produce these substances? How they discover these substances?
1) Ethnopharmacology
= ethnobotany
= traditional medicine
They all can be used alternatively, although pharmacology is referring more
pharmacological aspects of plants found in certain area and how they are used.
Ethnobotany is their botanical distribution; it is not for the pharmacist, but it is for
botanist, or plant taxonomist, plant anatomist, to see what kinds of plants are
occurring in this particular area.
2) Isolation from natural resources, it depends on the:
a. Availability of the plant material or the natural material.
b. The simplicity of the structure, how easily we can isolate the compounds.
c. Economical aspects.
Sometimes it is simple, and even it is economically cheaper than the synthetic
compounds so we continue with the isolation from natural resources.
We have to keep in mind, that when we are collecting plant material, the production
and occurrence of plant material is depending on different factors:
a. Soil factors.
b. Climate factors, e.g. in a dry season, there is no rain we will not be able to have
plant materials.
4
So, there are always limitations; although this source may be cheap, we have to
think on our backup.
When there is any catastrophe in the plant, we cannot produce or access to this
type of the product.
So it depends on the environmental factor:
- If it is too much rain, it can be destroyed.
- If it is very dry, it can be destroyed.
Sometimes, continuous collection of plant materials will affect the production of
this material from the nature., this depends on: this type of material isolated from
renewable parts ( leaves/fruits/flowers) or non- renewable parts (barks/roots).
If we use the bark or root of the plants, we will kill it, so the natural flow can be
limited if we are in need of non- renewable parts of plants, so you have to replant new
ones or to replace new ones or to replace sufficient supply from the nature.
Threaten species “in dangerous species” must be protected and not continue the
destructive collection.
3) Total synthesis:
Useful when the structures are not very complicated.
Natural products are characterized by the presence of big number of asymmetric
carbon (chiral center).
- The more the chiral centers, the more difficult to synthesize the compound.
So :
a. Structure complexity of the natural compounds makes them not easy to be
synthesized.
b. The cost; whether the starting material is available in a cheap way or not.
4) Combination enzymatic and chemical synthesis:
(Advanced in molecular biology)
5
Molecular biological method is used for several compounds, when we know the
genes responsible for the production of secondary metabolites. Then this gene
can be isolated from the plant, and incorporated into more available organisms.
E.g. Bacteria (E-coli).
They can incorporate genetic information of the plant into the microorganism
very easily.
Easy growing microorganisms available in a cheap form, then we can obtain the
different costly secondary metabolites. This is applied very widely nowadays for
the production of different anticancer drugs because the different natural
compounds are very limited, so we can produce the genetic information into the
microorganism which will produce the secondary metabolites.
5) Transgenic plants:
It’s another type of the modern methodology of the production. Although there
are big questions on the production by transgenic plants, still it is an accepted way
to produce secondary metabolites.
6) Cell and tissue culturing:
Especially on 1950’s, it was found this method as an easy one to obtain
expensive secondary metabolites.
It is costly and its yield is so minimal, so it will not be sufficient to cover the
demands.
7) HTS (High throughput screening):
-
For the discovery of new compounds
-
Just taking all available plant extracts and expose them to chemical and
biological screening with expecting that the other species will lead the same type
of secondary metabolites.
With the big interest of the synthetic medicinal chemistry, one might wonder why
they still interest in the 21st century to the plant kingdom (natural products
chemistry)? In fact it is because the alarming increase of different chronic diseases;
such as: diabetes, hypercholesterolemia and hypertension, and actually they are fully
satisfied to find creative treatment for these diseases from the synthetic medicinal
chemistry, and for the treatment of emergent diseases like allergic diseases; flu, and
other infections.
6
So, there is always in the nature hope, we can find something, and isolate it, which
is more effective with less adverse reactions.
The best results have been obtained from natural resources.
Some scientific institutions are ambitious, and they want to discover new
structures, more complicated, then naming them and determining the constituents of
these plants.
-
“Back to the nature“ trend which started over 3 years, and spread in Europe is
questionable because what we are taking from the natural plants are also
chemical entities, and can be as dangerous as synthetic compounds.
Chemotaxonomy:
-
Plant taxonomies are not satisfactory, they can not identify the plant species
according to there taxons, and they need some additional care from the
chemists, so this lead to the emergence of what we call: chemotaxonomy.
Different constituents are found, not only in families, they can be very specific for a
variety of families, so they can use these chemicals constituents for the proper
classification of plants.
In the phytochemistry, we are classifying plant constituents into two groups:
A) Primary metabolites: Which are essential for the existence and survival of the plants.
- They are occurring in all plants (in all green plants).
- Starting from photosynthesis, the plants are capable producing materials
necessary to cover their are essential needs such as:
-
Carbohydrates
-
Fats
-
Proteins
-
Some nucleic acids
-
Vitamins
7
B) Secondary metabolites:
- More important for phytochemistry.
- They are the bioactive constituents.
- Not distributed widely in all plants.
- Their percentage is very low.
In secondary metabolites we are usually we are dealing with 0.1% percentages or
less, and they are in part forms the characteristic behavior of that species, giving
the biological activity.
They are called secondary because biogenesis is linked to primary metabolites.
* We cannot produce the secondary metabolites without the primary one.
* There importance is primary, but there biogensis is secondary.
- Classification of the natural products can be achieved using different methods:
-
Chemistry
-
Pharmacological / physiological effects
-
Taxonomically
-
Biosynthetic pathway
We will discuss the different plant constituents based on their biosynthetic
origin, and we will mention the important biosynthetic pathways of secondary
metabolites.
Regardless of the terminal structure, the different secondary metabolites are
biosynthesized using 3 different pathways.
1) Acetate – Malonate Pathway
2) Acetate – Mevalonate Pathway
3) Shikimic acid pathway
Each of them is responsible for the production of certain classes of secondary
metabolites.
8
Among them, we have the shikimic acid pathway: responsible also for the
formation of nitrogenous substances.
Nitrogen fixation for the different secondary metabolites can be achieved easily
by trans-amination reactions.
Trans-amination reaction is a chemical reaction between 2 molecules. One is an
amino acid, which contains an amine (NH2) group and the other is a keto acid, which
contains a keto ( C=O ) group.
Here, the NH2 group on one molecule is exchanged with the =O group on the
other molecule. The amino acid becomes a keto acid, and the keto acid becomes an
amino acid.
It can be considered for the fixation of nitrogen to the bioactive substances.
In the shikimic acid pathway, we have a pathway which is responsible for the
formation of aromatic amino acids.
We have 3 important aromatic amino acids:
a. Phenylalanine
b. Tyrosine
c. Tryptophan
There is no pathway called "amino acid pathway"; it is a collection of all nitrogenous
substances to be discussed together.
Acetate- Malonate pathway follows certain 1,2,3, … steps
In order to yield substances we start with a starter; ending with expected structure
The other 2 pathways are the same.
- We will discuss the secondary metabolites according to their biosynthetic origin,
which means we will follow this pathway.
- In our lecture, we will discuss the 3 basic pathways, and then we will pool somehow
all nitrogenous substances in the so called "amino acid pathway"
9
1) Acetate-malonate pathway
This pathway is very familiar to us from our biochemistry or Pharmacognosy Lectures,
because it is applied somehow to the primary metabolites formation of the fatty acids.
In abroad sense, the fatty acids are products of the acetate-malonate pathway. With
some changes in their mechanisms we will obtain from this pathway the secondary
metabolites of the acetate-malonate pathway which can be grouped into:
a. Non-aromatic derivatives [polyynes/polyacetylenes]
b. Aromatic derivatives [polyketides]
- Polyynes/polyacetylenes are characterized by many triple bonds in their structures.
- Non-aromatic derivatives are very similar in their biogenesis to the common fatty
acids of the primary metabolites
- Polyketides are characterized by the presence of paketmethylone ? chain -ketones-
Polyketides can be:
1) Monocyclic derivaties:
- Simple benzene ring
2) Polycyclic derivates:
a. Bi-cyclic [naphthalene]
10
b. Tri-cylic [Anthracenes]
c. Tetracyclic [antibiotic]
- With the aromatic polyacetates, we will start from the monocyclic derivatives,
and in the monocyclic derivatives there are different secondary metabolites, and this
discusses some important cannabis derivatives (cannabinoids)
- We will talk about flavonoids, which are synthesized using 2 different
pathways, they are hybrid substances, not originating from one single pathway, but
need more than one biosynthetic pathway.
2) Acetate-mevalonate pathway
- The name of the pathway is given because of obligatory intermediate or from
the starter substances.
- For e.g. when we say Acetate malonate pathway, we have to assume this
pathway is starting with acetate and malonate. Or another possibility that it is an
obligatory intermediate.
- When we say acetate mevalonate pathway; Acetate to the starter and
mevalonate (mevalonic acid) is the obligatory intermediate for this pathway.
- In this pathway, we are primarily producing the terpenoid substances.
There is a very huge class of secondary metabolites (Thousands of terpenoid
substances have been isolated, and then classified depending on the number of
monoterpen units involved in mono- and poly- enes)
11
3) Shikimic acid pathway
Here we will discuss the different aromatic substances, although we have
mentioned many types of acetate malonate pathway are producing also mono-, or
polycyclic derivaties.
In the shikimic acid pathway we will discuss the formation of the aromatic
substances.
- Amino acid pathway is a collective pool for the discussion of the nitrogenous
substances.

Good Luck
Done By : Alaa Dabbous
12