IntroductionNatural products, especially those derived from plants, have been used for medicinal purposes since ancient timesClay tablets of the Babylonian, Assyrian, and Sumerian eras dated 2600 - 4000 BC are thought to be the earliest recordings of plant usage as herbal remediesEgyptians also had many paintings of medicinal plants on their tomb walls dated around 2200 – 2700 BCThe Ebers papyrus, which dates from around 1550 BC, is the most famous medical document of ancient Egypt and contains more than 800 medicinal recipes using medicinal plantsThis centuries-old usage of natural products certainly continues into the present, as half of prescription drugs in the market today contain plant-derived ingredients

Some important natural products1785:William Withering used foxglove extract to treat heart patients, and he

published this application. Digoxin was discovered due to this treatment; Glaxo Smith Kline markets this drug as Lanoxin, and it is used to treat arrhythmia and congestive heart failure

1803: Sertϋrner isolated morphine from opium1817: Isolation of strychnine1820: Isolation of caffeine and quinine1828: Isolation of nicotine1833: Isolation of atropine1855: Isolation of cocaine1868: Isolation of digitaline1897: Arthur Eichengrün and Felix Hoffmann at Bayer Company created aspirin .

Aspirin was the first synthetic drug synthesized from a natural product, salicylic acid, extracted from the willow bark

1928: Alexander Fleming discovered Penicillin from penicillium mold, and this discovery changed modern medicine and the treatment and understanding of infectious disease

Greek = Pharmakon + gnosis (Drug) (Knowledge)

The study of starting material intended for therapeutic and biological origin. In other words from plants, animals or by fermentation from micro-organisms

Deals with natural products used as drugs or for preparation of drugs

PharmacognosyPharmacognosy

PhytochemistryThe study of chemicals involved in the activity of

medicinal plants which are usually secondary metabolites. Many are known to provide protection against biological attacks and plant diseases. They also exhibit a number of protective functions for human consumers.

Techniques commonly used in the field of phytochemistry include extraction, isolation, structural determination using different spectroscopic methods (MS, UV, IR, 1D & 2D NMR) as well as various chromatography techniques (HPLC, LC-MS)

• Natural Products:-Entire organisms such as a plant or an animal which has not been

subjected to any treatment except to a simple process of preservation, i.e. drying

-Part of an organism, i.e. leaf or an isolated gland/exudate or other organ of an animal or microorganism

• Crude drugs: A term used to describe natural products which are not pure compounds but are whole/ parts of plants, extracts

and exudates • Ethnopharmacology: A branch of science concerned

with the study of plants in traditional medicine with emphasis on pharmacological aspects of culture’s medical treatment as well as its social appeal, including taste, symbology and religious context

How drugs of natural origin can be used?Industrial feasibility?

• Isolated and purified natural products: Cardiac glycosides, morphine, antibiotics,…

• Derivatives of natural products : Steroids (sex hormones, contraceptives, corticosteroids,…)• Total chemical synthesis of natural products: Tubocurarine, caffeine,….• Partial synthesized / modified natural products Different anticancer drugs (vinblastine, taxol,…)• New natural products or new natural product like small

molecules

Production of drugs based on natural products• Ethnopharmacology/ethnobotany/traditional

medicine• Isolation from natural resources (cost, limited access

to raw materials)• Total synthesis (complex structures)• Combination enzymatic and chemical synthesis

(advances in molecular biology)• Transgenic plants• Cell and tissue culture (expensive and tedious)• HTS (High Throughput Screening)

Some reasons for the interest in natural compounds in the 20th /21st century

• Search for chemicals from natural sources as curative agents, especially for chronic diseases (diabetes, hyperlipidemia, hypertension) or for diseases the synthetic chemistry was not successful (cancer)

• Increased interest in the chemical compounds from the viewpoint of pure science

• Worldwide interest in the different traditional medicines (“back to the nature”-trends)

• Interest in the use of chemical constituents as an aid in plant taxonomy (chemotaxonomy)

Plants and their metabolites• Primary metabolites: Compounds produced during the

fundamental pathways; essential for the plant life (H2O, CO2 → Photosynthesis): carbohydrates, fats, proteins, nucleic acids →primary activity of green plants

• Secondary metabolites: Not necessarily involved in the essential metabolism of the cell, but exert physiologic activity for the plant, its environment and human ( phyto-hormons, plant-protection, plant-insect-, plant-animal interactions, source of drugs); produced through specific pathways with a limited distribution in nature; condition and species sensitive; most pharmacologically active natural products are 2ry metabolites

Classification of natural products

Based on: • Chemical structures: e.g. carbohydrates, steroids,

alkaloids,…• Physiological effect(s)/Pharmacological activity: e.g.

vitamins, antibiotics, anticoagulant, hypotensive,…• Taxonomic: part used e.g. flower, family , genus,

species,…• Biosynthetic Pathway: e.g. shikimic acid derivatives,

mevalonic acid derivatives, acetate-malonate derived

The biosynthesis of the secondary metabolites

• Acetate-malonate pathway• Acetate-mevalonate pathway (mevalonic acid

pathway)• Shikimic acid pathway• “Amino acid “pathway

Acetate malonate pathwayA-Non-aroamtic derivatives (polyacetylenes, polyynes)B-Aromatic polyacetates (polyketides)

B1-Monocyclic compounds: -Lichen compounds -Phloroglucinol derivatives of male fern-Bitter principles of hops -Cannabinoids -Phenylchroman derivatives (Flavonoids)

B2-Polycyclic compounds:-Anthracenes -Chromones -Antibiotics from acetate metabolism

Acetate mevalonate pathway

• Isoprenoid compounds• Terpenes (mono-, sesqui-, di-, tri-, tetra-, poly-

terpenes(• Cardiac glycosides• Saponin glycosides• Steroids• Vitamin D

Acetate-derived Natural Products Acetate formed from carbohydrate via pyruvic acidProduce large no. of imp. natural products (flavonoids, anthraquinones, macrolides, terpenes & steroids)2 main routes originate with acetate pathway:1.Acylpolymalonate pathway leading to FA & polyketides2.Mevalonic acid pathway producing terpenes & steroids

Shikimic acid pathway

• Aromatic biosynthesis:• Phenols• Phenolic glycosides• Phenyl-propane-derivatives• Lignins• Lignans• Aromatic amino acids

“Amino acid” pathway

Includes all biogenetic drugs containing “N”.:-Alkaloids-Cyanogenic glycosides-Glucosinolates-Alliines-Antibiotics from amino acid metabolism-Anticancer drugs from amino acid metabolism

General Biosynthesis PathwayCO2 + H2O + Light PO4

Photosynthesis Nucleic acids

Carbohydrates Tannins Phenyl propanes

Glycolysis Shikimic acid Chorismic acid Aromatic Amino acids

Pyruvic acid

N2

Via citric acid cycle Amino acids

Acetic acid

Proteins

Peptides

Alkaloids

Fatty acids & Polyketides Mevalonic acid Terpenes

Steroids Purines

Most important building blocks

SCoA O

Acetyl Enzyme CoA

HO2COH

OH1

23

4

56

Mevalonic acid (MVA)

O

H

O

HO

OH

OH

Shikimic AcidSCoA O SCoA O

CO2HAcetyl-CoA Maonyl-CoA

HO2COH

OH1

23

4

56

Mevalonic acid (MVA)

1 23

4

5

Isoprene Unit

CO2H

HO

NH2

Tyrosine

CO2H

NH2

Phenylalanine

C6C3

C6C1

C6C2