Transcript Acetate-derived Natural Products

Introduction
Natural products, especially those derived from plants, have been used
for medicinal purposes since ancient times
Clay tablets of the Babylonian, Assyrian, and Sumerian eras dated 2600
- 4000 BC are thought to be the earliest recordings of plant usage as
herbal remedies
Egyptians also had many paintings of medicinal plants on their tomb
walls dated around 2200 – 2700 BC
The 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 plants
This 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 products
1785: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 opium
1817: Isolation of strychnine
1820: Isolation of caffeine and quinine
1828: Isolation of nicotine
1833: Isolation of atropine
1855: Isolation of cocaine
1868: Isolation of digitaline
1897: 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
Pharmacognosy
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
Phytochemistry
The 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 pathway
A-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-, polyterpenes(
• Cardiac glycosides
• Saponin glycosides
• Steroids
• Vitamin D
Acetate-derived Natural Products
Acetate formed from carbohydrate via pyruvic
acid
Produce large no. of imp. natural products
(flavonoids, anthraquinones, macrolides,
terpenes & steroids)
2 main routes originate with acetate pathway:
1.Acylpolymalonate pathway leading to FA &
polyketides
2.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 Pathway
CO2 + H2O + Light
PO4
Photosynthesis
Carbohydrates
Glycolysis
Nucleic acids
Tannins
Shikimic acid
Phenyl propanes
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
1
HO2C
SCoA
O
6
2
Acetyl Enzyme CoA
H
OH
3
4
O
5
OH
Mevalonic acid (MVA)
SCoA
O
HO
OH
OH
Shikimic Acid
O
CO2H
Maonyl-CoA
Acetyl-CoA
CO2H
CO2H
NH2
HO
1
HO2C
6
2
OH
3
4
Tyrosine
Phenylalanine
5
C6C2
5
OH
Mevalonic acid (MVA)
1
2
NH2
4
3
Isoprene Unit
C6C1
C6C3