Transcript Introduction to phytochemistry

Phytochemistry
2nd Semester – 2016/2017
Dr. Jehad Almaliti
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Part (1)
Introduction to
phytochemistry
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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
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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 from strychnine tree (Strychnos nux-vomica).
1820: Isolation of caffeine (from Coffee beans) and quinine from Cinchona (C.
officinalis) bark.
1828: Isolation of nicotine from tobacco (Nicotiana tabacum) leaves.
1833: Isolation of atropine from Atropa belladonna leaves and roots.
1855: Isolation of cocaine from coca (Erythroxylum coca) leaves.
1868: Isolation of digitaline from foxglove (Digitalis purpurea) leaves.
1897: Arthur Eichengrün and Felix Hoffmann at Bayer Company created aspirin.
Aspirin was the first semi-synthetic drug synthesized from a natural product,
salicylic acid, extracted from the willow (Salix spp.) bark.
1928: Alexander Fleming discovered Penicillin from penicillium mold, and this
discovery changed modern medicine and the treatment and understanding of
infectious disease.
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Importance of Natural Products in Drug Discovery
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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)
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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,…)
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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 (genetic engineering)
• Cell and tissue culture (expensive and tedious)
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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)
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Classification of natural products
Based on:
• Chemistry (Chemical structures): e.g. carbohydrates,
steroids, alkaloids,…
• Physiological effect(s)/Pharmacological activity: e.g.
vitamins, antibiotics, anticoagulant, hypotensive,…
• Taxonomic: e.g. family , genus, species,…
• Morphological: part used e.g. flower, leaves, roots,…
• Biosynthetic Pathway: e.g. shikimic acid derivatives,
mevalonic acid derivatives, acetate-malonate derived
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Primary and Secondary 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
• Are essentially the same in all organisms, apart from minor
variations.
– Kingdom Plantae
– Kingdom Animalia
– Kingdom Fungi
– Kingdom Bacteria
• These processes demonstrate the fundamental unity of all living
matter, and are collectively described as primary metabolism, with
the compounds involved in the pathways being termed primary
metabolites
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Secondary Metabolites
• Are assembled from (pieces of) primary metabolites
• May be more prevalent or unique to certain genus, species,
and similar compounds occur within genuses and families
• Not necessarily involved in the essential metabolism of the
cell, but exert physiologic activity for the plant, its
environment and human (phyto-hormones, plant-protection,
plant-insect-, plant-animal interactions, source of drugs);
• May have useful nutritional benefits to humans/other
organisms
• The genes and enzymes guiding biosynthesis vary from one
organism to the next (condition and species sensitive)
• Most pharmacologically active natural products are 2ry
metabolites
The biosynthesis of the secondary
metabolites
• Acetate-malonate pathway
• Acetate-mevalonate pathway (mevalonic acid
pathway)
• Shikimic acid pathway
• “Amino acid “pathway
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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
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Acetate malonate pathway
A-Non-aroamtic derivatives (polyacetylenes, polyynes)
B-Aromatic polyacetates (polyketides)
B1-Monocyclic compounds:
-Cannabinoids
-Phenylchromane derivatives (Flavonoids)
B2-Polycyclic compounds:
-Anthracenes
-Chromones
-Antibiotics from acetate metabolism
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Acetate mevalonate pathway
(Mevalonic acid p.w.)
• Isoprenoid compounds
• Terpenes (mono-, sesqui-, di-, tri-, tetra-, polyterpenes(
• Cardiac glycosides
• Saponin glycosides
• Steroids
• Vitamin D
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Shikimic acid pathway
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Aromatic biosynthesis:
Phenols
Phenolic glycosides
Phenyl-propane-derivatives
Lignins/Lignans
Aromatic amino acids
Tannins
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“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
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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
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Construction Mechanisms
Despite living organisms variations, pathways for synthesis &
modification of 1ry metabolites essentially same (minor
variations)
 Carbohydrates glycolysis
Energy
[O*]
 Fats
FA’
[O*]
Energy
 Proteins
AA’
Energy
 The number of building blocks are few
 Structural diversity from mix. of building units
H
ry
 Most imp. building blocks in biosynthesis of 2 met. O
Derived from following intermediates
SCoA
O
1
HO2C
6
HO
5
OH
OH
OH
Shikimic Acid
Mevalonic acid (MVA)
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2
Acetyl Enzyme CoA
OH
O
3
4
Most important building blocks
SCoA
O
1
HO2C
2
Acetyl Enzyme CoA
SCoA
O
6
H
OH
3
4
O
5
OH
Mevalonic acid (MVA)
SCoA
O
HO
OH
OH
Shikimic Acid
O
CO2H
Malonyl-CoA
Maonyl-CoA
Acetyl-CoA
CO2H
CO2H
NH2
HO
1
HO2C
6
2
OH
3
4
Tyrosine
Phenylalanine
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C6C2
5
OH
Mevalonic acid (MVA)
1
2
NH2
4
3
Isoprene Unit
C6C1
C6C3
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Most frequent Building Units
8 blocks are basic, many are natural chemicals
1) C1 unit: CH3 Simplest
Derived from S-methyl of L-methionine (
e.g. OCH2O (methylene dioxy gp.)
2) C2 unit: usually part of long alkyl chain
e.g. fatty acid OR part of aromatic system
SCoA
O
SCoA
)
O
CO2H
Acetyl-CoA
Maonyl-CoA
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Most frequent Building Units
cont.
3) C5 Unit: e.g. Isoprene unit formed from MA
1
HO2C
6
2
OH
3
5
5
OH
4
1
Mevalonic acid (MVA)
4
2
3
Isoprene Unit
4) C6C3 Unit: refers to phenylpropyl gp
Derived from shikimate-derived AA` L-phenylalanine
OR L-tyrosine. (sat. or unsat. C3 Side chain)
CO2H
CO2H
NH2
HO
Tyrosine
NH2
Phenylalanine
C6C2
C6C1
C6C3
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Most frequent Building Units
cont.
5) C6C2N Unit: derived from L-phenylalanine OR L-tyrosine
(common) through decarboxylation
6) Indole-C2N Unit: derived from L-tryptophan
CO2H
NH2
N
L-Tryptophan
-CO2H
NH2
N
Indole-C2N
7) C4N Unit: Usually as heterocyclic pyrollidine
CO2H
H2N
NH2
L-Ornithine
-CO2H H2N
-NH2
C4N
N
Pyrolidine
8) C5N Unit: Usually found as piperidine ring
H2N
CO2H
L-Lysine
NH2
-CO2H
-NH2
H2N
C5N
N
Piperidine ring
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Building Natural Products from the
Blocks
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