10/04/2014

“Within the infant rind of

this weak flower
Poison hath residence and
medicine power”
W. Shakespeare,
“Romeo and Juliet”, II, ii.

DRUG EFFECT SOURCE

Aspirin Analgesic Salix spirea

Cocaine Local anesthetic Erythroxylum coca

Tubocurarine Muscle relaxants Chondrodendron

Toxiferine tomentosum
PRIMARY METABOLITES SECONDARY METABOLITES
Morphine, Codeine Analgesics Papaver somniferum

Quinine Anti-malarial Cinchona ledgeriana

Taxol Cancer drug Taxus bravifolia

BIOCHEMISTRY NATURAL PRODUCTS
CHEMISTRY Vincristine, Anti-leukemia Catharanthus roseus
Vinblastine

Digitoxin Strengthens the Digitalis purpurea

heart muscle

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Story of Aspirin
•  Before the Christian era, preparations from various barks were used for treatment of pain, fluid
retention and gout. Clay tablets from the Sumerian period describe the use of willow leaves in the
treatment of rheumatism. Egyptians also knew the pain-relieving effects of potions made from
willow and myrtle leaves. However, because of St. Augustine’s dictum that all diseases of
OH Christians were due to punishment by demons, physicians in the Middle Ages were reluctant to
interfere with God’s will.
•  In the late 18th Century, Edward Stone in England, believing in old wives’ tales that willow trees
grow in moist places and therefore must contain remedies to pains caused by moisture (“The
cause of a disease offers a clue to its treatment”), powdered and dissolved in water the barks of
willow trees, and cured rheumatism pains.
•  In 1826 the active component, salicylic acid, was isolated. In 1859, Adolph Kolbe, a professor of
chemistry, identified and synthesized salicylic acid, in the laboratory at the Bayer Company. This
allowed salicylic acid to be produced at industrial scale and sold at a tenth of the price of the
material extracted from the willow bark.
Geraniol •  Felix Hoffmann was a junior chemist at the Bayer laboratory. His father was suffering from severe
rheumatoid arthritis. The new synthetic drug cured his pains but was irritating to the stomach.
Hoffmann set out to modify salicylic acid so that it would be more soluble in stomach acids. The
from Rosa centifolia more soluble form would pass through the stomach more rapidly causing less irritation. He
prepared derivatives of salicylic acid and tested them on his father. The acetyl derivative proved
miraculous.
•  Baeyer took the patent and marketed aspirin in 1899. “A” stands for acetyl and “sprin” for spirea,
the willow tree Salix spirea. It has low toxicity. Aspirin is the most successful medicine in history
and Bayer sells 11 billion tablets a year.

Synthetic drugs with similar structures to

aspirin
•  Aspirin is analgesic (pain-killer), antipyretic Aspirin Thylenol Phenacetin
(reduces fever), an anti-inflammatory antipyretic analgesic
agent (reduces swelling), and a uricosuric analgesic
(relieves symptoms of arthritis and gout). It
has also proven to be effective against CH3COO CH3CONH CH3CONH
heart attack. COOH

OH OCH2CH3

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O
O

Menthol
from Mentha piperita L. Camphor
peppermint from
Cinnamonum
camphora

R1 O

O Me
N
R2O
N
Me
N Morphine, R1=R2=H
Codeine, R1=Me, R2=H
from
Nicotine fom Papaver somniferum
Nicotina tabacum
Heroin, R1=R2=MeCO

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OH
H

H
O (CH2)4CH3

Cannabis sativa Tetrahydrocannabinol

CH CH2
HO
N
MeO

Quinine Cloroquine

N CH2CH2CH3
NH CHCH2CH2CH2N(CH2CH3)2 H
Me

Cl N

coniine

4

Me O PhCONH
N O C CH Ph
CH2OH
Atropine
Story of Taxol
•  Taxol has been isolated from the yew tree. The tree was
known to be very poisonous even in the old ages. In the
first century Pliny wrote that wine kept in yew barrels had
been poisoned.
•  Taxol was isolated in the late 1960s from the bark of the
Pacific yew tree, Taxus brevifolia, which grows in North
West America, as a result of a random screening of 110
000 samples from 35 000 plant species. The drug
discovery program was led by the US National Cancer
Institute.
•  Samples were tested in vitro, using human tumor cell
lines. Taxol has proved to be the most effective drug
against ovarian and breast cancer.
10/04/2014
AcO
O OH
O
CO
H
O
OH HO
Ph Ph CO OAc
O
Taxol
from Taxus brevifolia
•  Taxol works by stopping cell division. It interferes with the processing of
microtubules; promotes their formation, but stops their demolition so the cell
becomes clogged up and dies.
•  The yew tree has a long lifetime. It lives about 600-1000 years. 2.5 kg Taxol
has been isolated from about 1200 yew trees. The annual dose for one
person requires the bark of up to six, sixty-year-old, trees. Removing the
bark kills the tree. If about 100 000 people are to be treated, 600 000 trees
are necessary per year. This poses an ecological problem.
•  There are efforts all over the world to obtain more of the compound.
Structural analogues have not been found as effective as Taxol. Total
synthesis has proven to be very hard.
•  Another approach is partial synthesis. It has been observed that the needles
of the European yew tree, Taxus baccata, contain the compound 10-
deacetylbaccatin III, which can be converted to Taxol in a few steps. As the
needles grow back after harvesting, this approach offers a way to isolate the
compound without harming the tree. Now this route supplies the clinical
demand.
•  Another attempt to obtain the compound has been growing yew cells in the
laboratory, as nature already knows how to synthesize the compound.
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■ COLUMN CHROMATOGRAPHY
WHAT DO NATURAL PRODUCTS CHEMISTS
DO? Solvent
 
Extract
■LITERATURE OR FIELD RESEARCH FOR • Stationary phase
TRADITONAL MEDICINAL PLANTS  
• PHYSIOLOGICALLY ACTIVE PLANT  
GROUPS
■COLLOBORATE WITH BOTANISTS WHO
IDENTIFY AND COLLECT THE PLANTS

6 5 4 3 2 1

THIN LAYER CHROMATOGRAPHY

■DRY, TO AVOID DECOMPOSITION
■EXTRACT WITH DIFFERENT SOLVENTS

Pure
■DISTILL OFF THE SOLVENT ______________________
1 2 3 4 5 6
■IDENTIFY THE PURIFIED COMPONENTS BY
HEXANE CHLOROFORM WATER SPECTROSCOPY: UV, IR, NMR, MASS
EXTRACT EXTRACT EXTRACT
NEW? PHYSIOLOGICAL ACTIVITY?
Each one contains hundreds of organic compounds
■

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Isolation and Identification of the Sesquiterpene Lactone Constituents

of SESQUITERPENE LACTONES
Centaurea Cheirolopha and Centaurea Cuneifolia

*Centaurea plant species are rich in terpenoids, especially sesquiterpene lactones.

*One of the Largest Classes of Natural Products
*Sesquiterpene lactones are a special group of compounds that have received considerable 14 *Chemotaxonomically Important
attention because of their biological activities. They have been used in crude preparations
in folk medicine. For example α-santonin is widely used in the Far East to combat
2
10
9 *Farmacologically Active
intestinal worms. Artemisinin, the Chinese drug Qing Hao Su from Artemisia annua is an 1
antimalarial drug. Parthenolide from the herb feverfew is an antimigraine compound.
Antitumor, antibacterial, diuretic, and allergenic[activities have also been related to various 3 8 *Bitter Flavoring Agents
sesquiterpene lactones. 5
4
6
7 *Crystalline
*The α-methylene-γ-lactone moiety has been shown to be responsible for the physiological 11 13
activity of these compounds. This moiety functions as an enzyme-alkylating agent. 15 O
12

Basic Sesquiterpene Lactone Skeletons Sesquiterpene Lactones Isolated from Centaurea cheirolopha
14 14

10 10 OR
2 9 2 9 HO
1 1

3 8 3 8 O OH
O HO
5 7 5 7
4 4 O O
6 6
11 13 15 11 13 HOH2C OH O
OH
15 O O
12 12 R= OH OH O

O O O O O
Guaianolide Pseudo-guaianolide 1 2 3 4
Sesquiterpene Lactones Isolated from Centaurea cuneifolia
14
1 9
1 9 2 10
10 8
2 8 OR

14 7
7 3 5
3 5
4 13 4 6 11 13 O
6 11 O
HO

15 O 12 15 O 12
O O R= H R= OH
O
OH

Eudesmanolide Germacranolide 5 6