Science Dialogue

Yamanashi Prefecture Tsuru High School

2005/10/25

Introduction to Natural Products

and Medicinal Chemistry

David LEMIN, PhD.

JSPS Post-Doctoral Fellow
Pharmaceutical Sciences Faculty
Chiba University
 Yamanashi Prefecture
Tsuru High School

Brussels, Belgium

12h
 3 Regions : Flandria, Wallonia and Brussels.
3 Languages : French, Dutch and German.
Population : 10.3 Million (less than Tokyo)
Area : 30,528 sq km (about Kyushu)
Seat of both European Union (EU) and NATO.

Flandria,
Dutch speaking.

German speaking.
Brussels,
bilingual.
Wallonia,
French speaking.
 Grand-Place,
Brussels.

Atomium, Brussels.
EU Parlement,
Famous places Brussels.
The Lion , Waterloo.

Mannekenpis,
Brussels.
Onze Lieve Vrouw,
Antwerp.

The Canals, Brugge.

 Bruegel
Magritte 1525-1569
1896-1967

Famous painters

Delvaux
1897-1994
Carnival, Binche.

Flowers drawing,
Grand-Place, Brussels.

Famous Events

Le Doudou, Mons.
 Belgian Beers

Belgian Chocolates

Famous Food
Mussels and
Potato Fries
Belgian Waffels
A few things about me

David LEMIN

Born in 1975, Uccle, Brussels, Belgium.

High School Graduation, Sciences oriented, 1994.

Graduate Diploma in Chemical Sciences, Free University of Brussels, 1998.

Master Degree in Scicences , Free University of Brussels, 2001.

PhD. In Sciences , Free University of Brussels, 2004.

Japan Society for the Promotion of Sciences, Post-Doctoral Fellowship,

Chiba University, Octobre 2004 - Octobre 2006.
 Introduction to Natural Products Chemistry

Natural Product : A chemical substance produced by a living organism; a term

used commonly in reference to chemical substances found in nature that have
distinctive pharmacological effects.

Main Classes of Natural Products:

- Carbohydrates

- Lipids

- Proteins

- Nucleic Acids
 Carbohydrates

A broad category of chemical compounds, also reffered as Sugars. The most abundant
class of bio-organic molecules on Earth. Although relatively low in human, it constitute
about 75% by mass of dry plant materials.

Main functions: Energy storage, structure element , source of carbon of the bio-
synthesis of other subtsances, “Markers” on cell surface for cell-cell recognition.

OH
OH

OH O OH
OH O OH
OH
HO OO
OH OH HO
OH

OH
Lactose Glucose
 Lipids

A broad category of chemical compounds, also reffered as Fat. Most of those products
are non polar fat, oil, or wax that does not (or poorly) dissolves in water.

Main functions: Main componant of cells membrane, energy storage, communication

between cells (hormones).

O O
O
O O

O O
O
Triglyceride
O O
(+)
N P O OH
O
O (-)
P hos phatidylcho line

Testosterone
 Proteins

A broad category of chemical compounds composed of amino acids. Includins

Aminoacids, polypetides, Enzymes.

Main functions: Very large variety of functions, from maintenance or repairing of

existing tissues and synthesis of new ones to the catalysis of all the bio-chemical
reactions that take place in a living organism (Enzyms).
O
H 2N
OH
R
Secondary Structure
R = C H2S H : C ys
R = C H3 : A la Tertiary Structure
R = C H2C O O H : A sp
R = (C H2) 4N H 2 : L ys
....
....
....
...

A m ino A cid s

+
=

Quaternary Structure
Primary Structure
 Nucleic Acids

A category of complex chemical compounds involved in the transmition of genetic

information (DNA) and its transfert as information to the cell (RNA).

Main functions: Genetic information,

some simple nucleotides acts as source
Base: Adenine (A), of energy for chemical reaction (ATP,
Guanine(G), GTP,...).
Cytosine (C),
Thymine (T, DNA)
or Uracil (U, RNA)

Sugar:
Ribose (RNA),
Desoxyribose (DNA)

Phosphate group

NH2
N
N
O O O
(-) O P O P N N
P O
O O
(-) O (-) O
(-) O

HO OH
ATP
 Metabolism

The Metabolism is the sum of all the chemical reactions that take place in a
living organism.

Primary Metabolism: All the chemical reactions necessary for the live of the
organism by itself.

Primary Metabolites: All the chemical products involved in the Primary

Metabolism.

Secondary Metabolites: All the chemical products that are produced by the
living organism but are NOT involved in the primary metabolism. Not necessary
for the live of the organism by itself but usefull for interaction with others
(chemical communication, chemical defences).
Tobacco Plant

N
CH3
N
Nicotine

N
CH3
N
Nicotine

N
CH3
N
Nicotine
 Hormones, Pheromones and Allomones

Hormones: Chemical products use in the tranfer of information between tissues

or organs within a Body, in order to coordinate their activity.

Pheromones: Chemical products used between individuals of the same specie in

order to induce a specific behavior (Chemical communication).

Allomones: Chemical products released by an organism wich has a negative

effect on another organism (Chemical defence).
Chemical Communication : Trail Pheromones

Nest

O
N
H O

Food
Chemical Communication : Sexual Pheromones

D is p a r lu r e

Reproduction
Chemical Defence : Ladybugs

(-)
O (+)
N

Coccinelline

t i sm
sema
p o
A
Chemical Defence : Bombardier Beetle

Enzyme
2 H 2O 2 2 H2O + O2 + HEAT
hydrogen peroxide

OH O

Enzyme
+ H2 O 2 + 2 H2O + HEAT

OH O
hydroquinone p-benzoquinone
 Intoduction to Medicinal Chemistry

Evolution gave different organism different “Chemical Tools” to

communicate with individuals of the same specie or to defend themselves
against predators.

Question : As we share the same kind of Primary Metabolism,

doesn't those “Chemical Tools” have a effect on the human body?

Answer : Yes, and some times those “Chemical Tools” can be used
as Medicinal Drugs.
 Pharmacologically active Natural Products : Digitoxin

Natural Products having a particular activity on the human body wich is benefic
for the treatment of a particular Disease. O

OH

O O

HO
O O
Digitoxin
HO
O O

HO
OH

Digitoxin strongly stimulate the contraction of the heart.

Digitalis purpurea Treatment of heart deficiency.
 Natural Products Derivatives : The Aspirin Story

Natural Products wich are slightly modified in order to improve their activities
or decrease the side-effects.
- 400 BC Use of the bark and leaves of willow tree to
releave pain and fever (Greece).
- 1758 Edward Stone (England) chew the bark of a
willow tree ⇒ bitter ⇒⇒ discovery of Salicin and
Salicilic acid (side effect: stomach pain)
- 1897 Felix Hoffmann (BAYER, Germany) synthesise
Aspirin.
HO OH
Willow tree
O O
OH
HO
OH
Salicin
O OH
O OH
Ac2O
HO O O

Felix Hoffmann
1868-1946 Salicylic acid Aspirin
 Total Synthesis vs Semi-synthesis : The Taxol Story
- 1962 A. Barclay isolated Taxol from the bark of the Pacific Yew tree
(Taxus brevifolia)
- Present in very small quantity :
100 year-old tree to isolate 300mg = a single dose ⇒ need to prepare it.

- Total Synthesis starting from simple commercially available

molecules (more than 30 steps : less than 1% Total Yield)
- Semi-synthesis starting from complex natural product :
10-deacetylbaccatin III discovered from the needles of European Yew
Pacific Yew Tree tree (Taxus baccata) : 3 Steps, 50 % Total Yield.
Taxus brevifolia
O
O
HO O OH O O OH
NH O

HO O
O OH O
H H
HO O HO O
O O
O T a xo l O
O O

1 0 - d e a c e t y lb a c c a t in I I I

European Yew Tree

Taxus baccata
 Natural Products Analogs

Synthetic Products that has a structure partially similar to a

known Natural Product.

- Quinine was isolated in 1820 by Caventou and Pelletier

(France), from the bark of the cinchona tree, brought back from
south america by jesuit missionaries.

- Used for treatment of fever, pain and Malaria.

- 1934 I G Farben (Germany), synthesis of Chloroquine.

- 1978 (USA) synthesis of Mefloquine.

Cinchona tree
N
HO HN HO N
H
H
O

N Cl N N
Chloroquine CF 3 Mefloquine
Quinine
 Central Nervous System (CNS) and Homosedinone Analogs

- Homosedinone was isolated from Sedum acre in 1988.

- Wide screening from Pharmaceutical French company

Servier, for potential CNS Disease Therapeutics among
natually occuring products showed homsedinone has
interesting activities.

- Collaboration between Servier and Free University of

Brussels to prepare analogs of homosedinone and test their
activity on CNS.

O OH
Sedum acre
O
O OH N
O OH
CH3
N N

CH3 CH3
R O OH
h o m o s e d in o n e
N
CH3
N
Leukemia and ATP Analogs
NH2
N
N
O O O
(-) O P O P P N N
O
O O O
(-) (-) O (-) O

(+)
4Na HO OH

ATP

NH2
N
N
O O O
(-) O P X P P N N
O
O O O
(-) (-) O
(-) O
(+)
4Na R

X = -CH 2-, -CCl 2-

O
R=
O H

O
O O

O
 Chirality

Racemic mixture One enantiomer

(R )-L im o n e n e (S )-L im o n e n e
s m e lls o r a n g e s s m e lls le m o n s
 New Access to Mitomycin C Anti-Cancer Drug
- Isolated from Streptomyces caespitosus in 1958.

- Antibiotic and anti-cancer activity.

- Extensively used in combination chemotherapy

treatment of cancer. O
NH2
O
O
H2N O

N NH
O

Mitomycin C

(-)
Br
(+)
Ph
Ph N CO2tBu
N
Ar CHO + N N
Ar CO2tBu

Streptomyces one enantiomer

 Acknolegments

Japan Society for the Promotion of Sciences JSPS

- Post-Doctoral Fellowship for Foreign Researcher

- Science Dialogue Program

Prof. Tsutomu ISHIKAWA

and the members of the lab.

Ms. Kaori SHIMURA