Presented By

G.SUBHASRI
14UBCH040
II-BIO CHEMISTRY

MEDC 603 Fall 2007

Natural Products

General

Natural products evolved for self-defense!!

Amazing are the natural products that apparently evolved
only for the purpose of alleviating our diseases, e.g., the
statins
Traditionally natural products are plant products, e.g.,
morphine from Papaver somniferum or digitoxin from
Digitalis
Plants form the bulk of natural product suppliers current
estimate of number of plant species on earth is million
These days natural products are obtained from plants, algae,
insects, bacteria, yeast, animals, .

MEDC 603 Fall 2007

Natural Products

Advantages of Natural Products

Evolution against challenges

Structural diversity
Apparently unlimited quantity
Potency

Disadvantages of Natural Products

Synthesis
Isolation
Identification

MEDC 603 Fall 2007

Natural Products

Typically process of drug discovery from natural

sources

Pre-knowledge helpful (cultural folklore, Chinese

Materia Medica, Indian Ayurveda, .)
Collect source (plant, algae, animals, .)
Screen extracts (organic + aqueous extractions)
HIT!!
Chromatographic separation
Screen individual components
HIT or MISS??
Structural identification
Independent synthesis and re-bioassay

MEDC 603 Fall 2007

Natural Products

Selected Examples of Natural Product derived

Drugs
O
O

CH3
OH
H3C
HO

O
H3C

OH
OH
H3C
HO
OH

O
H3 C

CH3 H
H3C
O

OH
Digitoxin

H
H

OH
OH
CH3

O
O

CH3 H
H3C
O

OH
Digoxin

OH

Digitalis purpurea (Foxglove) and Digitalis lanata long known for their healthy heart
effects exert a positive inotropic effect on cardiac muscles treatment for heart
failure

MEDC 603 Fall 2007

Natural Products

Selected Examples of Natural Product derived

Drugs
OCH3
OH

OCH3
H

H
N

H
Quinidine

N
H
OH

Quinine

Quinidine bark of Cinchona tree anti-arrhythmic drug

Quinine no cardiac activity anti-infective malaria

MEDC 603 Fall 2007

Natural Products

Selected Examples of Natural Product derived

Drugs
MeO
N

N
H H

H
O

H
MeOOC

O
OCH3

Reserpine

OCH3
OCH3
OCH3

Reserpine alkaloid from Rauwolfia serpentina plant lead from the Indian
Ayurvedic system as good for heart ... used as anti-hypertensive the plant was a
source of ~20 different alkaloids

MEDC 603 Fall 2007

Natural Products

OO
H
OO
O H
_
C
O
H
R
H
C
H
C
3
3C
O
O
H3 C
H3 C
H3
H3 C
H
O
R
ravastatin
M
evastatinR
R
H P
1=
2=

Selected Examples of Natural Product derived

Drugs

L
o
v
a
s
t
a
t
i
n
R
=
H
;
R
=
C
H
1
2
3
S
im1R
C
H
2=
3

fungal metabolites ... first fungal metabolite was compactin which inhibited HMGCoA reductase compactin is isolated from Penicillium citrinum, Penicillium
brevicompactin and Penicillium cyclopium ... an anti-fungal agent too, but toxic ...

MEDC 603 Fall 2007

Natural Products

Selected Examples of Natural Product derived

Drugs
O

Warfarin

CH3

*
OH

OH

OH

Dicoumarol

Dicoumarol coumarin derivative coumarin is widely distributed in nature high

concentrations in tonka beans (Dipteryx odorata) and also in Melitotus albus (sweet
clover) a hemorrhagic disorder was observed in animals that had consumed spoiled
stuff composed of sweet clover

MEDC 603 Fall 2007

Natural Products
Selected Examples of Natural Product derived
Drugs

_
CH2OSO3

COO

NHSO3

O_
COO
OH

OH

OH

OH

O
OH

_
CH2OSO3

_
CH2OSO3

CH2OH

O
O

NHSO3

O_
COO
OH

O
OH
_

OSO3

O
NHCOCH3

O
OH
O

OH

_
NHSO3

Heparin trying to find a coagulant ... accidentally found an anticoagulant!

structure took decades to come about now we have low molecular weight heparin
and heparin pentasaccharide

MEDC 603 Fall 2007

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Natural Products
Overview of Natural Products as Drugs Status in
the Period 1981-2002

500
400
300
V = vaccines
B = biologicals
NP = natural products
NPD = natural product derivatives
SNP = synthetics derived from NP
S = straight synthetics

200
100
0

NP

NPD

SNP

Compiled from :
Newman, D. J., Cragg, G. M., and Snader, K. M. (2003) NATURAL PRODUCTS AS SOURCES OF
NEW DRUGS OVER THE PERIOD 1981 2002. Journal of Natural Products 66, 1022-1037.

MEDC 603 Fall 2007

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Natural Products

Structural Comparison between Natural Products

and Combinatorial Compounds
Combinatorial Compounds

Data from Feher and Schmidt, J. Chem.

Inf. Comput. Sci (2003) 43, 218.

Natural Products

Statistically defined chemical space is

similar for natural products and drugs,
while combinatorial compounds and
drugs do not share similar space.

Drugs

MEDC 603 Fall 2007

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Natural Products

Current Efforts
H3C
H
H CH
3

H3C

CH3

HO
OH
Trinervitane derivative

CH3
N
H3C

CH3

Me Me
Me

OH
CH3

OH

Epothilone D

Nasute termites . Soldier termites

use their nozzle (squirt gun) to tangle
up the invader in their toxic glue .
being developed by Entocosm, Australia
as an antibiotic . the natural product
is 10 times less potent than a clinically
practical antibiotic . a potent lead
molecule
Originally identified through synthesis
epoD was found to be produced by
certain bacteria genetic engineering
polyketide synthase gene knockout
(epoD to epoB) good yields being
developed by Kosan, CA as an antitumor
(inhibition of microtubule formation)

MEDC 603 Fall 2007

13

ANTICANCER AND ANTI-HIV DRUGS DERIVED FROM

AFRICAN AND OTHER PLANTS

Gordon Cragg, Ph.D.

NIH Special Volunteer
Natural Products Branch
Developmental Therapeutics Program
Division of Cancer Treatment and
Diagnosis
NCI-Frederick
Fairview Center, Suite 206
P. O. Box B
Frederick, MD 21702-1201, U. S. A.
Phone: 301-846-5387; fax: 301-846-6178
e-mail: craggg@mail.nih.gov
website: http://dtp.nci.nih.gov;
http://dtp.nci.nih.gov/branches/npb/index.html

Traditional Medicine and

Drug Discovery*
80% of the world population resides in developing
countries
80% of people in developing countries utilize plants
to meet their primary health care needs
Global pop. ca. 6.3 billion

ca. 4 billion people utilize plants to meet

their primary health care needs
*Farnsworth NR, et al. Medicinal Plants in Therapy. Bull. W.H.O. 63:965-981
(1985)

 Analgesics: Aspirin: Salix species/Europe

Morphine, Codeine;Papaver somniferum/
Mesopotamia (Iran, Iraq)
Cardiotonic: Digitalin: Digitalis purpurea/UKEurope
Malaria: Quinine: Cinchona spp./Amazonia
Artemsinin: Artemisia annua/China
Antihypertensive: Reserpine: Rauwolfia
serpentina/India
Memory enhancement: Physostigmine: Physostigma
venenosum/West Africa
Muscle relaxant: Tubocurarine:Chondrodendron spp./

NATURE THE SUPREME MOLECULAR ARCHITECT!

Epothilone A docked in tubulin active site
Epothilone A
Isolated from gliding
bacteria
(Myxobacteria)
OH
O
O
6

15

HO

11 13
S
O

Nettles et al., "The Binding Mode of Epothilone A on a,-Tubulin by Electron Crystallography"

Science, 6 August 2004, Vol. 305, pp. 866-869 (Copyright AAAS)

PLANT-DERIVED ANTICANCER DRUGS

IN CLINICAL USE OR DEVELOPMENT
Vinblastine/Vincristine: Catharanthus roseus/Jamaica,
Philippines (originally from Madagascar)
Etoposide: Podophyllum species/ Eastern US,
Himalayas
Paclitaxel/Docetaxel: Taxus species/NW US, Europe
Topotecan/Irinotecan: Camptotheca acuminata/China
Homoharringtonine: Cephalotaxus
harringtonia/China
Flavopiridol: Synthetic based on rohutikine from
Dysoxylum binectariferum/India

 1987: Collected liana Ancistrocladus korupensis leaves.

Korup National Park, Mundemba, S. West Cameroon.
Dr. Duncan Thomas (MBG) and Mr. Ndembe (Forestry Dept.).
New species (Thomas & Gereau, Novon, 1993, 3, 494-498).
1989: Michellamine B isolated. Active against a range of HIV-1
and HIV-2 strains (Boyd et al., J. Med. Chem, 1994, 37, 1740-45).
Sufficient isolated from fallen leaves for preclinical development.

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