Pharmacognosy- Natural Products

1. OVERVIEW OF
CONTRIBUTION OF NATURAL
PRODUCT IN NEW DRUG
DISCOVERY
BY
S. G. LAWARE
DEPT. OF PHARMACOGNOSY, COPC, SINNAR
NATURAL PRODUCT CHEMISTRY
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2. • Crude natural product extract – major source of medications
• It becomes possible to purify active ingredients from the extracts in 19th century.
e.g. alkaloids like morphine, quinine, atropine and cocaine.
• Purified natural products have advantages in term of
- Standardization of the dose
- Avoidance of side effects.
• In 20th century, microbial & plant secondary metabolites helped
- Double our life span
- Reduced pain & suffering
- Revolutionized medicine
• Natural products are the most important anticancer & anti infective agents.
• More than 60% of approved & pre-new drug application candidates are either natural products &
related to them.
NATURAL PRODUCT CHEMISTRY
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3. Natural Product list:
• Antibacterial antibiotics:
- Penicillin - Penicillium sp
- Streptomycin - Streptomyces sp
- Vancomycin - Streptomyces sp
• Antifungal drugs:
- Amphotericin B - Streptomyces sp
- Griseofulvin - Penicillium sp
• Antitumour drugs:
- Vincristin - Catharanthus roseus
- Taxol - Taxus brevifolia
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NATURAL PRODUCT CHEMISTRY

4. • Taxol – Anticancer natural product drug
• Isolated from bark of Taxus brevifolia commonly called “Pacific yew”.
• Isolated in 1971.
• Approved as medicine in 1993.
• Use to treat
• Ovarian cancer
• Breast cancer
• Cervical cancer
• Pancreatic cancer
Taxol is anti microtubule agent.
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NATURAL PRODUCT CHEMISTRY

5. OVERVIEW OF CONTRIBUTION OF NATURAL PRODUCT IN NEW DRUG
DISCOVERY
• Today the Definition of Pharmacognosy is change, whether it is right or wrong…….
NATURAL PRODUCT CHEMISTRY
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6. • Modern directions in natural products chemistry:
• Genomics of bacteria and plants
• Novel and efficient synthetic methods
• Genetic engineering of bacteria and plants
• Enzyme synthesis
• Computational methods and modeling
• High efficiency chromatography
• Spectroscopic methods
• High-throughput screening
• Synergism
• Biotransformation
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NATURAL PRODUCT CHEMISTRY

7. • Natural Products as Sources of New Drugs
(Ref: Newman, Cragg, and Snader, “Natural Products as Sources of New Drugs over
the Period 1981-2002,” J. Nat. Prod. 2003, 66, 1022-1037)
• Natural products remain an important source of new structures, though not the final
drug entity.
(B: biologicals (peptides); N: natural prod extract; ND: semi-synthetic starting from natural prod; S: totally synthetic using
random screening ; SN: totally synthetic but based on natural prod; V: vaccine)
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NATURAL PRODUCT CHEMISTRY
Indication Total drugs B N ND S SN V
antibacterial 90 9 61 19 1
anticancer 79 12 9 21 25 10 2
anti-inflammatory 50 1 13 36
TOTAL 868 91 40 209 386 131 11
Proportion 100% 10.5 4.6 24.0 44.5 15.0 1.2

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Natural Products as Sources of New Drugs
(Ref: Newman, Cragg, and Snader, “Natural Products as Sources of New
Drugs over the Period 1981-2002,” J. Nat. Prod. 2003, 66, 1022-1037)
NATURAL PRODUCT CHEMISTRY

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NATURAL PRODUCT CHEMISTRY

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Some milestones in natural products chemistry:
O
N
HO
HO
CH3
13
4
5
6
7
9
1012
13
15
16
N
N
O O
H
H
H
H
H
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Morphine
(aromatic alkaloid from opium,
Papaver somniferum)
Isolation: 1806, Sertürner
Structure: 1925, Robinson
Synthesis: 1954, Ginsberg
Biogenesis: 1959, Leete
Strychnine
(aromatic alkaloid from
Strychnos nux-vomica)
Isolation: 1818, Pelletier &
Caventou
Structure: 1946, Robinson
Synthesis: 1954, Woodward
2001, Eichberg
N
N
H
CH3O
HO
H
Quinine
(quinoline alkaloid from
Cinchona species)
Isolation: 1820, Pelletier &
Caventou
Synthesis: 1944, Woodward
NATURAL PRODUCT Chemistry

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Some milestones in natural products chemistry:
Camphor
(monoterpene from
Cinamomum camphora)
Isolation: 1845, Bouchardat
CH3
O
CH3 CH3
1
2
4
7 89
10
N
CH3
CO2CH3
O
C6H5
O
Cocaine
(aliphatic alkaloid from
Erythroxylon coca)
Isolation: 1859, Niemann
Synthesis: 1923: Willstätter
N
H
Coniine
(aliphatic alkaloid from
hemlock, Conium
maculatum)
Isolation: 1886, Ladenburg
Structure: 1926, Koller
NATURAL PRODUCT Chemistry

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Some milestones in natural products chemistry:
HO
CH3
CH3
1
6
3 5
10
11
8
9
13
14
17
18
19
20
21
23
24
25
26
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Cholesterol
(steroid from gallstones)
Isolation: 1909, Windaus
Structure: 1932, Wieland
Synthesis: 1964, Johnson
Biogenesis: 1966, Cornforth
CH2OH
O  glucoside
Salicin
(aromatic alcohol from
Salix species)
Structure and synthesis:
1906, Irvine
CH
OH
CH CH3
N(H)CH3
Ephedrin
(aromatic alkaloid from
Ephedra equisetrina and
E. sinica; "ma huang")
Structure and synthesis:
1920, Späth and Göring
NATURAL PRODUCT Chemistry

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Some milestones in natural products chemistry:
O
HO
HO
HO
O
O
O
OH
O
AcO
HO
HO
OH
O
O
OOH
OH
HO
OH
OH
HO
glucose
glucose-6-acetyl
glucose
arabinose
O
O
O
O
O
O
O
O
O
O
O
OH
CHO
. . . . . . . . .
Brevetoxin-A
(red tide toxin from
Gymnodinium breve)
Structure: 1986, Clardy
Synthesis: 1987, Nakanishi
Ginsengoside Rs2
(Panax ginseng)
Isolation and structure:
1962, Shibata
NATURAL PRODUCT Chemistry

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Some milestones in natural products chemistry:
O
O
H3C CH3
OH
HO
O
H
H
AcO
AcO
PhCO2
O
CH3
CH3
NHPh
O
OH
Ph HNHO
HO
O
O
CO2H
OCH3
O
.
.
.
.
OH
Dynemicin A
(antibiotic polyketide from
Micromonospora chersina)
Structure: 1989, Matsumoto and Clardy
Synthesis: 1991, Nicolau
Biosynthesis: 1992, Tokiwa et al.
Taxol
(antitumor diterpene from
Pacific yew, Taxus species)
Isolation: 1971, Wani et al.
Structure: 1971, Wani et al.
NATURAL PRODUCT Chemistry

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Some milestones in natural products chemistry:
(+)-Absinthin
(dimeric diterpene from Artemisia
absinthium L., an anthelmintic)
Isolation: 1953, Herout
Structure: NMR: 1980, Beauharie,
X-ray: 1985, Karimov
Synthesis: 2004, Zhang
O
O
O
O
OH
OHH
OO
O
O
O
OH
OH
OH
O
H
H
H
OH
O
(-)-Littoralisone
(neurotrophic growth factor, iridoid
from Verbena littoralis L.)
Isolation and structure: 2001, Li
Synthesis: 2005, Mangion
NATURAL PRODUCT Chemistry

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Some milestones in natural products chemistry:
O
OH Lauric acid
O
OH
Oleic acid
Linolenic acid
9
9
O
OH
1215
Some recent rediscoveries:
CH3
CH3
HO
H CH3
Cholesterol 7-Dehydrocholesterol
(Provitamin D)
CH3
CH3
HO
H CH3
CH3
H CH3
CH2
HO
Vitamin D3
NATURAL PRODUCT Chemistry

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The role of the study of natural products today
• Nature still holds many secrets which we can learn from:
chemical structure, biosynthesis, the role and relationship
of plants to other organisms.
• The study of natural products merges science with
culture.
• For countries which harbor rich biodiversity, the study of
natural products is an important way of developing one’s
natural resources.
• Natural products should use the new developments, e.g.,
molecular biology, computational science.
NATURAL PRODUCT Chemistry

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Issues and challenges in Natural Products today
1. Loss of biodiversity
2. Intellectual Property Rights
• Patent protection (pharmaceutical companies)
• Bio piracy (source countries)
3. Western drugs:
a. High cost of drug development
b. New drug leads and targets
4. Herbal products:
a. Regulation
b. Improvement in quality
c. Elucidation of mechanism of action
NATURAL PRODUCT Chemistry

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Research areas in natural products today
1. Structural elucidation (speed of analysis, sample throughput complexity
of structures)
2. Metabolonomics
3. Synergy and biotransformation
4. Biosynthesis
5. Biological activity
a. Ecological
b. Pharmaceutical properties / drug discovery
c. Healthcare and cosmetic products
6. Molecular biology and Biotechnology
7. Quantitative natural products chemistry
NATURAL PRODUCT Chemistry

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Natural products chemistry is at the intersection of
many fields:
Natural
Products
Chemistry
Pharmaceutical Science
Biochemistry
Biotechnology
Molecular Biology
Ecological Biochemistry
Taxonomy
Chemical synthesis
Entomology
Microbiology
Combinatorial
Chemistry
NATURAL PRODUCT Chemistry

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NATURAL PRODUCT Chemistry

22. Thank you
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NATURAL PRODUCT CHEMISTRY