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Farmakognosi Fitokimia

kode mk: PST 306


3 sks/3 jp
Semester gasal tahun akademik 2016/2017

Tim dosen :
Dr. Yustina Sri Hartini, Apt.
Dr. Erna Tri Wulandari, Apt.
Dandang gendiis (Clinacanthus nutans)
kencing manis/diabetes

Pegagan (Cantela asiatica)

Jambu kluthuk (Psidium


guajava)antidiare
Rencana pembelajaran

RPS mk Farmakognosi Fitokimia


RTP
RUBRIK PENILAIAN
pharmacon (Greek) gnosis (Roman)
-poison - knowledge, studies, i.e.

studies about medicines and poisons

The Greek "pharmakon" means defender, healer (the


ancient Egyptian "Pharmacy,; the name of the god Toth in
ancient Egypt. He was the patron of the medical affairs.
Pharmacognosy is "the doctrine of drugs and poisons.

Poison is in everything, and no thing is without poison.


The dosage makes it either a poison or a remedy

Paracelsus (493-1541)
Schmidt & Seydler (1811/1815
Analecta Pharmacognostica
the oldest modern science?

A translational or multidisciplinary science, and during the evolution


of the scope of this subject area, phytochemistry and phytochemical
analysis have become integral parts of Pharmacognosy.
research in Pharmacognosy changed significantly, from focusing
on identification of drugs the investigation of biological activity.
Research into ethnobotany, ethnomedicine, and ethnopharmacology
has also become an important element in Pharmacognosy.
Pharmacognosy is somewhat neglected nowadays as a major subject
area within the modern Pharmacy curricula, especially in the West.
Artemisia annua used in China, were studied in the West from the
1980s onward the development of a new class of effective
antimalarials : the artemisinins.
the study of the physical, chemical, biochemical and
biological properties of drugs, drug substances, or potential
drugs or drug substances of natural origin as well as the search
for new drugs from natural sources. (The American Society of
Pharmacognosy)
Classical pharmacognosy deal with the taxonomy and
morphology of plant drugs, neglected their chemistry. Modern
Pharmacognosy involves the broad study of natural products
from various sources including plants, bacteria, fungi, and
marine organisms. The way to new discoveries : by identifying
new structurures & pointing to new biological activities.
deals with ;natural products used as drugs or for the
preparation of drugs. Multydisiplinary subject that comprises
parts of botany, organic chemistry, biochemistry and
pharmacology (Samuellson, 1992)
The study of those natural substances, principally plants, that
find use in medicine (Trease and Evans, 1996)
Ethnobotany : It is a broad term referring to the
study of plants by humans
Ethnopharmacology : it is a related study of ethnic
groups and their use of drugs
Ethnomedicine : It refers to the use of plants by
humans as medicine

Tugas untuk minggu depan: sharing isi journal:


Ethnopharmacology: quo vadis? Challenges for the
future, Michael Heinrich, Rev Bras Farmacogn 2014,
24:99-102.
Are ethnopharmacologycal surveys useful for the
discovery and development of drugs from medicinal
plants? Albuquerque et al., Rev Bras Farmacogn
2014, 24:110-115.
Egyptians (Ebers papyrus, 1550 BC)
Authors of antiquity
Hippocrates (460-377 BC)
The Father of Medicine
Dioscorides (40-80 AD)
De Materia Medica (600 medicinal plants)
The 18th century, Pharmacognosy:
Johann Adam (1759-1809)
Linnaeus (naming and classifying plants)

At the end of the 18th century, crude drugs were still being used
as powders, simple extracts, or tinctures

The era of pure compounds, In 1803, a new era in the history of


medicine: Isolation of morphine from opium, Strychnine (1817),
Quinine and caffeine (1820), Nicotine (1828), Atropine (1833),
Cocaine (1855)

In the 19th century, the chemical structures of many of the


isolated compounds were determined

In the 20th century, the discovery of important drugs from the


animal kingdom, particularly hormones and vitamins.

Microorganisms have become a very important source of drugs


Molecular pharmacognosy: an explanatory model, Jan G. Bruhn
and Lars Bohlin, Drug Discovery Today, 1997, 2 (6): 243-246

Obat jadi

Obat
tradisional
Fig. 1. Explanatory model for molecular pharmacognosy
2 4
2 4

Pharmacognosy: a molecular sciences that explores naturally


occurring structure-activity relationships with a drug potential
Taxol

TABLE 1: CHRONOLOGY OF THE DISCOVERY AND PRECLINICAL DEVELOPMENT OF TAXOL


1962: First collection of Taxus brevifolia by USDA botanists
1964: Confirmed KB activity
1965: Recollection of bark and assignment to Dr. Monroe Wall, RTI
1966: Confirmed in vivo activity mainly mouse leukemia models
1969: Taxol first isolated in pure form (0.01% yield from bark)
1969: Survey of plant parts and abundance by USDA
1971: Isolation and structure first reported by Wall, Wani, et al.
1974: Good in vivo activity against B16 mouse melanoma
1975: B16 activity confirmed. Increased interest
1977: Accepted as a candidate for preclinical development Tumor panel testing started
1977: Strong activity observed against human solid tumors, the MX-1 mammary and CX-1
colon xenograft models
1978: Recognized as a mitotic spindle poison
1979: Unique mechanism of action determined.
1980: Formulation completed. Supplies adequate for toxicology studies
1982: Toxicology studies completed.
1982: Approved for INDA filing with FDA the formulation vehicle was observed.
Application for IND status with the FDA was approved in 1982, 20 years after the
first collection of the source plant material, and taxol was advanced into clinical
1983: Phase I clinical trials begin.
1985: Phase II trials begin
1986-1989 - Trials limited by drug supply issues
1989: Activity observed against refractory ovarian cancer
1989: Bristol-Myers Squibb (BMS) selected as Cooperative Research and
Development Agreement (CRADA) partner.
1989: Seven year exclusivity granted to BMS for investment in development
1991: Activity observed against metastatic breast cancer
1992: NDA approved by FDA for treatment of refractory ovarian cancer
1994: FDA approval for treatment of refractory breast cancer
Some milestones in natural products chemistry:

H
HO
3 1 N
H
4
N
HO
12 10
O H
13 9
N H CH3O
H H
5
15 N 10
6
7 16 CH3 O O
H N
HO

Morphine Strychnine
Quinine
(aromatic alkaloid from opium, (aromatic alkaloid from (quinoline alkaloid from
Papaver somniferum) Strychnos nux-vomica)
Cinchona species)
Isolation: 1806, Sertrner Isolation: 1818, Pelletier &
Isolation: 1820, Pelletier &
Structure: 1925, Robinson Caventou
Caventou
Synthesis: 1954, Ginsberg Structure: 1946, Robinson
Synthesis: 1944, Woodward
Biogenesis: 1959, Leete Synthesis: 1954, Woodward
2001, Eichberg
Some milestones in natural products chemistry:

10
CH3
CH3 N
1 O CO2CH3
2 N
O
9 8
C6 H5
7 H
CH3 CH3 O

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Coniine
Cocaine
Camphor (aliphatic alkaloid from
(aliphatic alkaloid from
(monoterpene from hemlock, Conium
Erythroxylon coca)
Cinamomum camphora) maculatum)
Isolation: 1859, Niemann
Isolation: 1845, Bouchardat Isolation: 1886, Ladenburg
Synthesis: 1923: Willsttter
Structure: 1926, Koller
Some milestones in natural products chemistry:

21
24
20 23 26
18
CH3 25 OH N(H)CH3
27
CH2OH 19
CH3
11 13 17 CH CH CH3
14
O glucoside 1 9
10 8
3 5
6
HO
Ephedrin
Cholesterol (aromatic alkaloid from
Salicin (steroid from gallstones) Ephedra equisetrina and
(aromatic alcohol from
Isolation: 1909, Windaus E. sinica; "ma huang")
Salix species)
Structure: 1932, Wieland Structure and synthesis:
Structure and synthesis: Synthesis: 1964, Johnson 1920, Spth and Gring
1906, Irvine Biogenesis: 1966, Cornforth
Some milestones in natural products chemistry:
arabinose OH
glucose
OH
Ginsengoside Rs2 OH HO
HO OH O
(Panax ginseng) O
O
O
Isolation and structure: OH
1962, Shibata
glucose
HO
O
HO
O
Brevetoxin-A
HO
AcO O
(red tide toxin from
O
HO Gymnodinium breve)
HO
OH Structure: 1986, Clardy
glucose-6-acetyl Synthesis: 1987, Nakanishi
OH

O O

. CHO

. . . . .
O O

. .
O
O
O O
O
. O
O
Some milestones in natural products chemistry:
.
AcO O OH . .
H3C CH3 CO2H
O Ph O HO O HN .
O
CH3
Ph NH O OCH3
CH3 H
OH H O
HO AcO
PhCO2 HO O OH

Taxol
(antitumor diterpene from Dynemicin A
Pacific yew, Taxus species) (antibiotic polyketide from
Micromonospora chersina)
Isolation: 1971, Wani et al.
Structure: 1971, Wani et al. Structure: 1989, Matsumoto and Clardy
Synthesis: 1991, Nicolau
Biosynthesis: 1992, Tokiwa et al.
Some milestones in natural products chemistry:

OH
OH

O
O H
H OH
H
O
O O
O
OH
O H O
O OH
O
OH
(+)-Absinthin O
(dimeric diterpene from Artemisia (-)-Littoralisone
absinthium L., an anthelmintic)
(neurotrophic growth factor, iridoid
Isolation: 1953, Herout from Verbena littoralis L.)
Structure: NMR: 1980, Beauharie,
Isolation and structure: 2001, Li
X-ray: 1985, Karimov
Synthesis: 2005, Mangion
Synthesis: 2004, Zhang
Artemisia annua

Artemisinin
P. falciparum vs cincin peroksida
Triptolide
antiproliferatif ca pankreas vs
diterpenoid epoksid
Tripterygium wilfordii Celastrol
antioksidan, anti-
inflammatory,[anticancer, and
Celastrus regeliii insecticidal activities. obesity-
controlling effects in mice vs
pentasiklik triterpenoid
Zingiberacea
Capsaicin
Capsicum sp sensasi panas, iritan utk mamalia
Curcumin
Belajar di praktikum FF
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.
Indication Total drugs B N ND S SN V
antibacterial 90 9 61 19 1
anticancer 79 12 9 21 25 10 2
antiinflammatory 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
B: biologicals (peptides); N: nat prod extract; ND: semi-synthetic starting from nat prod; S: totally
synthetic using random screening ; SN: totally synthetic but based on nat prod; V: vaccine

Although the combinatorial strategy has succeeded as a method


of optimizing structures, there is still no de novo combinatorial
compound that has made it to drug product.
Natural Products as Sources of New Drugs
(Ref: Mark Butler, The Role of Natural Product Chemistry in Drug
Discovery, J. Nat. Prod. 2004, 67, 2141-2153)
NATURAL PRODUCT

they can be
1. Entire organism (plant, animal, organism)
2. Part of an organism (a leaf or flower of a plant, an
isolated gland or other organ of an animal)
3. An extract or an exudate of an organism
4. Isolated pure compounds
Why do we need plants?
1. Source of drug molecules
Most drugs can be synthesised
Still more economical to use the plant
Papaver opium -> morphine, codeine (strong medicinal
pain)
Quinine

Cinchona bark, South American tree


Used by Incas; dried bark ground and mixed with wine
First used in Rome in 1631
Extracted 1820
Large scale use 1850
Chemical synthesis 1944
Actual tree remains the most economic source
2. Source of complex molecules that can be
modified to medicinal compounds
Examples: morfin->Codein, Soya: saponins -> steroids

3. Source of toxic molecules


To study the way the body responds to
their pharmacological use
Investigating pharmacological
mechanisms
picrotoxin nerve conduction
4. Source of compounds to use as templates
for designing new drugs
Morphine:
No better painkiller. Once structure worked
out wanted to improve it. What is required?
Diacetylmorphine (heroin):
OH group -> O-O-diacetyl. Still addictive?
Codeine:
Methylate hydroxyl phenolic; O-Me. 1/5
analgesic capacity of morphine, useful to
suppress cough reflex

Dihydromorphinone:
Reduced =, oxidised 2y alc. Potential analgesic.
5. Source of novel structures
these might never be thought of
Tapak dara /Catharanthus periwinkle (Vinca
rosea) -> vincristine (alkaloid dimer)
6. Source of plant drugs
As a powder or extract
The pure compound is often not isolated because:
Active ingredient is unknown
Active ingredient is unstable
Isolation process is too costly

250,-500,000 species of higher plants on earth


<10% investigated and only for one activity
Value of natural products
Compounds from natural sources play four significant roles in
modern medicine:
1. They provide a number of extremely useful drugs that are
difficult, if not impossible, to produce commercially by synthetic
means
2. Natural sources also supply basic compounds that may be
modified slightly to render them more effective or less toxic
3. Their utility as prototypes or models for synthetic drugs
possessing physiologic activities similar to the originals
4. Some natural products contain compounds that demonstrate
little or no activity themselves but which can be modified by
chemical or biological methods to produce potent drugs not
easily obtained by other methods
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 ones
natural resources.
Natural products should use the new developments, e.g.,
molecular biology, computational science.

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Issues and challenges in Natural Products today
1. Loss of biodiversity
2. Intellectual Property Rights
Patent protection (pharma companies)
Biopiracy (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

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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

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The study of natural products is multidisciplinary

Biology Chemistry

Taxonomy . Botany Organic synthesis

Agriculture . Pharmacology . Pharmaceutical Science . Organic analytical chemistry

Entomology . Microbiology . Biotechnology/Molecular Biology . Biochemistry

Genomics . Proteomics

Metabolonomics
Techniques used in natural products chemistry
1800 1850 1900 1950 1975 2000

Type of research undertaken:


Isolation, characterization
Pharmacognosy & Pharmacology
Organic synthesis
Chromatography Spectroscopy
Biogenetic studies
Biochemistry; Enzymology
Molecular Biology
Metabolonomics

Techniques used:
basic physico-chemical measurements
TLC column chrom GC HPLC / Electrophoresis
X-ray UV-vis IR MS / NMR
Radioisotopes
Enzymes Computational methods
Tissue culture
Mol Bio / Biotech
Combinatorial chem
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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