Transcript IV. The role of natural products in drug discovery

Pharmacognosy and Drug
Discovery
Prof. Suleiman Olimat
The World Health Organization (WHO) estimated that as
much as 80 per cent of the world’s population relies on
traditional forms of medicine, chiefly plants .
More than 80,0000 of the 250,000 species of flowering plants
of the world have been documented to be used in various
human cultures around the world for medicinal purposes .
However, the number could be higher as knowledge on the
indigenous uses of plants as medicines was mostly passed on
orally from one generation to another and has largely
remained undocumented. Some of the traditional knowledge
might be lost as some practitioners were secretive and
reluctant to reveal enough information .
The Role of Plant-Derived Compounds
in Drug Development
Despite the recent interest in drug discovery by
molecular modeling, combinatorial chemistry, and
other synthetic chemistry methods, naturalproduct-derived compounds are still proving to be
an invaluable source of medicines for humans.
Other than the direct usage of plant secondary
metabolites in their original forms as drugs, these
compounds can also be used as drug precursors,
templates for synthetic modification, and
pharmacological probes.
Types of drugs derived from plants
1. Herbal drugs, derived from specific parts of a
medicinal plant
2. Compounds isolated from nature
3. Nutraceuticals, or “functional foods”
IV. The role of natural products in drug
discovery
1. Combinatorial chemistry
2. High-throughput screening of natural products
3. Combinatorial biosynthesis
4. Ethnopharmacology
Three New Nobel Prize
Scientists deal with Pharmacognosy and
Natural Products Chemistry),
congratulate three scientists whose
work in pharmacognosy, the study of
natural compounds, led to being
awarded the 2015 Nobel Prize this year.
The 2015 Nobel Prize in Physiology or
Medicine winners Drs. William C.
Campbell, Satoshi Ōmura and Youyou
Tu were honored for the discovery of
novel natural products that became
impactful therapies for infections by
roundworm parasites and malaria.
Dr. Ōmura was honored by the Nobel committee
jointly with Dr. Campbell, previously at the Merck
Institute for Therapeutic Research, where he showed
that Avermectin was active against the roundworm
parasites. Avermectin and its analog Ivermectin,
created by Dr. Campbell and colleagues, are now the
standard of care for these infections in both humans
and animals and have dramatically reduced the
human suffering from river blindness and elephantitis.
Due to the effects of Avermectin and its analogs,
these diseases are on the verge of eradication.
Avermectins
The avermectins are a series 16-membered
macrocyclic lactone derivatives with potent anthelmintic and
insecticidal properties. These naturally occurring compounds are
generated as fermentation products byStreptomyces avermitilis, a
soil actinomycete. Eight different avermectins were isolated in 4 pairs
of homologue compounds, with a major (a-component) and minor (bcomponent) component usually in ratios of 80:20 to 90:10. Other
anthelmintics derived from the avermectins
include ivermectin, selamectin, doramectin andabamectin.
Ivermectin
Ivermectin (22,23-dihydroavermectin B1a + 22,23dihydroavermectin B1b) is a broadspectrum antiparasitic drugin the avermectin family.
Uses
Ivermectin is a broad-spectrum antiparasitic agent,
traditionally against parasitic worms. It is mainly used
in humans in the treatment of onchocerciasis (river
blindness), but is also effective against other worm
infestations (such as
as strongyloidiasis, ascariasis, trichuriasis, filariasis an
d enterobiasis), and some epidermal parasitic skin
diseases, including scabies.
The drug rapidly kills microfilariae, but not the adult
worms.
An Ivermectin cream has been approved by the FDA
for treatment of rosacea (is a chronic skin condition
characterized by facial redness, small and superficial
dilated blood vessels on facial skin).
Dr. Youyou Tu
Dr. Tu has been honored for her discovery of the
antimalarial compound artemisinin, which she isolated
from the plant Artemisia annua (Asteraceae).
Artemisia annua, also known as sweet wormwood or
qīnghāo, is a plant that had been used in traditional
Chinese herbal medicines, for fevers from infection.
Artemisia annua
Artemisinin
Artemisinin proved a spectacularly effective
drug against malaria by rapidly killing
Plasmodium parasites at an early stage in their
development. Artemisinin, is part of current
combination therapy for malaria that has been
reported to reduce the mortality from this
parasite by 20-30%, saving hundreds of
thousands of lives per year.
Artemisinin
Taxus brevifolia
(Taxol)
Plant Secondary Metabolites as Drug
Precursors
Some natural products obtained from plants can be used as smallmolecule drug precursors, which can be converted into the
compound of interest by chemical modification or fermentation
methods. The semisynthetic approach is usually used to resolve the
shortage of supply due to the low yield of compounds from
plants and/or the high cost of total synthesis. For compounds with
complex structures and many chiral centers, protracted methods
may be needed for their synthesis, and thus these methods would
not be feasible economically.
The following examples indicate that some secondary metabolites
from plants are useful drug precursors, although they are not
necessarily pharmacologically active in their original naturally
occurring forms.
Cropping of the bark of the slow-growing Pacific yew tree, Taxus
brevifolia Nutt., is not a feasible method to provide sufficient amounts
of the antitumor drug paclitaxel (1, Taxol) to meet the market demand
(paclitaxel was originally isolated in only 0.014 % w/w yield from the
bark of Taxus brevifolia) . Even though this compound can be
produced by total synthesis, this has proven to
be inefficient in affording large quantities of paclitaxel . Fortunately,
10-deacetylbaccatin III (2) can be isolated in relatively large amounts
from the needles of other related yew species, such as Taxus baccata
L. (a renewable resource), and can be converted chemically in several
steps into paclitaxel .
During the period 1993–2002, the main pharmaceutical
manufacturer, Bristol-Myers Squibb, adopted the semisynthetic
method to produce paclitaxel from 10-deacetylbaccatin III . Since
2002, Bristol-Myers Squibb has produced paclitaxel using a plant cell
culture method.
Dioscorea species
Diosgenin , a steroidal sapogenin obtained from the
tubers of various
Dioscorea species that grow in Mexico and Central
America, can be convertedchemically in several steps
into progesterone , a hormone that can be used as a
female oral contraceptive . Originally, progesterone was
isolated from sow ovaries with a very low yield (20 mg
from 625 kg of ovaries), and later was synthesized from
cholesterol with very low efficiency . Progesterone is also
a key intermediate for the production of cortisone , an
important anti-inflammatory drug. Progesterone can be
converted into 11α-hydroxyprogesterone by microbial
hydroxylation at C-11, followed by chemical reactions, to
produce cortisone . Until now, diosgenin is still an
important starting material for the production of
various steroid hormones.
Diosgenin
Progesterone from Diosgenin
(Illicium verum)
Star Anise
Oseltamivir phosphate ( Tamiflu)
Oseltamivir phosphate (7, Tamiflu) is an orally active neuraminidase inhibitor
developed for the treatment and prophylaxis of influenza viruses A and B
[34, 35]. The starting material for the oseltamivir synthesis is (−)-shikimic acid
(8), an important biochemical intermediate in plants and microorganisms [36].
Previously, shikimic acid was extracted solely from the fruits of the shikimi
tree (Illicium verum Hook.f.), also known as star anise, which contains a large
amount of this compound . Later on, shikimic acid was obtained from the
fermentation of genetically engineered Escherichia coli strains, which are deficient
in the shikimate kinase gene . Currently, Roche, the drug manufacturer,
still relies on both extraction and fermentation methods to obtain ton
quantities of shikimic acid . Several routes for the production of oseltamivir
independent of shikimic acid have been developed , but these alternatives
are still not cost efficient .
Galega officinalis L.
Guanidine is a natural product with good
hypoglycemic activity isolated from
Galega officinalis L., but is too toxic for
clinical use . Many derivatives of
guanidine have been synthesized, and
metformin (dimethylbiguanide) was later
found to be clinically suitable for
treatment of type II diabetes .
Guanidine and Metformin
Gila Monster
)Heloderma suspectum(
Have you ever seen a pink yellow lizard? You were
probably looking at a Gila Monster. Did you no it’s
poisonous? Gila Monsters are cool, or at least
that’s only what I think. You will find the habitat,
physical description, its diet, and its life cycle very
interesting.
Physical description
The Gila Monster is very interesting when it
comes to the physical description. Gila
Monster has a fat tail. It also has bony scales.
Also the Gila Monster is 56 centimeters long.
The Gila Monsters appearance is very
attractive
Life Cycle
When The Gila Monster hatches it starts its life
cycle like other lizards. Did you know The Gila
Monster is hatched? The Gila Monster can live
an average of 25 years. It takes it two years
for it to grow from baby to adult. The Gila
Monster lives a long life.
Exenatide
• Exenatide, a drug that is a synthetic form of a
substance found in Gila monster saliva, led to healthy
sustained glucose levels and progressive weight loss
among people .
• Exenatide, marketed as Byetta, was approved by the
Food and Drug Administration in April 2005 to treat
type 2 diabetes in patients who were not able to get
their high blood sugar under control in a
combination with one or more of three other
medications, metformin or sulfonylurea
thiazolidinedione.