2. • 400,000 higher plant species
• 10% characterized chemically
• One-fourth of pharmaceuticals derived from
plants
• 11% of the 252 basic and essential drugs
(WHO) are exclusively derived from flowering
plants
• Plant-derived drugs have huge market value
US$30 billion in USA (2002)
3. Secondary metabolites have no recognized
role in maintaining fundamental life
processes but have important role in the
interaction of the cells with its environment
Only half the structures elucidated
Chemically highly diverse but characteristic of
a plant
4. • Not clear
• Important for survival of the plants in its
ecosystem
• Antimicrobial, anti-insect, deter potential
predators
• Discourage competing plant species
• Attract pollinators or symbionts
• Flavors, fragrances, dyes, pesticides and
pharmaceuticals
5. • Based on biosynthetic origins structurally
divided into five major groups
• Polyketides: Acetate-mevalonate
• Isoprenoids: Terpenoids and steroids from 5-
C precursor isopentenyl diphosphate (IPP)
• Alkaloids: via classical mevalonate pathway
or the novel MEP (non-mevalonate or
Rohmer) pathway
• Phenylpropanoids: having C6-C3 units from
aromatic amino acids phenylalanine or
tyrosine
• Flavonoids: combination of phenylpropanoids
and polyketides
6. • Often long, complex multi-step events
catalyzed by various enzymes and still largely
unknown
• Alkaloid biosynthesis: Best studied, 12,000
structures are known
• Production of specific alkaloid: Often
restricted to certain plant families
• Flavonoids are abundant in many plant
species
8. Much greater than any chemical library
Enormous reservoir
‘Omics’-based – functional genomics –
screening
Limited success of combinatorial chemistry or
computational drug design
9. • Designed organic chemistry enables
optimization of molecular structures – Not
attractive
• 1981-2002: 28% (351) of 1031 new drug
entities (NDEs) either natural products or
derivatives
• 24% synthesized based on natural resources
• Major group: Anti-microbial (66%), Anti-
cancer (52%), Anti-hypertensive, Anti-
inflammatory
10. • Plants are difficult to cultivate or becoming
endangered
• Chemical synthesis – complex
structure/specific stereochemical
requirements
• Cell or organ culture: attractive alternative
• But limited commercial success because of
empirical nature of selecting high-yielding,
stable cultures and lack of biosynthetic
pathway and its regulation
11. Production limitation
Treatment of undifferentiated cells with
elicitors such as methyljasmonate, salicylic
acid, chitosan and heavy metals
Organ culture: Hairy root (alkaloids) or shooty
teratoma (tumor-like) cultures monoterpenes
12. • Shikonin from Lithospermum erythrorhizon
• Berberine from Coptis japonica
• Rosmarinin acid from Coleus blumeii
• Sanguinarine from Papaver somniferum
• Paclitaxel from Taxus brevifolia
• Bottlenecks – low productivity, process
technological issues (Bioreactor design,
cultivation conditions)
• Functional genomics – Newer opportunities
13.
14. Plasma membrane like shipping/receiving department regulates
what enters and leaves the cell, where cell makes contact with the
external environment
Nucleus is like CEO controls all cell activity, determines what
proteins will be made
Cytoplasm like factory floor contains the organelles, site of most
cell activity
ER like assembly line where ribosomes do their work
Ribosomes like workers in the assembly line build the proteins
Golgi apparatus like finishing/packaging department prepare
proteins for use or export
Lysosomes like maintenance crew responsible for breaking down
and absorbing materials taken in by the cell
Cytoskeleton like support beams (walls, ceilings, floors) maintains
cell shape
Mitochondria /chloroplasts like power plant transforms one form
of energy into another
15. Saponins – plant constituent which bring
about frothing in an aqueous solution.
Historically used for their detergent
properties.
Saponins = glycosides
Saponins have haemolytic properties
when injected into the blood stream are
highly toxic (used as an arrow poisons).
When taken orally, saponins are harmless.
2 Types of saponins are recognized –
pentacyclic triterpenoid and steroidal types.
16. Therefore hydrolyzed (by acids) to give an aglycone
and different sugars related to uronic acids.
Aglycone called sapogenin (insoluble in water).
Structure of the sapogenin (aglycone) determines
the type of saponin
(steroidal or tetracyclic triterpenoid and pentacyclic
types).
Both types of glycosides have a glycosidal linkage
at C-3.
Both types of saponins have a common biogenic
origin (mevalonic acid and isoprenoid units)
17. Also called tetracyclic
triterpenoids
Found in many
monocotyledons such
as Wild yam (Dioscorea
vilosa).
Saponin – Diosgenin.
Also found in
dicotyledons
fenugreek.
Strophanthus and
Digitalis contain both
steroidal saponins
(glycosides) and
cardiac glycosides.
18. Generate much interest
due to their
relationship with
compounds such as
sex hormones,
cortisone, diuretic
steroids, vitamin D and
the cardiac glycosides.
Some are used as
starting materials for
the synthesis of these
compounds.
Diosgenin is the main
sapogenin used by
industry .
19. Formed via the
mevalonic acid
pathway.
During this
pathway,
cholesterol forms
part of numerous
sapogenins (not
all).
20. Natural products serve as starting points for
the partial synthesis of commercial
products.
E.g. Cortisone – synthesized from Hecogenin.
Sex horomones (oral contraceptives) –
synthesized from diosgenin.
Diosgenin can also be used to make
corticosteriods.
21. Wild yam is a plant. It contains a chemical,
diosgenin, which can be made in the
laboratory into various steroids, such as
estrogen and dehydroepiandrosterone (DHEA)
There are over 600 species of wild yam. Some
species are grown specifically as a source of
diosgenin for laboratories to use in making
steroids. These species are generally not
eaten due to a bitter flavor.
Only about 12 of the 600 species are
considered edible
Dr. Lili AnnSMM4999 - Literature Review 21
22. Dehydroepiandrosterone (DHEA, more
correctly didehydroepiandrosterone; brand
name Ovigyn-d, Ovaflo, Fidelin, Ovomax), also
known as androstenolone or prasterone (INN), as
well as 3β-hydroxyandrost-5-en-17-one or 5-
androsten-3β-ol-17-one, is an
important endogenous steroid hormone
Dr. Lili AnnSMM4999 - Literature Review 22
23. Insufficient evidence to rate effectiveness for...
Use as a natural alternative to estrogens.
Postmenopausal vaginal dryness.
PMS (Premenstrual syndrome).
Weak bones (osteoporosis).
Increasing energy and sexual desire in men and
women.
Gallbladder problems.
Painful menstrual periods.
Rheumatoid arthritis.
Infertility.
Menstrual disorders.
Other conditions.
Dr. Lili AnnSMM4999 - Literature Review 23
24. In 1961, the Vikhroli factory started manufacturing
diosgenin. This heralded the manufacture of several steroids
and hormones derived from diosgenin
26. The total turnover of bulk steroids in the
world is estimated to be about 500 million US
dollars and estimated world usage to be
somewhere between 550-650tones of
diosgenin.
Dr. Lili AnnSMM4999 - Literature Review 26
27. .
It occurs throughout the North Western
Himalayas extending from Kashmir and Punjab
eastwards to Nepal and China at the altitude of
900-3000 meters above msl. It completes
growthcycle in five years. It is an extensive
climber with unarmed stem twining to the left.
Leaves alternate,rhizome horizontal, scattered
roots, skin light brown. Part used is rhizome and
harvesting is done afterthree years during
December, at dormant stage. Diosgenin varies
from 2-5% on dry weight basis.
Dr. Lili AnnSMM4999 - Literature Review 27
28. The plant occurs in wet parts of Eastern
Himalayas including North Bihar, West
Bengal,Nepal, Sikkim, Bhutan and Abhore hills
upto 5500 meters and prefer well drained
soils particularlyriver banks. It is a climber
with smooth or slightly ridged, unarmed stem
twining to the left. Leavesare alternate or
rarely opposite. Part used is rhizome which is
short rather stout, gray brown to nearlyblack,
creeping horizontally. Diosgenin varies
between 2-5% on dry weight basis
Dr. Lili AnnSMM4999 - Literature Review 28
29. Definition: Wild yam is
the underground roots
and tubers of
Dioscorea villosa.
There is no suggestion
that the plant was used
as a contraceptive in
the past. It has,
however traditionally
been used to treat
menstrual, ovarian &
labour pains.
30. Constituents
◦ Steroidal saponins
(mainly dioscin)
◦ Phytosterols, alkaloids,
tannins, starch.
Actions:
◦ Anti-spasmodic, anti-
inflammatory, anti-
rheumatic, diaphoretic,
diuretic, qi tonic,
expectorant
OTHER USES
In Zulu traditions, wild yam
is used to treat convulsions,
epilepsy and hysteria.
Also used for colic, dry
cough, depression,
diarrhoea, diabetes,
emotional weakness,
immune weakness, IBS, leg
pain, low sperm count, lung
weakness, morning
sickness, neuralgia, night
sweats, RA, senility,
spermatorrhoea, threatened
miscarriage.
Topically: salve for eczema,
poultice for bruises and
scabies.
32. Dr. Lili AnnSMM4999 - Literature Review 32
Steroidal Saponins:
These saponins are less widely distributed in nature than the
pentacyclic triterpenoid type. Phytochemical surveys have shown their
presence in many monocotyledonous families, particularly the
Dioscoreaceae (e.g. Dioscorea spp.), Amaryllidaceae (e.g. Agave spp.)
and Liliaceae (e.g. Yucca and Trilluim spp.). In the dicotyledons, the
occurrence of diosgenin in fenugreek is of potential importance.
35. Diosgenin after converted into 16-Dehydropregnenolon acetate is most
widely used as an active ingredient in preparation of many steroid drugs, sex
hormones and oral contraceptive pills
36. Progesterone, the steroidal triterpenoid of Dioscorea, plays a imp role
in pharma companies.
Progesterone plays a major role in pharmaceuticals by being a
significant component of birth control pills to prevent women
from becoming pregnant.
Progesterone can be biosynthetically
produced from steroidal diosgenin, which
originates from triterpenoids. Diosgenin
undergoes acetylation to make 2. It then
oxides to produce 3 and performs ester
hydrolysis to form dehydropregnenolone
acetate 4. Afterwards, hydrogenation
turns 4 into pregnenolone acetate 5.
Then a hydroxyl group is added to
replace the -OAc group to form
pregnenolone 6. Lastly, Oppenauer
oxidation and tautomerism occurs to
produce progesterone.18 This reaction is
very similar to converting cholesterol
converting into progesterone based on the
fact that both reactions rely on oxidation to
form progesterone.19 A study has proven
that pregenolone and progesterone can
also be biosynthesized by yeast.
37. Progesterone had and still does play a major role in the
pharmaceutical world of birth control. Millions of
women use
it to prevent pregnancy. Preventing pregnancy is not the
only
benefit of using birth control pills. It also reduces acne,
protects against certain types of cancer related to the
reproductive system, adjusts and keeps the menstrual
cycle in
order, etc. On the other hand, there are negative side
effects
such as weight gain, headaches, etc.
Dr. Lili AnnSMM4999 - Literature Review 37
38. Steroids were very expensive and difficult to extract
for medical purposes back in the early 20th
century [14]. In fact, forty oxen were required to get
enough cortisone to treat one patient for one
day [14]. Also, it took 50,000 cows to yield twenty
milligrams of progesterone!!! [14] After diosgenin
from wild yam was able to be synthesized into human
steroids such as progesterone and estrogen, the cost
dropped significantly and steroids were
affordable [14]. Since progesterone is one of the
major components of birth control, wild yam
provided the precursor to the first affordable birth
control pills [14]. And it saved a lot of cows!!!
39. All steroid hormones are biologically derived
from the essential precursor, cholesterol, the
most commonly occurring steroid. Despite its
bad reputation in promoting heart disease,
cholesterol and its metabolism is pivotal in
good health.
Cholesterol is found in all living organisms
including blue-green algae and bacteria.
Plant tissues contain low levels of cholesterol
while animal products are rich sources of
cholesterol.
40. The natural pathway to steroid formation
begins with the conversion of cholesterol to
pregnenolone, the common intermediate in
steroid synthesis. Pregnenolone is then
converted into the specific steroid based on
the tissue where this occurs
41. The pharmaceutical synthesis of steroids begins
with diosgenin being converted into
progesterone. Progesterone can then be modified
to create a wide range of steroid products
including birth control pills, hormone
replacement therapies, cortisone injections as
well as the anabolic steroids described above.
Awareness of this process has led dietary
supplement manufacturers to exploit this
knowledge by adding wild Mexican yam extracts
to their bodybuilding stacks in the expectation
that the body can also convert diosgenin into
pregnenolone where it can be used in the
formation of androgen steroids.
42. The Marker degradation is a three-step synthetic
route in steroid chemistry developed by American
chemist Russell Earl Marker in 1938–40. It is used
for the production of cortisone and mammalian
sex hormones (progesterone, estradiol, etc.)
from plant steroids, and established Mexico as a
world center for steroid production in the years
immediately after World War II.[1] The discovery of
the Marker degradation allowed the production
of substantial quantities of steroid hormones for
the first time, and was fundamental in the
development of the contraceptive
pill and corticosteroid anti-inflammatory drugs.
43. The first large-scale application of the route
took place in 1943, when Russell Earl
Marker collected 10 tons of yam tubers to
synthesize 3 kilograms (6.6 lb)
of progesterone, which was the largest single
amount of progesterone that had been
produced by that time. That single batch had
a value of US$240,000 (approximately $3
million in 2009) at the time it was
synthesized.
44. One person who was keenly aware of plant saponins was Russell
Marker, a maverick biochemist. In 1939 he published a study on
sarsasapogenin, the saponin in Smilax used to make sarsaparilla.
The next year he published studies on diosgenin, a saponin
isolated from a Mexican yam species of the genus Dioscorea.
From diosgenin he was able to synthesize the human hormone
testosterone in eight steps and progesterone in just five steps.
Marker made plans to use yams for mass production of human
steroids, but proposals were rejected by the pharmaceutical
companies, who saw no need for the venture. So in mid-1942,
Marker got an indefinite separation from his wife and went to
live in Mexico. In Mexico he set up a laboratory in his room to
make steroids from yams. Marker worked round-the-clock for
several weeks to make progesterone. Then he offered the
progesterone for sale to a businessman in Mexico City, who
offered him $80 per gram. However, the businessman was in
shock when Marker handed him two kilograms of the stuff
($160,000), which he had produced in such a short time.
Dr. Lili AnnSMM4999 - Literature Review 44
45. A company called Syntex was then organized to
make steroids from Mexican yams, using the
syntheses invented by Marker. After a while, the
maverick Marker left the company, but he left
also with the secret of a crucial step in the
process. Shortly after, Syntex hired Dr. George
Rosenkranz, who went to Mexico and figured out
the missing step. Rosenkranz took yams and was
able to make progesterone, then testosterone,
and finally the female hormone esterone.
Rosenkranz is credited with the saying, "Adam
goes into the test tube and Eve comes out."
Dr. Lili AnnSMM4999 - Literature Review 45
