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• 400,000 higher plant species
• 10% characterized chemically
• One-fourth of pharmaceuticals derived from
plants
• 11% of...
Secondary metabolites have no recognized
role in maintaining fundamental life
processes but have important role in the
int...
• Not clear
• Important for survival of the plants in its
ecosystem
• Antimicrobial, anti-insect, deter potential
predator...
• Based on biosynthetic origins structurally
divided into five major groups
• Polyketides: Acetate-mevalonate
• Isoprenoid...
• Often long, complex multi-step events
catalyzed by various enzymes and still largely
unknown
• Alkaloid biosynthesis: Be...
Vinblastine, vincristine: Madagaskar periwinkle
– Catharanthus roseus
Anticancer – Paclitaxel (Taxol),
podophyllotoxin, ca...
Much greater than any chemical library
Enormous reservoir
‘Omics’-based – functional genomics –
screening
Limited success ...
• Designed organic chemistry enables
optimization of molecular structures – Not
attractive
• 1981-2002: 28% (351) of 1031 ...
• Plants are difficult to cultivate or becoming
endangered
• Chemical synthesis – complex
structure/specific stereochemica...
Production limitation
Treatment of undifferentiated cells with
elicitors such as methyljasmonate, salicylic
acid, chitosan...
• Shikonin from Lithospermum erythrorhizon
• Berberine from Coptis japonica
• Rosmarinin acid from Coleus blumeii
• Sangui...
Plasma membrane like shipping/receiving department regulates
what enters and leaves the cell, where cell makes contact wit...
Saponins – plant constituent which bring
about frothing in an aqueous solution.
Historically used for their detergent
prop...
Therefore hydrolyzed (by acids) to give an aglycone
and different sugars related to uronic acids.
Aglycone called sapogeni...
Also called tetracyclic
triterpenoids
Found in many
monocotyledons such
as Wild yam (Dioscorea
vilosa).
Saponin – Diosgeni...
Generate much interest
due to their
relationship with
compounds such as
sex hormones,
cortisone, diuretic
steroids, vitami...
Formed via the
mevalonic acid
pathway.
During this
pathway,
cholesterol forms
part of numerous
sapogenins (not
all).
Natural products serve as starting points for
the partial synthesis of commercial
products.
E.g. Cortisone – synthesized f...
Wild yam is a plant. It contains a chemical,
diosgenin, which can be made in the
laboratory into various steroids, such as...
Dehydroepiandrosterone (DHEA, more
correctly didehydroepiandrosterone; brand
name Ovigyn-d, Ovaflo, Fidelin, Ovomax), also...
Insufficient evidence to rate effectiveness for...
Use as a natural alternative to estrogens.
Postmenopausal vaginal dryne...
In 1961, the Vikhroli factory started manufacturing
diosgenin. This heralded the manufacture of several steroids
and hormo...
Dr. Lili AnnSMM4999 - Literature Review 25
The total turnover of bulk steroids in the
world is estimated to be about 500 million US
dollars and estimated world usage...
.
It occurs throughout the North Western
Himalayas extending from Kashmir and Punjab
eastwards to Nepal and China at the a...
The plant occurs in wet parts of Eastern
Himalayas including North Bihar, West
Bengal,Nepal, Sikkim, Bhutan and Abhore hil...
Definition: Wild yam is
the underground roots
and tubers of
Dioscorea villosa.
There is no suggestion
that the plant was u...
Constituents
◦ Steroidal saponins
(mainly dioscin)
◦ Phytosterols, alkaloids,
tannins, starch.
Actions:
◦ Anti-spasmodic, ...
Dr. Lili AnnSMM4999 - Literature Review 31
Dr. Lili AnnSMM4999 - Literature Review 32
Steroidal Saponins:
These saponins are less widely distributed in nature than t...
Dr. Lili AnnSMM4999 - Literature Review 33
Dr. Lili AnnSMM4999 - Literature Review 34
Diosgenin after converted into 16-Dehydropregnenolon acetate is most
widely used as an active ingredient in preparation of...
Progesterone, the steroidal triterpenoid of Dioscorea, plays a imp role
in pharma companies.
Progesterone plays a major ro...
Progesterone had and still does play a major role in the
pharmaceutical world of birth control. Millions of
women use
it t...
Steroids were very expensive and difficult to extract
for medical purposes back in the early 20th
century [14]. In fact, f...
All steroid hormones are biologically derived
from the essential precursor, cholesterol, the
most commonly occurring stero...
The natural pathway to steroid formation
begins with the conversion of cholesterol to
pregnenolone, the common intermediat...
The pharmaceutical synthesis of steroids begins
with diosgenin being converted into
progesterone. Progesterone can then be...
The Marker degradation is a three-step synthetic
route in steroid chemistry developed by American
chemist Russell Earl Mar...
The first large-scale application of the route
took place in 1943, when Russell Earl
Marker collected 10 tons of yam tuber...
One person who was keenly aware of plant saponins was Russell
Marker, a maverick biochemist. In 1939 he published a study ...
A company called Syntex was then organized to
make steroids from Mexican yams, using the
syntheses invented by Marker. Aft...
Nag chatri - a great place for diosgenin
Nag chatri - a great place for diosgenin
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Nag chatri - a great place for diosgenin

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Nag chatri

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Nag chatri - a great place for diosgenin

  1. 1. • 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)
  2. 2. 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
  3. 3. • 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
  4. 4. • 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
  5. 5. • 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
  6. 6. Vinblastine, vincristine: Madagaskar periwinkle – Catharanthus roseus Anticancer – Paclitaxel (Taxol), podophyllotoxin, camptothecin Analgesic – Morphine Semi-synthetic drugs – steroidal hormones derived from diosgenin – Dioscorea; corticosteroids, contraceptives, sex hormones
  7. 7. Much greater than any chemical library Enormous reservoir ‘Omics’-based – functional genomics – screening Limited success of combinatorial chemistry or computational drug design
  8. 8. • 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
  9. 9. • 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
  10. 10. 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
  11. 11. • 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
  12. 12. 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
  13. 13. 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.
  14. 14. 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)
  15. 15. 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.
  16. 16. 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 .
  17. 17. Formed via the mevalonic acid pathway. During this pathway, cholesterol forms part of numerous sapogenins (not all).
  18. 18. 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.
  19. 19. 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
  20. 20. 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
  21. 21. 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
  22. 22. In 1961, the Vikhroli factory started manufacturing diosgenin. This heralded the manufacture of several steroids and hormones derived from diosgenin
  23. 23. Dr. Lili AnnSMM4999 - Literature Review 25
  24. 24. 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
  25. 25. . 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
  26. 26. 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
  27. 27. 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.
  28. 28. 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.
  29. 29. Dr. Lili AnnSMM4999 - Literature Review 31
  30. 30. 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.
  31. 31. Dr. Lili AnnSMM4999 - Literature Review 33
  32. 32. Dr. Lili AnnSMM4999 - Literature Review 34
  33. 33. 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
  34. 34. 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.
  35. 35. 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
  36. 36. 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!!!
  37. 37. 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.
  38. 38. 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
  39. 39. 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.
  40. 40. 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.
  41. 41. 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.
  42. 42. 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
  43. 43. 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

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