Triterpenoid

Triterpinoids• Derived from two molecules of farnesyl  PP joined

together to produce the precursor Squalene • The pharmaceutically most important are the

pentacyclic triterpinoids (also called saponins) • There are two types of saponins1- Pentacyclic Triterpenoids 2- Steroidal Saponins.• The saponins are soap like. They are glycosides

consisting of a large algycone (sapogenin) (non-polar) and a sugar molecule (polar). This dual nature leads to surface activity: Plants containing saponins have long been used for their detergent properties

Representative TriterpeneRepresentative Triterpene

SqualeneSqualene(shark liver oil)(shark liver oil)

tail-to-tail linkage of the two central isoprene unitstail-to-tail linkage of the two central isoprene units

OPPFPP

FPP

allylic cation

squalene

squalene

lanostterol

HO

1. Pentacyclic triterpenoids• The pentacyclic triterpenoid skeleton exemplified by lupeol, α-

amyrin and β-amyrin are encountered in the form of triterpenes saponins structure.

• Glycyrrhizic acid has been used in the treatment of gastric and duodenal ulcers

• Obtained from liquorice (licorice), which is the dried, unpeeled root of the herb Glycyrrhiza glabra (Fabaceae).

• A number of varieties exist including Spanish, Russian and Manchurian liquorice. G. glabra originated from the Mediterranean and the Middle East, and has been cultivated in Europe since the 16th century.

• Extract contains up to 12% glycerrhizic acid, up to 2% flavonoids, and up to 15% of sugars

HO

b-amyrin

HO

a-amyrinβ-amyrin α-amyrin

• Glycyrrhizic acid is the major triterpenoid saponin in licorice root and the main sweetener of the herb.

• The saponin is used frequently as a tool for recognizing the herb and has been obtained from G. glabra, G. uralensis, G. inflata, G. aspera, G. korshinskyi, and G. eurycarpa, materials of licorice extract .

• Following extraction, the herb yields the licorice products of commerce that are used as sweetening agents; flavoring for American-type tobaccos, chewing gums, candies,

• Phenolic constituents of Glycyrrhiza species

• The main phenols of licorice are glycosides of liquiritigenin (4′,7-dihydroxyflavanone) and isoliquiritigenin(2′,4,4′-trihydroxychalcone), e.g., liquiritin, isoliquiritin, liquiritin apioside, licuraside.

• As minor phenolic compounds, many isoprenoid-substituted flavonoids, chromenes, coumarins, dihydrostilbenes,and dihydrophenanthrenes were isolated from Glycyrrhiza species. Some of them characterized each plant .

• Glycyrrhizic (or glycyrrhizinic) acid is a diglucuronide of the aglycone glycyrrhetic (glycyrrhetinic) acid. The bright yellow colour of liquorice root is provided by flavonoids (1-1.5%), including liquiritin and isoliquiritin, and their corresponding aglycones .

• Considerable amounts (5-15%) of sugars (glucose and sucrose) are also present.

• Glycyrrhizin is reported to be 50-150 times as sweet as sucrose, and liquorice has thus long been used in pharmacy to mask the taste of bitter drugs. Its surfactant properties have also been exploited in various formulations, as have its demulcent and mild expectorant properties.

• More recently; some corticosteroid-like activity has been recognized, liquorice extracts displaying mild anti-inflammatory and mineralocorticoid activities. These have been exploited in the treatment of rheumatoid arthritis, Addison's disease (chronic adrenocortical insufficiency) and various inflammatory conditions.

• Glycyrrhetic acid has been implicated in these activities, and has been found to inhibit enzymes that catalyse the conversion of prostaglandins and glucocorticoids into inactive metabolites.

The structure of glycyrrhetinic acid is close to that of cortisone. Both molecules are flat and similar at position 3 and 11. This might be the basis for licorice's anti-inflammatory action.

• This results in increased levels of prostaglandins, e.g. PGE2 and PGF2α, and of hydrocortisone .

• Perhaps the most important current application is to give systematic relief from peptic ulcers by promoting healing through increased prostaglandin activity.

• A semi-synthetic derivative of glycyrrhetinic acid, the hemisuccinate carbenoxolone sodium , is now widely prescribed for the treatment of gastric ulcers, and also duodenal ulcers.

• The mineralocorticoid effects (sodium and water retention) may exacerbate hypertension and cardiac problems.

• Surprisingly, a deglycyrrhizinized liquorice preparation is also marketed for treatment of peptic ulcers, but its efficiency has been questioned.

Ginseng

• The roots of the herbaceous plants Panax ginseng (Araliaceae) from China, Korea and Russia, and related Panax species have been widely used for the treatment of a number of diseases, including anaemia, diabetes, gastritis, insomnia, and sexual impotence, and as a general restorative.

• The dried and usually peeled root provides white ginseng, whereas red ginseng is obtained by steaming the root, this process generating a reddish-brown caramel-like colour.

• Ginseng is classified as an 'adaptogen', helping the body to adapt to stress, improving stamina and concentration, and providing a normalizing and restorative effect. It is also widely promoted as an aphrodisiac.

• Long-term use of ginseng can lead to symptoms similar to those of corticosteroid poisoning, including hypertension, nervousness and sleeplessness in some subjects, yet hypotension and tranquillizing effects in others.

• It contains a large number of triterpenoid saponins based on the dammarane subgroup, saponins that have been termed ginsenosides, or panaxo-sides.

• These are derivatives of two main aglycones, protopanaxadiol and protopanaxatriol, though the aglycones liberated on acid hydrolysis are panaxadiol and panaxatriol respectively.

• Sugars are present in the saponins on the 3- and 20-hydroxyls in the diol series, and the 6- and 20-hydroxyls in the triol series.

• Over 25 ginsenosides have been characterized from the different varieties of ginseng, with ginsenoside Rb-1 of the diol series typically being the most abundant constituent. Ginsenoside Rg-1 is usually the major component representative of the triol series.

Actions and Uses• Ginseng has been found to: - protect the body & nervous system from stress- stimulate & increase metabolic function- increase physical & mental efficiency- lower blood pressure & glucose levels when they are

high, and raise them (blood pressure & glucose levels) when they are low.

• The German Commission E approved ginseng as a tonic for invigoration and fortification in times of fatigue and debility or declining capacity for work and concentration. Also approved ginseng for use during convalescence.

2 .Modified Triterpenoids

• Modifications that lead to loss of several skeletal carbon atoms (e.g. steroids).

• Steroids are modified triterpenoids containing the tetracyclic ring system of lanosterol but lacking methyl groups at C-4 and 14. Cholesterol is the basic structure but modifications lead to:

a. steroidal saponins,

b. cardioactive glycosides,

c. bile acids,

d. corticosteroids.

squalene

lanostterol

HO

Lanosterol

2.a. Steroidal saponins

• Examples of this group include Sarsaparilla and Diosgenin

• The steroidal saponins are much less widely distributed in nature than the pentacyclic triterpenoid saponins.

• Plant steroidal sapogenins (aglycones) are often used as starting materials for the synthesis of the sex hormones (testosterone, oestrogen, progesterone), corticosteroids and mineralocorticoids

• Diosgenin, obtained from the tubers of the vine-like Yams or Dioscorea. An important food in many countries (like potatoes)

• A variety of species exist, including Dioscorea alata (water yam), Dioscorea batatas (Chinese yam), Dioscorea villosa (Wild Yam).

• Chinese yam is seen as a sweet soothing herb that stimulates the stomach and spleen and has a tonic effect on the lungs and kidneys. 

• Wild yam root has been used for hundreds of years to treat rheumatism and arthritis-like ailments.

• Tubers are chopped, fermented for a few days and then heated in aqueous acid. The Sapogenins (primarily Diosgenin) are then solvent extracted.

• Hecogenin, another precursor is obtained commercially from Sisal leaves (Agova sisalone)

• Demand for diosgenin is very high, around 10,000 tonnes of tuber each year 

• Without the yams, the pharmaceutical industry would not be able to meet the worldwide demand for synthetic corticosteroids

Sarsaparilla • Sarsaparilla was traditionally used as a blood purifier

and anti-rheumatic by many herbalists.• Sarsaparilla was introduced into Europe as a treatment

for syphilis.• Also found to be useful in scaling skin conditions such

as psoriasis.• Also used as flavored-drink. Sarsaparilla was formerly a

major flavoring agent in root beer. These days most added flavorings are artificial (especially in Asia).

• Consisting of the dried roots of Smilax aristochiaefolia (Mexican), Smilax regelii (Honduran) and Smilax febrifuga (Ecuadorian).

constituents

• The roots contain up to 2.4% steroidal saponins mainly the glycosides of sarsasapogenin and smilagenin.

• Sarsasopogenin has also potential as a precursor for steroid production

2.b. Steroids

The conversion of oxidosqualene into sterols

Mechanism

O

OH

O

OH

H

HH

lanosterol

squalene oxide

+

enzyme

Biosynthesis of isoprenoids

The conversion of squalene into sterols

O

OH

OH

H H

OH

H

OH

H

H H

OH

H

H H

lanosterolsqualene oxidecholesterol

animals

animals, fungi

cycloartenol

plants

plant sterols

fungi

ergosterol

i.a.

sitosterol

OCS*

*OCS oxidosqualene cyclase

The conversion of oxidosqualene into sterols

Mechanism

The cyclisation behaves as a concerted process: the stereochemistry of the C-C double bonds is preserved in the primary cyclization product. This is a general rule, known as the Stork-Eschenmoser hypothesis. It can be mimicked to some extent by simple chemical means.

Biosynthesis of steroids

The conversion of lanosterol into cholesterol

OH

OHH H

OH OH

OHOHH H

OHH H

H

OHH H

H

lanosterol

cholesterol

zymosterol

desmosterol

P450-14DM(lanosterol14a-demethylase,CYP51)

sterol14-reductase

sterol4,4-demethylase

sterol- 7, 8-isomerasesterol-C5-

desaturase

sterol- 7-reductase

sterol- 24-reductase

Structure of Cholesterol •Fundamental framework of steroids is the tetracyclic unit shown.

Structure of Cholesterol

•Cholesterol has the fundamental steroid skeleton modified as shown.

HOHO

CHCH33

HH

HH

HH

CHCH33

CHCH33 CHCH33

CHCH33

Cholesterol

•Cholesterol is the biosynthetic precursor to a large number of important steroids:

• Bile acidsVitamin DCorticosteroidsSex hormones

Corticosteroids

Cholesterol HOHO

CHCH33

HH

HH

HH

CHCH33

CHCH33 CHCH33

CHCH33

•Enzymatic degradation of the side chain and oxidation of various positions on the steroid skeleton convert cholesterol to corticosteroids.

Cortisol

•Cortisol is the most abundant of the corticosteroids. Enzyme-catalyzed oxidation of cortisol gives cortisone.

OO

CHCH33

HH

HH

HH

CHCH33OOHH

HHOO

OO

OOHH

Cortisone

•Corticosteroids are involved in maintaining electrolyte levels, in the metabolism of carbohydrates, and in mediating the allergic response.

OO

CHCH33

HH

HH

HH

CHCH33OOHH

OO

OO

OOHH

Sex Hormones

Testosterone

• Testosterone is the main male sex hormone.

OO

HH

HH

HH

HH33CC

HH33CCOHOH

Estradiol

• Estradiol is a female sex hormone involved in regulating the menstrual cycle and in reproduction.

HOHO

HH

HH

HH

HH33CCOHOH

Progesterone

•Supresses ovulation during pregnancy.

OO

HH

HH

HH

HH33CC

HH33CCOO

TetraterpenoidsCarotenoids

Carotenoids

•Carotenoids are naturally occurring pigments.•Structurally, carotenoids are tetraterpenes. They have 40 carbons. Two C20 units are linked in a head-to-tail fashion.•Examples are lycopene and -carotene.

Carotenoids

Lycopene (tomatoes)Lycopene (tomatoes) -Carotene (carrots)-Carotene (carrots)

• Examples being Beta-Carotene, Vitamin A1 (retinol), and Vitamin A2 (dehydroretinol)

• Vitamin A2 has 40% of the activity of Vitamin A1• Vitamin A is a fat-soluble vitamin found only in the animal

kingdom, particularly in fish oils• The carotenes are C40 compounds vitamin A precursors

(provitamine) found in the plant kingdom. • They are converted to vitamin A in the small intestine by body

flora.• Hence very small children have a very limited capacity to

effect this conversion.

• Retinol is converted in the gut to cis-retinol. This then binds to opsin in the eye to form rhodopsin. Rhodopsin, when exposed to light triggers an electrical signal

Reference1) Paul, M. Dewick (1997). Medicinal natural products a biosynthetic

approach, 152-216.

2) Lihong Hu, Zhongliang Chen,² Xiaofang Cheng and Yuyuan Xie., Chemistry of ginkgolides: structure±activity relationship as PAF antagonists. Pure Appl. Chem., Vol. 71, No. 6, pp. 1153±1156, 1999.

3) W.-S. Fang* and X.-T. LiangRecent Progress in Structure Activity Relationship and Mechanistic Studiesof Taxol Analogues. Mini-Reviews in Medicinal Chemistry, 2005, 5, 1-12