bitter principles lec.-2

Bitter Principles

Lecture-2

By

Dr. Ahmed Metwaly

Objectives:• Sesquiterpene Lactones

I. Artemisinin

1. Biological Sources

2. Chemical structure

3. Biosynthesis

4. Uses

5. Dosing

6. Mechanism of action

II. Elephantopin

1. Biological Sources

2. Chemical structure

3. Uses

• Diterpenes

I. Columbin

1. Biological Sources

2. Chemical structure

3. Uses

II. Forskolin

1. Biological Sources

2. Chemical structure

3. Uses

• Triterpenes

I. Quassin

1. Biological Sources

2. Chemical structure

3. Isolation

4. Characteristic Features

5. Uses

6. Toxicity

7. Test for identification

II. Limonin

1. Biological Sources

2. Chemical structure

3. Uses

Artemisinin

Structure;

A characteristic feature in the structure of artemisinin is the

presence of an endoperoxide moiety which is essential for the

antimalarial activity.

Chemical name;(3R,5aS,6R,8aS,9R,12S,12aR)-Octahydro-3,6,9-trimethyl-3,12-epoxy-

12H-pyrano[4,3-j]-1,2-benzodioxepin-10(3H)-one

Biological Source;

It is obtained from the

leaves and the closed,

unexpanded flower heads of

Artemisia annuna Linn.,

family Asteraceae.

Artemisia annuna

This particular herb has been used in the Chinese system of

medicine exclusively for the treatment of malaria since more

than one thousand years.

A characteristic feature in the structure of artemisinin is the

presence of an endoperoxide, artemisinin was isolated and

identified in 1972.

To date, Artemisinin and its simple derivatives have been

tested in China to treat more than 1.5 million, patients

suffering from malaria and particularly cerebral malaria; and it

has been shown to be valuable and effective against resistant

strains of Plasmodium

Biosynthesis in A. annua

Uses;

• Artemisinin is an excellent antimalarial, approximately

equal in potency to chloroquine. There are two reasons for

the great interest being shown in artemisinin and its

derivatives.

a- Active against chloroquine resistant strains of Plasmodium

falciparum.

b- The high lipid solubility ensures rapid penetration into CNS;

so it’s a first-line drug for the treatment of cerebral malaria

caused by P. falciparun, which is otherwise fatal.

Dosing;

Artemisinin and derivatives have half-lives on the

order of an hour. Therefore, they require at least

daily dosing over several days. For example, the

WHO-approved adult dose of co-artemether is

four tablets at 0, 8, 24, 36, 48, and 60 hours (six

doses)

Mechanis of Action;

The drug has a high affinity for hemozoin, a storage form of

haem which is retained by the parasite after digestion of

hemoglobin, leading to a highly selective accumulation of the

drug in the parasite. Artemisinin then decomposes in the

presence of iron, probably from hemozoin and releases free

radicals (hydrogen peroxide) which kill the parasite. The

peroxide bridge is therefore a crucial part of the drug molecule as

was suspected from structure activity studies

Modifications in Structure;

On account of the poor water solubility of artemisinin an

attempt was made to improve either its water solubility ir its

lipid solubility. In the former instance, Sodium artesunate i.e.,

the sodium salt of its hemisuccinate ester was developed; while

in the latter instance,

Artemether i.e., its corresponding methyl ether analogue was

produced. Evidently, sodium artesunate is employed for

intraveneous injections and artemether is used as a potent long

acting drug.

The WHO has recommended artemisinin combination

therapies (ACT) be the first-line therapy for P. falciparum

malaria worldwide. Combinations are effective because the

artemisinin component kills the majority of parasites at the

start of the treatment, while the more slowly eliminated

partner drug clears the remaining parasites.

Several fixed-dose ACTs are now available containing an

artemisinin component and a partner drug which has a long

half-life, such as mefloquine (ASMQ), lumefantrine

(Coartem), amodiaquine (ASAQ), piperaquine (Duo-

Cotecxin), and pyronaridine (Pyramax).

Elephantopin

Structure;

Elephantopin is a sesquiterpene lactone containing two lactone

rings and an epoxide function.

Chemical name;

(1aR,8S,8aR,11aS,11bR)-1a-Methyl-9-methylene-5,10-dioxo-

2,3,5,7,8,8a,9,10,11a,11b-decahydro-1aH-3,6-(metheno)furo[2,3-

f]oxireno[2,3-d][1]oxacycloundecin-8-yl methacrylate

Biological source;

Elephantopin is obtained from Elephantopus elatus,

Family Compositae

Elephantopus elatus

Uses:

Elephantopin has been shown to have an antitumour activity.

CoIumbin

Structure;

Columbin is a furanoditerpene

Biological Source;

Calumba which is dried sliced roots of Jateorhiza palmata ,

Family Menispermaceae

Jateorhiza palmata

Uses:

Calumba is used as a bitter tonic. It contains no tannin, so it

may be prescribed with iron salts. In the BHP, it is specifically

indicated for anorexia and flatulent dyspepsia.

Forskolin (Coleonol)

Forskolin is a recently discovered labdane diterpene that

originates from the Ayruvidic system of medicine.

(3R,4aR,5S,6S,6aS,10S,10aR,10bS)-6,10,10b-trihydroxy-3,4a,7,7,10a-

pentamethyl-1- oxo-3- vinyldodecahydro-1H- benzo[f]chromen-5- yl acetate

Biological source;

from the Indian Coleus plant (Coleus forskohlii)

Coleus forskohlii

Uses;

• Forskolin has been demonstrated to have hypotensive,

cardiotonic and platelet aggregation inhibitory activity;

because of its adenylate cyclase stimulant activity, it is

considered a promising drug for the treatment of glaucoma,

congestive cardiopathy and asthma.

• Forskolin is now obtained from the cell culture, is being

marketed in Japan (hypotensive and spasmolytic).

• Forskolin activates the enzyme adenylyl cyclase and

increases intracellular levels of cAMP. cAMP is an

important second messenger necessary for the proper

biological response of cells to hormones and other

extracellular signals.

Quassin

Chemical name: (3aS,6aR,7aS,8S,11aS,11bS,11cS) -1,3a,4,5,6a,7,7a,8,11,

11a,11b,11c-dodecahydro-2,10-dimethoxy-3,8,11a,11c- tetramethyldibenzo[de,g]

chromene-1,5,11-trione

Structure ;

Quassin is an intensely bitter oxygenated triterpenoid

characterized by having a lactone structure. Quassin and related

compounds constitute the group of quassinoids or amaroids

Biological source:

Quassin is the main constituent

of quassia wood, which is the

stem wood of Picrasma excelsa

known in commerce as Jamaica

quassia or of Quassia amara

known in commerce as Surinam

Quassia family Simarubaceae .

Quassia amara

Isolation;

• The aqueous decoction of t wood is concentrated and

neutralized with Na2CO3.

• Tannic acid solution is added gradually, until no more

precipitate is formed.

• The precipitate is collected, triturated with lead carbonate

(to form lead tannate and liberate quassin) then dried on a

water bath.

• The produced mass is powdered and repeatedly extracted

with alcohol 80 %.

• The combined alcoholic extracts are concentrated and left

to allow crystallization of quassin.

Characteristic Features;

Quassin is obtained as rectangular plates from dilute methanol

having mp 222°C.

2. Its specific optical rotation [α]20 D + 34.5° (C = 5.0 g in

CHCl3).

3. It has uvmax: ~ 255 nm (ε ~ 11,650).

4. It is extremely bitter; and it has the bitterness threshold 1 :

60,000.

5. It is found to be freely soluble in benzene, acetone, ethanol,

chloroform, pyridine, acetic acid, hot ethyl acetate; and

sparingly soluble in ether and petroleum ether.

Test for Identification;

• Add concentrated H2SO4 and sucrose to few crystals of

quassin, a red color is produced.

• An alcoholic solution of quassin gives crimson color with

phloroglucin and HCl.

Uses;

• Quassia wood extract is used as a bitter tonic.

• The drug has anthelmintic properties, and is administered as

enema for expulsion of threadworms.

• It also used as insecticide.

Limonin

Structure;

Limonin is a modified triterpenid compound belonging to

the class of limonoids with or derived from a 4,4,8-trimethyl-17-

furanylsteroid skeleton.

Limonoids constitute a group of secondary metabolites

which are commonly found in the order Rutales mostly in family

Meliaceae and less frequently in the Rutaceae

Biological source;

• Limonin is isolated from the pericarp of Citrus limonis and

other Citrus species (Rutaceae).

• It occurs in the fruits and its juice as a non-bitter monolactone

precursor which undergoes further lactonisation with

formation of a second lactone ring to yield limonin

Citrus limonis

Uses;

• Limonoids act as insecticides, insect growth regulators and

insect antifeedants.

• They have antibacterial, antifungal and antiviral properties.

• They have possible anticarcinogenic activity.

Summary:• Sesquiterpene Lactones

I. Artemisinin

1. Biological Sources

2. Chemical structure

3. Biosynthesis

4. Uses

5. Dosing

6. Mechanism of action

II. Elephantopin

1. Biological Sources

2. Chemical structure

3. Uses

• Diterpenes

I. Columbin

1. Biological Sources

2. Chemical structure

3. Uses

II. Forskolin

1. Biological Sources

2. Chemical structure

3. Uses

• Triterpenes

I. Quassin

1. Biological Sources

2. Chemical structure

3. Isolation

4. Characteristic Features

5. Uses

6. Toxicity

7. Test for identification

II. Limonin

1. Biological Sources

2. Chemical structure

3. Uses

First Quiz (5marks)

Mention a natural drug can be used as a treatment for;

1. Threadworm

2. Roundworm

3. Hypertension

4. Anorexia

5. Cerebral malaria