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Prof. Dr. Amani S. Awaad
Professor of PharmacognosyPharmacognosy Department,
College of Pharmacy Salman Bin Abdulaziz
University,
Al-Kharj. KSA.
Email: [email protected]
Pharmacognosy -2
PHG 322
*To recognize what are Anthraquinones
*To memorize Classes of Anthraquinones
*To know Anthraquinones ,types ,structures,
extraction , isolation, identification and
biological activates
To know Coumarin, ,types ,structures,
extraction , isolation, identification and
biological activates
ANTHRAQUINONES
Anthraquinones
are colored substances and many of them are
used technically as dyes
occur in plants, lichen and fungi in different forms at
different oxidation levels;
It have the substituent of hydroxy, hydroxymethyl,
methoxy, carboxyl and so on, and the vast majority
of anthraquinone compounds containing hydroxyl
Anthraquinones
Chemistry & Classification
The anthraquinones in plant can exist in form of liberation
(aglycone) or combined with sugar into (glycosides).
*The degree of oxidation are varies.
*It can be change depending on the pH
i) The aglycones
*The structural variations observed for the aglycones are limited.
*Outside of the fact that two phenolic hydroxyl groups are always
present in the 1- and 8-positions, only the 3- and 6-carbons may be
substituted: the former is always substituted by a carbon of varying
degree of oxidation (methyl, hydroxyl methyl, or carboxyl), and the
latter is sometimes substituted by a phenolic hydroxyl group,
which is either free or etherified by methanol.
This general substitution scheme clearly indicates
that these compounds arise biogenetically from the
condensation of an octa-acetate.
Anthraquinones
Chemistry & Classification
The bond with the aglycone normally involves the phenolic hydroxyl group in the 8-position (in the case of glucose), or the one in the 6-position (in the case of rhamnoseor apiose).
The aglycone may be linked to two sugars; in 6- and 8-postions like glucofrangulin A,
it is not rare for 1,8-dihydroxyanthrones to occur as C-glycosides, with the bond forming between the C-1 of glucose and the C-10 of the aglycone Aloin A
ii) The glycosides.
The sugar of anthraquinone glycosides
mostly is glucose, in addition to rhamnose,
xylose, arabinose and in rare cases apiose
Anthraquinones
Anthraquinones compounds includes;
anthraquinone derivatives as well as
varying degrees of reduction products,
such as; Anthrone, anthranol,
oxanthranol, Dianthrone.
Chemistry & Classification
1
4
9
10
8
5
Anthraquinone
Reduction
Oxidation
OxanthroneAnthrone
O
O
O
OHH
O
HH
Oxidation
Anthranol
OH
tautomerization
ReductionO
O
HH
Dianthrone
-In anthrone (i.e. 10-H-anthracen-9-ones),
carbon 10 is methylene carbon.
- Depending on the pH, anthrones can occur
alongside their tautomeric forms, the
anthranols.
-In practice, anthrones and anthranols are
often designated by the term "reduced forms"
and anthraquinones by that "oxidized forms".
Reduced forms and oxidized forms.
Anthraquinones
Chemistry & Classification
(i)Anthrone & Anthranol
Anthraquinone Anthranol & AnthroneReduction
These reduced anthraquinone derivatives occur either free or combined as glycosides
They are isomeric and one may be partially converted to the other in solution.
OHOH OH
CH3
OOH OH
CH3
(ii) Dianthrone
These are compounds derived from two anthrone molecules,
which may be identical or different.
One of the best known is sennoside derived from two
molecules of glucose and two molecules of rhein-anthrone.
On hydrolysis, sennoside yields the aglycone sennidin
Anthraquinones
Chemistry & Classification
(ii)Oxanthran
These are intermediate products between anthraquinones
and anthranols.
Oxanthrone Anthraquinoneoxidation
Cascarosides A & B. They are both O- and C-glycosides. Each one contain
two sugar unites.
Aloin(Barbaloin) it is formed from the removal of one sugar from
Cascarosides.(a C-glycoside).
O OH
CH2OH
O
RR1
Glc
R= Glc, R1= H Cascaroside A
R= H, R1= Glc Cascaroside B
O
O
OH OH
R2R1
Chrysophanol R1=CH3 R2=H
Emodin R1=CH3 R2=OH
Rheochrysidin R1=CH3 R2=OCH3
Aloe-emodin R1=H R2=CH2OH
Anthraquinones
Anthraquinones are colored, orangy-red.
compounds sparingly soluble in cold water, and soluble in organic solvents and alcohols.
The carboxylic aglycones can be extracted with an aqueous sodium bicarbonate solution.
The glycosides are soluble in water and hydroalcoholic solutions.
Treating O-glycosides in acidic medium causes their hydrolysis, but the cleavage of C-C bond of C-glycosides can only be obtained in the presence of ferric chloride.
The same reagent but in neutral conditions, will achieve the transformation of dianthrones into anthraquinones.
Physico-Chemical Properties
Acid
ic hydro
lysis
+ F
eC
l
Aci
dic
hydro
lysi
s
O OHOH
HO
OH
Anthraquinones
Characterization
For Aglycones:
Extract plant material with organic solvent.
Shake with NH4OH or KOH.
For O-Glycosides:
Boil plant material with dil. HCl for 10 min, filter and shake with
organic solvent (Ether or Benzene). Separate the organic solvent. Shake
with NH4OH or KOH.
For C-Glycosides:
Boil plant material with dil. HCl/FeCl3, filter and shake with organic
solvent (Ether or Benzene).Separate the organic solvent. Shake with
NH4OH or KOH.
For 1,8-dihydroxyanthraquinones,
uses magnesium acetate in methanol. The resulting red color is more
intense and more stable to light than that from the simple reaction with
potassium hydroxide
Positive result indicated by Rose Red colour in the aqueous alkaline layer.
Borntrager’s and Modified Borntrager’s test:
Extraction and separation
Commonly method:
(1) back streaming extraction with ethanol, then remove the solvent by depressed evaporation to get
the crude extract.
(2) extracting with ammonia or 0.1% - 0.5% sodium hydroxide solution at room temperature.
(3) remove the fat-soluble impurities from alkaline extraction with ether.
(4) acidifying the alkaline extraction.
(5) extract the anthraquinones with ether and retrieve solvent.
Anthraquinones
A Extraction
B. Seperation
TLC: PTLC using silica gel plate and different solvent syste
Column chromatography: used absorbent are silica gel,
polyamide, in general aluminium oxide is not applied in
order to avoid irreversible chemical absorption. Sephadex
and reverse silica gel chromatography often have good effect.
Anthraquinones
Extraction and separation
C. Identification
i) UV spectroscopyii) Infrared spectroscopy iii)NMR spectroscopy iv ) Mass spectroscopy
Anthraquinones
Pharmacological Properties
Depending on the dose administered, 1,8-anthraquinone
derivatives exert a more or less violent laxative or purgative
activity.
at therapeutic doses they are stimulant laxatives: the activity
linked to the structure of these compounds: the most interesting
derivatives are the O-glycosides of dianthrones and
anthraquinones, as well as the C-glycosides of anthrones, in
other word the group of compounds without a CH2- in the 10-
position
The activity of the glycosides of monomeric anthrones is excessive, which explains why the drug containing them (for example buckthorn bark) are only used after prolonged storage or after appropriate heat treatment, during which they are oxidized to anthraquinone glycosides.The free aglycones (anthraquinones) are practically active.The free aglycones present in the drug or formed by initial gastric hydrolysis upon reaching the intestine, are absorbed in the small intestine, glucoconjugated in the liver, and almost totally excreted in urine.
Anthraquinones
Pharmacological Properties
The glycoside of anthraquinone and dianthrones are polar molecules,are water soluble- and have a high molecular weight so they are notresorbed nor hydrolyzed in the small intestine.
In the colons they are hydrolyzed by the β-glucosidases of theintestinal flora, and the free anthraquinone are reduced:
Thus the active forms are the anthrones formed in situ, which explainsthe latency observed between compound intake and the laxative effect.
For some authors, anthraquinone glycosides may be consideredprodrugs: the sugars would act as transporters by preventing the activemoiety from being absorbed prior to being freed in the colon under theinfluence of bacterial enzymes
Hydroxyanthraquinone derivatives affect intestinal motility (they
increases peristalsis, particularly in the left colon and in the sigmoid),
and they affect the absorption of water and electrolytes.
By inhibiting the Na-K ATPase activity of enterocytes, they cause an
inhibition of water, sodium and chloride re-sorption, and an increase in
the secretion of potassium at the level of intestinal mucosa
AnthraquinonesAnthraquinones Containing Drugs
Drug Name: Sennae FoliumOdour: Faint, characteristic.Taste: To begin with sweetish, the bitter.Plant Source: Cassia angustifoliaOther Names: SennaHabitat: Cassia species is found in the tropical and subtropical regions of all continents except Europe. Most verities are indigenous to North, Central, and South America.Family: Caesalpiniaceae
Constituents:a. Anthracene derivatives (2.5-3.5%): - Sennoside A, A1 and B as well as sennosides C & D
b. Naphthecene derivatives:6-hydroxymusizin glucoside (0.85% in Cassia senna)Tinnevellin-6-glucosides (0.3% in Cassia angustifolia
Sennae Folium
Anthraquinones
Effects
Laxative Effects
Senna is an anthranoid-type stimulating laxative.The laxative effect is due to the action of sennosides and their active metabolite, rhein anthrone, in the colon.
The laxative effect is realized by inhibition of water and electrolyte absorption from the large intestine, which increases the volume and pressure of the intestinal contents.
This will stimulate colon motility resulting in propulsive contractions.
In addition, stimulation of active chloride secretion increases water and electrolyte content of the intestine. These changes in active electrolyte transport are dependent on calcium in the serosal surface.
The laxative action of senna is partially via stimulation of colonic fluid and electrolyte secretion, and this secretion is mediated by stimulation of endogenous prostaglandin E2 formation.
Sennae Folium
Anthraquinones Containing Drugs
Anthraquinones
Effects
Indications and Usage: Approved by Commission E:
Constipation
Senna is used for constipation and for evacuation of the bowl prior to
diagnostic tests of gastrointestinal and colerctal area.
Contraindications: The drug is not to be administered in the
presence of intestinal obstruction, acute inflammatory intestinal
diseases or appendicitis
Precautions and Adverse Reactions:
General:
Spasmodic gastrointestinal complaints can occur as a side effect to
the drug’s purgative effect or Overdosage.
In rare cases, prolonged use may lead to cardiac arrhythmias,
nephropathies, and edema and accelerated bone deterioration.
Senna abuse has also resulted in tetany, aspartyglucoseamine
excretion, and hypogammaglobulinemia
Anthraquinones Containing DrugsSennae Folium
Anthraquinones
Effects
Electrolyte Abnormalities:
long-term use leads to loss of electrolytes, in particular potassium ions.
As a result of hypokalemia, hyperaldosteronism, albuminuria, hematuria,
inhibition of intestinal motility, and muscle weakness may occur.
Enhancement of cardioactive glycosides and antiarrythmics may also
occur with hypokalemia.
Finger Clubbing: Senna abuse has resulted in finger clubbing, which
was reversible upon discontinuation of the drug.
Cathartic Colon:Anatomic alteration of the colon is seen secondary to chronic use with Senna (more than three times weekly for 1 year or longer). The result is a loss of haustral folds. A finding that suggests neuronal injury or damage to colonic longitudinal musculature.Carcinogenesis: Carcinogenic activity in the colon following long-term administration of anthracene drugs has not yet been fully clarified.Study findings are contraversial regarding the correlation between the administration of anthracene drugs and the frequency of carcinomas in the colon.
Sennae Folium
Anthraquinones Containing Drugs
Anthraquinones
Effects
Melanosis Coli:Prolonged use of Senna may lead to melanosis coli. Precursors of the melanic substance in melanosis coli may be derived from anthranoid laxatives.Occupational Sensitization: IgE-mediated allergy, asthma, and rhinoconjuctivities have been reported after occupational exposure to senna products.Tissue Damage: chronic treatment with anthranoids in high doses reduces vasoactive intestinal polypeptide and somatostatin levels in the colon, which may represent damage to the enteric nervous tissue.
Drug Interactions: Digitalis Glycosides- With prolonged use or abuse of senna, loss of potassium may potentaite digitalis toxicity.Antiarrythmics- Loss of potassium associated with prolonged use of senna may potentiate arrhythmias when given concomitantly with antiarrythmic medications.Estrogen- The serum level of estrogen is decreased when given concomitantly with senna due to the effect of intestinal transit on the absorption of estrogen
Anthraquinones Containing DrugsSennae Folium
Anthraquinones
Effects
Indomethacin (NSAIDS): Indomethacin given concomitantly with senna pod extract had a dose-dependant inhibition of net fluid transport due to the inhibition of prostaglandin E2, which decreases the therapeutic effect of senna.
Nifedipine (Calcium channel blocker)- Therapeutic effects induced by rhein anthrone also involve the calcium channel which can be blocked by nifedipin, but not verapamil.
Pregnancy- The drug should not be used during pregnancy or while nursing.
Pediatric Use- Not to be used by children under 2 years of age. Children between the ages 2-12 years should follow proper dosage recommendations.
Elderly- Elderly patients should initially take half of the normal prescribing dose
Sennae Folium
Anthraquinones Containing Drugs
AnthraquinonesAnthraquinones Containing Drugs
Drug Name: AloeOdour: Characteristic, strong.Taste: Bitter, unpleasantPlant Source: Aloe barbadensis/capensis/veraOther Names: AloeHabitat: Aloe is thought to have originated in the Sudan and Arabian Peninsula. Today the species is cultivated and found in the wild in northern Africa, the near east, Asia and in the southern Mediterranean region. The plant is cultivated in subtropical regions of the United States and Mexico, and on the Dutch Antilles, as well as coastal regionsFamily: Liliacea
Constituents:Aloe barbadensis:Anthracene Derivatives:Anthrone-10-glycosyls ,Aloin A,Aloin B, 7-hydroxyaloins A and B, 1,8-dihydroxy ions, Aloe-emodin, 2-alkylchromones (Flavonoids)2. Compounds: Aloe capensisAnthracene Derivatives:Anthrone-10-glycosyls,Aloin A,Aloin B,5-hydroxyaloin, 1,8-dihydroxy Anthraquinones, Aloe-emodin, Aloinosides A and B, 2-alkylchromones(Flavonoids)
O
R1R2
CH2OR3
OHOH
R1 R2 R3
Aloin A D-glucose H H
Aloinoside A D-glucose H H
Aloin B H D-glucose Rhamnose
Aloinoside B H D-glucose Rhamnose
Aloe
Anthraquinones
Anthraquinones Containing Drugs
Effects: Laxative Effects: Aloe anthranoids such as 1,8-dihydroxy-anthracene derivatives exert a laxative effect. The laxative effect is due to anti-absorption osmotic properties. The compound induces active secretion of electrolytes and water from the lumen of the bowel. Absorption of electrolytes and water from the colon is inhibited resulting in a volume increase. The volume increase of the bowel content leads to an increase in pressure and stimulates intestinal peristalsis.There is some evidence that endogenous nitric oxide modulates the diarrhea effect of aloe. Studies demonstrate a laxative effect 9 hours after ingestion.
Antibacterial/Antiviral effect:Aloe-emodin exerts dose-dependent growth inhibition of H. pylori through inhibition of arylamine N-acetyltransferase (NAT) activity. Aloe-emodin has antibacterial effects on four strains of methicillin-resistant staphylococcus aureus. Aloe-emodin inactivates enveloped viruses and is directly viracidal to herpes simplex virus type 1 and 2 varicella-zoster virus, pseudorabies virus, and influenza virus.Antineoplastic effects:Emodin suppresses tyrosine kinase activity of HER-2/neu-encoded p185neu receptor tyrosine kinase resulting in antineoplastic effects. This is beneficial in controlling HER-2/neu over expressing cancer cells
Aloe
AnthraquinonesAnthraquinones Containing Drugs
Antibacterial/Antiviral effect:Aloe-emodin exerts dose-dependent growth inhibition of H. pylori through inhibition of arylamine N-acetyltransferase (NAT) activity. Aloe-emodin has antibacterial effects on four strains of methicillin-resistant staphylococcus aureus. Aloe-emodin inactivates enveloped viruses and is directly viracidal to herpes simplex virus type 1 and 2 varicella-zoster virus, pseudorabies virus, and influenza virus.
Antineoplastic effects:Emodin suppresses tyrosine kinase activity of HER-2/neu-encoded p185neu receptor tyrosine kinase resulting in antineoplastic effects. This is beneficial in controlling HER-2/neu over expressing cancer cells
The Immunmodulatory restore the UVB- induced damages on epidermal Langerham cells.Aloe vera increase collagen content of the granulation tissue and its degree of cross linking to contribute to wound healing. Aloe vera acts as a modulatory system toward wounds with anti-inflammatory effects.The use of Aloe vera is associated with a delay in wound healing compared to standard treatment.Aloe vera gel exerts anti-inflammatory activity through its inhibitory action on the arachidonic acid pathway via cyclooxygenase.Due to its anti-thromboxane effects, aloe vera decreases the morbidity of progressive dermal ischemia in frostbite. Aloe vera contains a carboxypeptidase that inactivates bradykinin, salicylates, and a substance that inhibits thromboxane formation
Aloe
AnthraquinonesAnthraquinones Containing Drugs
Indications and Usage: Approved by Commission E:
Constipation
Contraindications: aloe is contraindicated in cases of intestinal
obstruction, acutely inflamed intestinal diseases (e.g. Crohn’s
disease, ulcerative colitis), appendicitis and abdominal pain of
unknown origin
Precautions and Adverse Reactions: General:if cramping of gastrointestinal tract after single doses occurs, the dosage should be reduced.Spasmodic gastrointestinal complaints are side effects to the drug’s purgative effect.Heart arrhythmias, nephropathies, edema and accelerated bone deterioration may occur in rare cases.Prolonged use of Aloe may lead to pigmentation in the intestinal mucosa (pseudomelanosis coli), a harmless side effect, which usually reverses upon discontinuation of the drug.Long-term use can also lead to albuminuria and hematuria
Aloe
AnthraquinonesAnthraquinones Containing Drugs
Hypersensitivity: Hypersensitivity, manifested by generalized nummular eczematous and popular dermatitis, has been reported after long-term use of oral and topical Aloe preparations.Loss of Electrolytes: Long-term use can cause loss of electrolytes, in particular potassium. The loss of potassium can result in hyperaldosteronism, inhibition of intestinal motility and enhancement of the effect of cardioactive medications
Malignancy:
Prolonged use of anthracene drugs increases the relative risk of colon
carcinoma.
Recent studies fail to demonstrate a connection between the
administration of anthracene drugs and frequency of carcinomas of the
colon.
Low molecular weight compounds found in Aloe vera gel are
cytotoxic.
The component 1,8-dihydroxyanthraquinone inhibits the catalytic
activity of topoisomerase II resulting in genotoxicity and mutagen
Aloe
Anthraquinones
Anthraquinones Containing Drugs
Tissue Damage: chronic treatment with high doses of Aloe reduces vasoactive intestinal peptide and somatostatin levels, which may damage enteric nervous tissue.
Drug Interactions:Cardiac glycosides and arrhythmic drug- chronic use of Aloe can lead to potassium loss, which can increase the actions of cardiac glycosides and antiarrhythmic drugs.Thiazide diuretics, Loop diuretics, licorice and corticosteroids-there is an increase in the possibility of potassium deficiency when aloe is used along with these agents.
Pregnancy: The drug should not be used during pregnancy.
Pediatric Use: The drug should not be prescribed to children less than 12 years of age.
Aloe
COUMARINS
Coumarins are derivatives of benzo-α-pyrone, or lactones of o-hydroxycinnamic acid (o-coumaric acid).
Coumarine
OO
Coumarine
O O
2-pyrone
OH
OH
O
2'-hydroxy-Z-cinnamic acids
The name coumarine is derived from the Caribbean word “Coumarou” (Dipteryx
odorata Willd., Fabaceae), for the Tonka tree from which coumarine with the
characteristic aroma of new- mown hay was isolated. Un-substituted coumarine
is widespread in nature.
Tonka tree .
Coumarine are 2H-1-benzopyran-2-ones which may be considered, on first
approximation, as the lactones of the 2'-hydroxy-Z-cinnamic acids
Nearly 1000 coumarin have been described, and the simplest among them are
widely distributed in all of the vegetable kingdom. Certain families among
angiosperms produce a wide range of structures: Fabaceae, Asteraceae, and
especially Apiaceae and Rutaceae, in which the most complex molecules occur
Based on the substitution in benzene and pyrone rings.
Most of these naturally occurring lactones are oxygenated at
C-7 position. This substituted is the precursor of the 6,7-di-
and 6,7,8-trihydroxylated coumarins.
CoumarinChemistry & Classification
Accordingly Coumarin can be classified into the following:
i) simple coumarins.
ii) Furanocoumarins.
iii) Pyranocoumarins.
iv) Benzocoumarins.
v) Chromones.
vi) Dicoumarines.
The difference between these classes is the position of the
radical in the coumarin lactone ring, which varies between
C-6, C-7 and C-8.
CoumarinChemistry & Classification
i) Simple coumarins,
Simple coumarins are 5,6-benzene-2-pyrone
skeleton with; hydroxyl, alkoxy, alkyl substituents
both in benzene ring and the pyrone ring.
shikimin (7-O-glucosyl-umbelliferone),
aesculin (7-O-glucosyl-asculetin,,
scoploin (7-O-glycosides-scopletin).
Umbelliferone (7-hydroxy coumarin)
Aesculetin (6,7–dihydroxy coumarin)
Scopoletin (6-methoxy-7-hydroxy-coumarin)
The hydroxyl groups of these simple
coumarins are either methylated, or oftentimes
one of them is engaged in a Glycosidic linkage
7-hydroxy coumarin is the precursor of the
6,7-di- and 6,7,8-trihydroxylated coumarins.
O OR1O
R= H Umbelliferone
R1= Glc Skimin
O O
Coumarin
O OR1O
R= OH aesculin
R1= Glc aesculetin
O OR1O
R= H scoploin
R1= Glc scopoletin
R R
R
CoumarinChemistry & Classification
This group consists of a 5-membered furan
ring attached to the coumarin nucleus,
Furanocoumarins are formed in result of
furan ring and coumarin condensation in;
6,7 positions (psoralen-derivatives) or
7,8 (angelicin-derivatives) or
2’,3’ : 7,8(Bergapten-derivatives)
ii) Furanocoumarins
Furanocoumarins can be exist as;
linear (e.g. psoralen, imperatorin),
and angular (e.g. angelicin, visnadin)
O
Angelicn
OO O
Psoralen
OO O
OCH3
Bergapten
CoumarinChemistry & Classification
iii) pyranocoumarins
Both furano- and pyranocoumarins are natural isomers to coumarin that may be linearly and angularly
prenylated at C-6 and C-8, respectively, in furanochromones and pyranochromones, respectively.
Prenylation in the 6-position yields the so-called "linear" furano- and pyranocoumarins; in the 8-position
it affords the "angular" homologs
Pyranocoumarins are result of condensation of
coumarin with 2’2’-dimethylpyrane in
positions 5,6 (dimethylxantyletin); 6,7 or 7,8
(visnadine) and may have substitutes in any of
rings. 2’2’dimethylxantyletin visnadin
Pyranocoumarins can be exist as;
linear (e.g. Xanthyletin),
and angular (e.g. Seselin, visnadine)
visnadine
O OO
OMe
O OO
Xanthyletin
CoumarinChemistry & Classification
iv)Benzocoumarins
O O
Benzocoumarin
O O
v) Chromones
Chromone (or 1,4-benzopyrone) is a derivative of
benzopyran with a substituted keto group on the pyran
ring. It is an isomer of coumarin.
Derivatives of chromone are collectively known as
chromones.
e.g. 6,7-dimethoxy-2,3-dihydrochromone has been
isolated from Sarcolobus globosus
O
6,7-dimethoxy-2,3-dihydrochromone
H3CO
H3CO
O
Benzocoumarins containing benzyl ring condensed
with coumarin in 3,4 positions
Occurin Anacardiaceae and Rosaceae.
Hydroxyderivative of 3,4-benzocoumarin is a
structural component of ellagic acid. 3,4-
benzocoumarin-hydroxy-derivative
CoumarinChemistry & Classification
vi) Di& tri-coumarins
-It is a phytoalexin formed due to fungal effect
-Dimer of 4-hydroxycoumarin. eg(Dicoumarol).
Daphnoretin
Edgeworoside C Edgeworoside A
Edgeworthia chrysantha
edgeworic acid, was isolated from the flower buds of
Edgeworthia chrysantha
CoumarinProperties, Extraction, and Characterization
Coumarins in the free state are soluble in alcohols and in organic solvents
such as ether and chlorinated solvents, with which they can be extracted.
Their glycosides are more or less soluble in water.
i)Properties
ii)Extraction & purification
Coumarins can be extracted using organic solvents. Isolation can be
carried out using different chromatographic techniques (PTLC,CC,
etc..,
For purification purposes, it is possible to take advantage of the
properties specific to the lactones:
- opening and solubilization in alkaline conditions,
- closing in acidic medium.
Coumarin
ii)Extraction & purification
It is also possible, in some cases, to use sublimation.
However, the applicability of these two procedures is limited by
the risk of including alterations of the original structu
The risk of artifact formation also exists with chromatographic
techniques on classic stationary phases (silica gel),
mainly for acylated coumarins; gel fractionation then becomes
of interest for compounds in the free state as well as glycosides.
Semipreparative HPLC is widely used (on normal and reverse
phase
Properties, Extraction, Characterization and identification
CoumarinProperties, Extraction, Characterization and identification
*Coumarins have a characteristic UV spectrum which is heavily influenced by the
nature and the position of substituents, and by alkalization (KOH,NaOCH3).
*When examined under UV light, TLC spots from coumarin-containing drugs have
colors which are enhanced in the presence of ammonia, and range from blue to yellow
and purple.
*For a quantitative estimate of these compounds within a drug, it is possible to use
spectrofluorimetric technique (after elution of the TLC spots), or, more simply, HPLC
iii)Characterization
iv)Structural identification
i) UV ii) Infrared iii) 13C & 1HNMRiv) Mass
CoumarinPharmacological Properties and Uses
The pharmacological interest of coumarin containing drugs is limited.Aesculin is said to be a venous tonic and vascular protective agent and is sometimes referred to as a "vitamin P factor"
some of them used for symptomatic treatment of venous and lymphatic vessel insufficiency.
Some furanocoumarins are photosensitizers, therefore they are indicated for the therapy of psoriasis andvitiligo.
Visnadin, a pyranocoumarins isolated from khella, has been extracted and marketed for its coronary vasodilator effect and presented as having a favorable action on senile cerebral insufficiency
Coumarin
COUMARIN-CONTAINING DRUGS
Drug Name: Folia Hippocastani
Description: The leaves are long, 5 to 7 palmate, with a 20 cm long grooved petiole. The leaflets are initially red-haired, 20 cm long, cuneate-obovate, acute and dentate. The leaflets are rich green above the beneath are light green.
Plant Source: Aesculus hippocastanum
Other Names: Horse Chestnut
Habitat: Although the herb is indigenous to the mountains of Greece, Bulgaria, northern Iran and the Himalyas, it is cultivated elsewhere, especially in northern Europe including the british Isles. Denmark, Scandanavia and Russia.
Family: Hippocast
Coumarin
COUMARIN-CONTAINING DRUGSConstituents:
Hydroxycoumarins: chief component is
aesculin, in addition fraxetin and scopoletin.
Flavoniods (rutin, quercitrin)
Tannins &. Triterpene saponins
Fraxetin
Effects:
The main active principles of the anti-exudative
effect and improvement of venous tone are
hydroxycoumarins (aesculetin, and frexetin),
triterpene saponins in the petioles and leaf
veins, a flavonoid and a rich supply of tannins.
Although the drug is said to have an anti-
exudative effect and improve venous tone,
there is a lack of clinical data to support the
effect.
Coumarin
COUMARIN-CONTAINING DRUGS
Fraxetin
Indications and Usage:Unproven Uses: Eczema, superfacial and deep varicose veins, leg pains, phlebitis, hemorrhoids, pains before and during menstruation.
Precautions and Adverse Reactions:
General: One case of liver damage following intramuscular administration of an extract of the drug is known.
Drug Interactions: Horse Chestnut leaf has a coumarin component and may interact with warfarin, salicylates and other drugs with anti-coagulant properties
Coumarin
COUMARIN-CONTAINING DRUGS
Drug Name: Meliloti Herba
Odour: Sweetish, of coumarinTaste: bitter, somewhat pungent and salty.Plant Source: Melilotus officinalis (L.) PALL.Other Names: Yellow, sweet, field melilot, yellow sweet cloverHabitat: The plant is found all over Europe, Australia and North America, as well as in temprate regions in Asia.
Compounds: In The Fresh Plant- Coumaric acid glycosides: Melilotoside
Compounds: In The DehydratedFree coumarin (0.4-0.9%): formed from the
coumarinic acids during dehydration, furthermore 3,4-dyhydrocoumarin, melilotol, melilotin.
Hydroxycoumarin: including among othersumbelliferone, scopoletin, herniarin, fraxidin.
Volatile oils, Flavonoids: including among others,kampferol- and quercetin- glycosidesTriterpene saponins
O OMelilotin
O
Glucose
COOH
Melilotoside
Coumarin
COUMARIN-CONTAINING DRUGS
Effects:
The drug is an antiphlogistic, antiexudative and antiedematous effect, which explain its use for inflammatory and congestive edema. It increases venous reflux and improves lymphatic kinetics. Animal experiments showed an increase in healing wounds.
Indications and Usage:
Approved by Commission E:Blunt injuries, Hemorrhoids, Venous conditions
Precautions and Adverse Reactions:
General: Administration of the drug in higher dosages can lead to headache and stupor; transitory liver damage is possible for a very small number of particularly susceptible patients.Elevation of liver enzyme values usually disappears following discontinuance of the drug
Coumarin
COUMARIN-CONTAINING DRUGS
Drug Name: Ammeos visnagae Fructus
Taste: Some what bitter and arpmatic.
Plant Source: Ammi visnaga (L.) LAM.
Other Names: Khella, Bishop’s Weed
Habitat: The plant grows in the Mediterranean
region, and is cultivated in the U.S., Mexico, Chile
and Argentina.
Family: Apiaceae (Umbe
Constituents:
Furanochromones: particularly (Khellin, Visnagin, Khellol and khellol glucosidePyranocoumarins (Visnadin ,Samidin) Volatile Oil ,. Fatty Oil, Flavon
OO
O
O
O
O
O
Samidin
Coumarin
COUMARIN-CONTAINING DRUGS
Effects: The drug intensifies coronary and myocardial circulation, acting as a mild positive ionotrope. It has antispasmodic effect on smooth muscles.
Indications and Usage: Unproven Uses: Bishop’s Weed has been used for angina pectoris, cardiac insufficiency, paroxysmal tachycardia, extrasystolis, hypertonia, asthma, whooping cough and cramp like complaints of the abdomen.
Precautions and Adverse Reactions: Infrequently, a cholestatic jaundice (reversible) is observed following administration of the drug. The drug also possesses a phototoxic effect.
Over dosage: Long-term use or overdose of the drug can lead to queasiness, dizziness, and loss of appetite, headache or sleep disorders. - Very high dosages, corresponding to over 100 mg khellin, may cause elevated levels (reversible) of liver enzymes in blood plasma.
Coumarin
COUMARIN-CONTAINING DRUGSDrug Name:
Angelicae RadixOdour: Intensly spicy.
Taste: At first aromatic, then acrid, bitter, and last ingly pungent.Plant Source: Angelica archangelica L.Other Names: AngelicaHabitat: Angelica is thought by some botanist to be indigenous to Syria, Holland or Poland. Family: Apiac
Constituents:
Furanocoumarins (Bergabtene,
Xanthotoxin, Scopoletin,Umbelliferone,
Angelicin)
Caffeic acid derivatives: Chlorogenic acid,
Volatile
Coumarin
COUMARIN-CONTAINING DRUGS
Effects: The root acts as an antispasmodic, cholagogueand stimulatory for secretion of gastric juices.
Indications and Usage: Approved by Commission E; Dyspeptic complaints. Loss of appetite
Precautions and Adverse Reactions:
The furanocoumarins contained in angelica root sensitize the skin to light and can lead to inflammation of the skin in combination with UV rays. It is therefore advisable to avoid sunbathing and intensive UV radiation for the duration of treatment with Angelica or its preparations
CoumarinFuranocoumarins and Phototoxicity
The Phototoxicity of certain plant specieces.
The accidents which they cause always occur after contacts
with the plant followed by exposure sunlight, and they are
enhanced by humidity.
This is Phototoxicity results in an acute dermatitis, sometimes
wit h blisters and vesicles.
In many cases, a hyperpigmentation follows which may last
along time.
In the absence of specific treatment the symptoms in order.
The phototoxic constituents, common of all these specieces, are linear furanocoumarins: psoralen, bergabten. It has been shown that these furanocoumarins can undergo cycloadditions in the 3,4- or in the 4',5'-position or both with the pyrimidine bases of DNA. Furanocoumarins may each be involved in one or two cycloadditions, and in the latter case, they can form cross-links between the base pairs of the nucleic acids and induce lesions to the genome. It is possible that these properties have something to do with Phototoxicity, whose mechanism remains to be elucidated: the mainly explain the mutagen and carcinogenic properties
CoumarinFuranocoumarin Applications
Medical Applications:The photodynamic sensitizing properties of bergabten and methoxsalen are applied during PUVA ( psoralen+ Ultraviolet A)treatment, or photochemotherapy of psoriasis, vitiligo, and other dermatological disorders. The technique consists of the administration, generally by the oral route, of the furanocoumarin (20 to 40 mg as a single dose), followed, two hours later, by exposure to sunlight or UV radiation of wavelength (320-380 nm or UVA). UVA exposures must be brief initially (10-15 minutes)and are lengthed progressively; results are generally obtained in about 20 session
Localized treatment is possible, but must be conducted with the greatest caution. PUVA treatment is contraindicated for pregnant women and children, in case of cutaneous disorder aggravated by sunlight. And in cases of renal or cardiac insufficiency. This therapy is not without risks: gastrointestinal disorders, accelerating aging of the crystalline lens of the eye, or photosensitization (avoid overexposure: using protective clothing, sunscreens, sunglasses),long-term furanocoumarin photochemotherapy may induce cancer: several studies have clearly demonstrated a significant increase in the incidence of cancer (skin, but also lung) in treated patients
CoumarinFuranocoumarin Applications
Other Applications, CosmetologyNatural products such as bergamot oil are authorized as photodynamic sensitizers
in sun lotions. They increase the number of melanocytes, as well as their melanin production; this
is how they provide extra protection against UV radiation.However, their use-in tanning and cosmetic products- is not without risk: the
occurrence of symptoms linked to Phototoxicity is not exceptional.
The phototoxic reaction is influenced by many factors:
-type of skin, skin hydration,
-time elapsed between the application of furanocoumarin-
containing products and irradiation,
- duration and frequency of irradiation, and so forth.
Other Toxic Coumarins
Some coumarin synthesized by lower fungi are toxic; for example aflatoxins are carcinogenic.
These polycyclic toxins, which arise biosynthetically from a decaacetate, are produced by
various strains of Aspergillus which develop, under the right conditions of temperature and
humidity, during storage of plant materials, especially peanuts.
Their absence must be carefully verified in animal feed and human food. (oil, milk, butter)
