bitter principles lec.-3
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Bitter Principles
Lecture-3
By
Dr. Ahmed Metwaly
Objectives:Non–Terpenoid Bitters
• Phenolic bitters
I. Humulone(α-Lupulinic acid)
1. Biological Sources
2. Chemical structure
3. Characteristic features
4. Isolation
5. Uses
6. Chemical test
II. Lupulone (β- Lupulinic acid)
1. Biological Sources
2. Chemical structure
3. Characteristic features
4. Isolation
5. Uses
6. Chemical test
• Chromone bitters
I. Khellin
1. Biological Sources
2. Chemical structure
3. Characteristic features
4. Isolation
5. Uses
6. Mechanism of action
7. Chemical test
II. Visnagin
1. Biological Sources
2. Chemical structure
3. Characteristic features
4. Isolation
5. Uses
6. Chemical test
• Coumarin bitters
I. Xanthotoxin
1. Biological Sources
2. Chemical structure
3. Characteristic features
4. Isolation
5. Uses
6. Mechanism of action
7. Chemical test
II. Imperatorin
1. Biological Sources
2. Chemical structure
3. Characteristic features
4. Isolation
5. Uses
6. Chemical test
Phenolic bitters
Humulone (α-Lupulinic acid) and Lupulone (β- Lupulinic acid)
Structure
These are crystalline phloroglucinol derivatives, the α-acids e.g. humulone
and the β-acids e.g. lupulone
Humulone; (6S)-3,5,6-Trihydroxy-2-(3-methylbutanoyl)-4,6-bis(3-methylbut-2-en-1-
yl)cyclohexa-2,4-dien-1-one
Lupulone; 3,5-dihydroxy-2-(3-methylbutanoyl)-4,6,6-tris(3-methylbut-2-
enyl)cyclohexa-2,4-dien-1-one
Phloroglucinol Humulone Lupulone
O
ROHHO
O
HC
CCH3
CH3CH2
Humulone R = OH
Lupulone R =
Biological Source;
Humulone and lupulone are the
chief active constituents
obtained from the dried flowers
(strobiles) of Humulus lupulus
(hops) family Cannabinaceae
Moraceae.
The bitterness of hops is mainly
due to acidic bitter principles
humulone, lupulone and about
10 % of resins
Hops bear glandular hairs
which are known as lupulin,
which contain most of the bitter
principles that account for the
use of the product in brewing
and in medicine.
Humulus lupulus
Isolation of humulone
Hops strobiles are macerated with alcohol and filtered.
The filtrate is heated with animal charcoal to adsorb the bitter
principle, the suspension cooled and filtered.
The charcoal is boiled with alcohol to extract the bitter principles.
The alcohol extract is evaporated and the residue treated with boiling
water that extracts humulone.
The aqueous solution is cooled and humulone extracted by shaking
with ether.
The ether extract is evaporated to yield humulone.
Characteristic Features
1. The crystals obtained from ether have mp 65-66.5°C
2. It has a distinct bitter taste especially in alcoholic solution.
3. Humulon is observed to be more stable to air than lupulon.
4. It is a monobasic acid.
5. It has a specific optical rotation [α]20 D – 212° (1.0 g in 15.5 g 96% v/v
ethanol)
6. It has uvmax (ethanol): 237, 282 nm (ε 13, 760; 8330).
7. It is found to be soluble in usual organic solvent.
8. It is slightly soluble in boiling water from which it normally separates out as
a milky precipitate
on cooling.
9. It readily forms a sodium salt which is rapidly soluble in water.
10. Bacteriostatic Potency: Humulon suffers no loss of bacteriostatic
potency against Staphylococcus aureus. However, the addition of ascorbic
acid in low concentrations extends the duration of bacteriostatic action.
Test for identification;
An alcoholic solution of humulone gives a reddish-violet color with alcoholic
ferric chloride (phenolic).
Uses;
Humulone and lupulone contribute to the bitterness of hops.
They are used as aromatic bitters and exert a mild sedative action.
Hops are used in the manufacture of beer for taste improvement
(flavoring agent).
Humulone was found to exert a bacteriostatic activity
Chromone bitters
O O
OCH3
R
O
CH2R1
R R1
Khellin OCH3 H
Visnagin H H
Khellol glucoside H O-Glucose
Khellin and Visnagin
Khellin ; 4,9-Dimethoxy-7-methylfuro[3,2-g]chromen-5-one; (Khellin is a
Furanochromone compound.
Visnagin; 4-methoxy-7-methylfuro[3,2-g]chromen-5-one;
Khellol glucoside; 7-[(β-D-glucopyrano)-methyl 4-methoxy-7-
methylfuro[3,2-g]chromen-5-one
Biological source;
Fruits of Ammi visnaga
family Umbelliferae.
The fruit contains about 1
% of khellin beside two
other crystalline
compounds, visnagin
(about 0.1 %) and khellol
glycoside (about 0.3 %).
Ammi visnaga
Powdered Ammi visnaga fruits
Extract with ether.
Ether extract
- Concentrate - Cool (refrigerator)
Green
Oily
Cream colored
Fatty
Green
Crystalline
Discard by filtration (suction)
Discard by dissolvingin Petroleum ether
Repeated crystallization from metahnol
Mother liquor Crystals
Khellin- Evaporate to dryness- Benzene
Visnagin &
traces of Khellin
Benzene solution
- Petroleum ether - Cool- Filter
Crystals
Khellin
Filtrate
Visnagin
Dry & recrystallize
from methanol
Upper layer Lower layer Middle layer
Isolation;
Properties;
Khellin:
1.Khellin occurs as bitter needle crystals, m.p. 153ºC.
2.It is freely soluble in CHCl3 and alcohol, less soluble in ether, sparingly
soluble in petroleum ether and cold H2O, but more soluble in hot water
and hot CH3OH.
Visnagin:
1.Visnagin occurs as colorless thread-like needles.
2.It is freely soluble in CHCl3, sparingly soluble in alcohol, insoluble in cold
water and petroleum ether
Khellol glucoside;
1. It is obtained as crystals from ethanol having mp 179°C.
2. It has uvmax (ethanol): 250, 325 nm.
3. It is found to be soluble in acetic acid, hot ethanol slightly soluble in hot
methanol; and almost
insoluble in acetone, ethyl acetate, ether, chloroform, cold alkali.
Tests for identification;
Khellin:
1.Mix few crystals of khellin with solid KOH or NaOH a rose red color is
produced (not given with K2CO3 or Na2CO3 or bicarbonate).
2.Mix few crystals of khellin in a porcelain dish with a drop of H2SO4 or of
phosphoric acid, a reddish-orange color is produced, that turn to bright yellow
on addition of 2-3 drops of H2O.
3.Add about 1-ml nitric acid (1:1) to few mg of khellin in a porcelain dish, then
add 5 ml NaOH solution, violet color is produced.
4.To few crystals of khellin, add an equal quantity of ninhydrin followed by 2 –
3 drops of concentrated H2SO4, an emerald green color is produced on
stirring.
Visnagin:
Triturate few crystals of visnagin with solid KOH or NaOH, a faint rose red
color is produced (paler than that produced with khellin)
Identification Test Khellol glucoside may be identified by making its
following tetraacetate derivative due to the presence of four OH moieties
Khellol Glucoside Tetracetate It is obtained as flakes from ethanol having
mp 153°C. It is freely soluble in acetone, ethanol, ethyl acetate; and almost
insoluble in petroleum ether.
Uses ;
• Khellin can be used for Vitiligo
Vitiligo is a disease which causes loss of
pigmentation in portions of skin.
Mechanism of Khellin action is;
When khellin is applied topically in
combination with UVA light, it is able to
stimulate melanocytes (cells that produce
melanin) in hair follicles for successful
treatment of vitiligo
Khellin can be used for Kidney Stones and Renal colic
Khellin has also been used to treat renal
colic, which is due mostly to stone
formation. It were seen to relieve renal
colic by relaxing the ureter and acting as
a diuretic.
As khellin act as vasodilator, It is used in treatment of coronary
insufficiency, angina pectoris and in bronchial asthma.
Vinagin and kellol glucosides also have a vasodilator effects.
Side effects;
Unwanted side effects include dizziness, reversible cholestatic jaundice,
pseudoallergic reaction, and elevated levels of liver enzymes
Coumarin bitters
Xanthotoxin, Imperatorin and Bergapten
OO O
R
R1
R R1
Psolaren H HXanthotoxin H OCH3
Imperatorin H OCH2- CH=C(CH3)2Bergapten OCH3 H
Xanthotoxin 9-methoxy-7H-furo[3,2-g]chromen-7-one
9-(3-Methylbut-2-enoxy)-7-furo[3,2-g]chromenone
Biological source;
Xanthotoxin (Ammoidin or Methoxsalen) is obtained from the fruits of Ammi
majus (Umbelliferae).
Imperatorin (Ammidin) occurs in the fruits of Ammi majus (Umbelliferae).
Bergapten was first isolated from the oil of bergamot from Citrus bergamia
(Rutaceae) and fruits of Ammi majus and some other plants belonging to
family Umbelliferae .
Ammi majus
Isolation of Xanthotoxin and Imperatorin;
Xanthotoxin and Imperatorin are isolated from the petroleum ether
extract of the fruits of Ammi majus according to the following scheme:
Powdered Ammi majus fruits
- Extract with petroleum ether - Concentrate - Decantation while hot
Crystalline mass
Dark green , semi-solid
Crude xanthotoxin
- Dissolve in boiling alcohol- Cool
Pale green crystals
Mother liquor- Concentrate- Cool
Crude imperatorin
Xanthotoxin
- Dissolve in ether- Concentrate and cool
Imperatorin
Properties;
Xanthotoxin occurs as a crystalline solid substance with bitter taste. It is
insoluble in cold water, more soluble in boiling H2O, petroleum ether,
ether, benzene, CHCl3, ethyl acetate and glacial acetic acid.
Imperatorin occurs as prisms or needle crystals with the same
characters as xanthotoxin.
Test for Identification;
Test Xanthotoxin Imperatorin
Triturated few crystals in a
porcelain dish with
concentrated H2SO4.
Test with Marquis reagent.
Reduction of ammoniacal
silver nitrate and
Fehling's solution.
Test with Wagner's reagent.
Boil with dilute HNO3.
Orange yellow
color that turns to
light green.
Orange color that
turns to grass
green.
No reduction
Precipitate
Yellow color turns
to crimson on
treatment with
alkali.
Deep orange color
that turns to brown.
Orange color that
turns to brown.
Reduction
No precipitate
Yellow color turns to
purple on treatment
with alkali.
Xanthotoxin used to treat psoriasis
psoriasis
Uses
Xanthotoxin used to treat psoriasis, eczema and vitiligo in conjunction
with exposing the skin to UVA light from lamps or sunlight.
The dosage comes in 10 mg tablets, which are taken in the amount of 30 mg
75 minutes before a PUVA (psoralen + UVA) light treatment.
Mechanism of action;
The exact mechanism of action of methoxsalen with the epidermal
melanocytes and keratinocytes is not known.
Psoralens given orally are preferentially taken up by epidermal cells. The
best known biochemical reaction of methoxsalen is with DNA. Methoxsalen,
upon photoactivation, conjugates and forms covalent bonds with DNA which
leads to the formation of both monofunctional (addition to a single strand of
DNA) and bifunctional adducts (crosslinking of psoralen to both strands of
DNA). Reactions with proteins have also been described.
The exact Topical mechanics are unknown but it has been suggested that
melanocytes in the hair follicles are stimulated to move up the follicle and to
repopulate the epidermis. Methoxsalen modifies the way skin cells receive
the UVA radiation, allegedly clearing up the disease.
Contraindications; Patients with high blood pressure or a history
of liver problems are at risk for inflammation and irreparable damage to
both liver and skin. The eyes must be protected from UVA radiation.
Side effects include nausea, headaches, dizziness, and in rare
cases insomnia.
Summary:Non–Terpenoid Bitters
• Phenolic bitters
I. Humulone(α-Lupulinic acid)
1. Biological Sources
2. Chemical structure
3. Characteristic features
4. Isolation
5. Uses
6. Chemical test
II. Lupulone (β- Lupulinic acid)
1. Biological Sources
2. Chemical structure
3. Characteristic features
4. Isolation
5. Uses
6. Chemical test
• Chromone bitters
I. Khellin
1. Biological Sources
2. Chemical structure
3. Characteristic features
4. Isolation
5. Uses
6. Mechanism of action
7. Chemical test
II. Visnagin
1. Biological Sources
2. Chemical structure
3. Characteristic features
4. Isolation
5. Uses
6. Chemical test
• Coumarin bitters
I. Xanthotoxin
1. Biological Sources
2. Chemical structure
3. Characteristic features
4. Isolation
5. Uses
6. Mechanism of action
7. Chemical test
II. Imperatorin
1. Biological Sources
2. Chemical structure
3. Characteristic features
4. Isolation
5. Uses
6. Chemical test
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