2.6
Miscellaneous Bitter Principles
There
are some
bitter principles which normally do not fall into the various
categories already discussed from Sections
2.1 through
2.5. A few important
potent drugs used as bitter principles that belong to this group are, namely:
picrotoxin,
quassin, cantharidin, which shall now be described separately as under:
2.6.1
Picrotoxin
Synonym
Cocculin.
Biological
Sources It is obtained as the bitter
principle from the seed of Anamirta cocculus L. Wight & Arn. (Menispermaceae);
and also found in Tinomiscium philippinense Diels.
Chemical Structure
Picrotoxin is a molecular compound of one mole
picrotoxinin (C
15H
16O
6),
q.v., and one mole
picrotin (C
15H
18O
7),
q.v., into which it is readily separated. Thus,
picrotoxin may be
resolved into the two components by boiling with 20 parts of benzene. In this
manner,
picrotoxinin remains dissolved in benzene whereas
picrotin that
is practically insoluble in benzene
can be separated easily. Likewise,
this cleavage may also be accomplished by chloroform more
efficiently.
Thus, we have:
Isolation Various steps
involved in the isolation of picrotoxin are:
1. The seeds are dried,
powdered coarsely, sieved and defatted with petroleum ether in a Soxhlet apparatus.
2. The defatted powder (marc)
is subsequently extracted by boiling with ethanol or with water.
3. The filtrate thus obtained
is treated with lead acetate solution (5% w/v), filtered and the excess of ‘lead’
is removed by passing freshly generated H2S gas (i.e., Pb is
precipitated as PbS).
4. The resulting solution is
filtered, residue discarded and the filtrate is concentrated to a syrupy consistency
in a Rotary Thin Film Evaporator. The syrupy liquid is kept in a refrigerator
overnight.
5. Picrotoxin crystallizes
out as a crude substance.
6. It may be further purified
by treating with ethanol or boiling water and activated charcoal powder to
obtain the pure substance.
Characteristic Features
1. It is obtained as shiny
rhomboid leaflets mp 203°C.
2. It has an intense bitter
taste and is extremely poisonous.
3. It has specific optical
rotation [α]16D – 29.3° (C = 4 in absolute ethanol).
4. Solubility Profile: 1
g dissolves in 150 ml cold water; 45 ml boiling water, in 13.5 ml 95% ethanol,
in 3 ml boiling ethanol; sparingly soluble in ether, chloroform; and readily
soluble in aqueous solution of NaOH and in strong NH4OH.
5. It is highly toxic to fish.
6. It is stable in air, but is
affected by light.
7. Picrotoxin is almost neutral
to litmus.
Identification Tests These
are as stated below:
1. Sulphuric Acid Test: Dissolve
2-3 mg of picrotoxin in a few drops of sulphuric acid, a goldenyellow-colour
is produced that gets changed to reddish-brown gradually.
2. Anisaldehyde Test: Moisten
a few crystals of picrotoxin with H2SO4 and just
add 1-2 drops of a solution of anisaldehyde in dehydrated ethanol (1 : 5), a
permanent blue colouration is produced.
3. Potassium-Cupric Tartrate
Test: Add about 5-10 mg of picrotoxin to 2 ml of potassiumcupric tartrate
solution (0.5%) with 10 ml of water, a red precipitate is formed gradually in
the
cold, but a little faster on
warming.
4. Vanillin HCl Test: A
few mg of picrotoxin when boiled with vanillin hydrochloride solution (0.1%
w/v) it gives rise to a green colouration.
5. Reduction Tests:
Picrotoxin reduces Fehling’s solution to give a brick-red precipitate; and Tollen’s
reagent to give a silver mirror.
6. Mix 0.2 g KNO3 with
four drops of H2SO4 in an evaporating dish. Sprinkle a
few crystals of picrotoxin on the resulting mixture and add dropwise
NaOH solution (2N), until it is present in a little excess quantity. The
crystals of picrotoxin shall initially acquire a red colouration that fades out
slowly.
Uses
1. It is used as a
CNS-stimulant. Therefore, it may be employed intravenously as an antidote in barbiturate
poisoning and other narcotics also.
2. It also finds its
application as an effective respiratory stimulant.
3. Very small quantities of the
powdered seeds are sufficient to stupify fish.
-------------------------------------------------
* Rotenoids: The
rotenoids take their name from the first known example rotenone and are usually generated by ring
cyclization.
2.6.2 Quassin
Synonym Nigakilactone D
Biological Sources It is
obtained from the wood of
Quassia amara L., (
Simaroubaceae)
commonly known in commerce as
Surinam quassia. It is also obtained from
the stem wood of
Picrasma excelsa (Sw.) Planch. (
Aeschrion
excelsa or
Picroena excelsa) known in commerce as
Jamaican quassia.
All these species belong to the natural order
Simaroubaceae).
Chemical Structure
2, 12-Dimethoxypicrosa-2,
12-diene-1, 11, 16-trione; (C22H28O6).
Isolation The following
steps may be adopted in a sequential manner for the isolation of quassin.
1. The quassia wood is
chopped into small pieces and subjected to aqueous decoction, which is filtered
and concentrated to the original weight of the wood taken; and finally
neutrallized carefully with Na2CO3.
2. Tannic acid solution (5%
w/v) is added slowly until no more precipitate is obtained.
3. The precipitate thus
obtained is filtered, collected and transferred to a pestle and mortar,
triturated with solid lead carbonate (or with freshly prepared lead oxide), so
as to liberate quassin and form lead tannate; and the resulting mass is
dried on a water bath.
4. The dried mass is powdered
and then subjected to extraction with 80% (v/v) ethanol successively.
5. The combined ethanolic
extract is filtered and concentrated under vacuo and left for cooling overnight,
when the crystals of quassin would separate out.
Quassin may also be
obtained by the resolution of the mixture of bitter constituents of quassia
wood by the method of
London et al.*
Characteristic Features
1. Quassin is obtained
as rectangular plates from dilute methanol having mp 222°C.
2. Its specific optical
rotation [α]20D + 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.
Identification Tests
1. Add to a few crystals of quassin
2-3 drops of concentrated, H2SO4 and sucrose when a
red colouration is produced.
2. Phloroglucin Test: Dissolve
2-3 mg quassin in 1-2 ml ethanol, and add to it a few crystals of phloroglucin
and a few drops of concentrated. HCl, when a crimson red colour is obtained.
Uses
1. It possesses insecticidal
properties.
2. The quassia wood extract is
used as a bitter tonic.
3. Quassin exhibits
anthelmintic properties, and on being administered as enema expels thread worms
specifically.
2.6.3 Lactucin
Biological Sources It is
obtained from the dried milky juice of Lactuca virosa L. (Asteraceae)
(Bitter Lettuce; Wild Lettuce); and from the plant of Cichorium
intybus L. (Compositae).
Chemical Structure
[3aR – [3aα, 4β, 9aα, 9bβ)]-3,3a,4,5,9a,9b-Hexahydro
4-hydroxy-9-(hydroxymethyl)-6-methyl-3-methyl-eneazuleno [4, 5-b] furan-2,
7-dione; (C15H16O5).
Isolation Lectucin may
be isolated by the method suggested by Schenck et al.*
Characteristic Features
1. It is obtained as crystal
from methanol which sinters at 218°C and has mp 228-233°C.
2. It exhibits specific optical
rotation [α]D + 49° (C = 0.90 in methanol); and +77.9° (C = 3.44 in pyridine).
3. It has uvmax: 257
nm (ε 14,000).
4. It is found to be soluble in
water, ethanol, methanol, ethyl acetate, anisol and dioxane.
Identification Tests It
may be identified from its derivative:
Lectucin para–hydroxyphenylacetate
hydrate (C23H22O7) (Intybin; Lactucopicrin;): It
is obtained as crystals from water which get decomposed at 148-151°C. It shows
specific optical rotation [α]D17.5 + 67.3° (pyridine).
--------------------
* London et
al., J. Chem. Soc., 3431, 1950.
2.6.4 Erythrocentaurin
Biological Sources It is
obtained from the plant
Centaurium umbellatum Gilib. (
Erythraea centaurium
Pers.),
Gentinaceae or
Swertia japonica (Maxim.) Makino
Gentianaceae.
It is also
accomplished by carrying out the hydrolysis of
swertiamarin
and
erytaurin with emulsin.
Chemical Structure
5-Formyl-3,
4-dihydroisocoumarin; (C10H8O3).
Isolation Erythroceantaurin may
be isolated from C. umbellatum by the method of Kariyone and
Matsushima.**
Characteristic Features
1. It is obtained as long
needles having mp 140-141°C.
2. It turns red on being exposed
to sunlight.
3. It has uvmax: 223, 290 nm
(log ∈ 4.30, 3.13).
Uses It is mostly
employed as a bitter tonic.
-----------------------------------------------
* Schenck et.
al., Arch. Pharm., 294, 17 (1961).
** Kariyone and Matsushima J., Pharm.
Soc., Japan, 47, 25 (1927).
2.6.5 Gentisin
Synonyms Gentianin;
Gentiin; Gentianic Acid.
Biological Sources It is
obtained from the roots of Gentiana lutea L. (Gentianaceae) (Yellow
Gentian).
Chemical Structure
1,
7-Dihydroxy-3-methoxy-9H-xanthen-9-one; (C14H10O5).
Characteristic
Features
1. It
is obtained as yellow needles from ethanol having mp 266-267°C.
2. It
has uvmax (methanol): 260, 275, 315, 410 nm (log ∈ 435, 4.30, 4.10, 3.70).
3. It
is observed to be very slightly soluble in water or organic solvents.
Identification
Test
Gentisin
Diacetate (C18H14O7) It is obtained as crystals from ethanol having mp
196-197°C. Its absorption max (metanol): 240, 270, 300 nm (log ε 4.58, 4.05,
4.10).
Uses
It may be used to stimulate gastric
secretion, improve appetite and digestion, and alleviate debility.
2.6.6
Cantharidin
Synonym
Cantharides Camphor.
Biological
Sources It is the active vesicating
principle of cantharides (q. v) and other insects, in notorious
‘Spanish Fly’
aphrodisiac, which essentially comprise of the dried insects (Beetles)
Lytta
(
Cantharis)
vesicatoria belonging to the order
Coleoptera;
and family
Meloidae. It has been found that the soft parts of the insect
are the chief seat of
cantharidin. Besides, cantharidis contain 0.5 to 0.95
of
cantharidin.
Chemical
Structure
Exo-1,
2-cis-Dimethyl-3, 6-epoxy hexahydrophthalic anhydride; (C10H12O4).
Isolation
The various steps involved in the
isolation of cantharidin are:
1.
The dried insects are collected and powdered. It is now treated with an acid
whereby the cantharidin gets liberated in the form of its corresponding
salts.
2.
The resulting product is subjected to extraction, of both cantharidin and
fat, by the help of ethyl acetate in a Soxhlet apparatus.
3.
The solvent is removed carefully under reduced pressure and the crude
cantharidin crystallizes out.
4.
The fat may be removed by the help of petroleum ether, in which cantharidin is
only negligibly soluble.
5.
Ultimately, the crude defatted
cantharidin is dissolved in a minimum
quantity of hot ethanol and allowed to cool when cantharidin crystallizes out
in its purest form.
Charactersitic
Features These are as follows:
1. Cantharidin
is obtained as orthorhombic plates or as scales having mp 218°C.
2. It
sublimes at 110 °C (12 mm Hg, 3-5 mm distances).
3. It
is practically insoluble in cold water and somewhat soluble in hot water. 1g
dissolves in 40 ml acetone; 65 ml chloroform; 560 ml ether; 150 ml ethyl
acetate; and soluble in oils.
Identification
Tests
1. Formaldehyde
Test: Add to a few crystals of cantharidin 1-2 drop of dilute
formaldehyde solution mixed with H2SO4, the development
of a brown to black colouration on warming identifies it.
2. A
solution of cantharidin in olive oil is vesicant to the skin (i.e.,
sensitive upto an extent of 0.14 mg).
Uses
1. It
is mostly used as a vesicant.
2. It
is also employed as a rubefacient and counterirritant in veterinary practice.
