Monoterpenoid Indole alkaloids RAUWOLFIA (SNAKEWOOD) roots and rhizomes of Rauwolfia serpentina ( Apocynaceae). total alkaloids (0.5-2.5%) form a complex mixture of nearly 30 different compounds, mostly indoles. used by India to ranging the traditional healers of treat a variety of ailments, from snake-bite to insanity .
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aloidsids 22 11
Monoterpenoid Indole alkaloids
RAUWOLFIA (SNAKEWOOD)
roots and rhizomes of
Rauwolfia serpentina
( Apocynaceae).
total alkaloids (0.5-2.5%) form a
complex mixture of nearly 30
different compounds, mostly indoles.
used by
India to
ranging
the traditional healers of
treat a variety of ailments,
from snake-bite to insanity.
Three main groups of alkaloids are distinguished:
1- Yohimbane-type Derivatives.The most interesting ones are substituted at the 16- 17, and 18 positions):
reserpine (trimethoxybenzoate of methyl reserpate) and
recinnamine (trimethoxycinnamate of methylreserpate).
2- Heteroyohimbane Derivatives.very closely related to the previous ones, with heterocyclic E ring:
Ajmalicine (also known as raubasine), reserpiline, 10, 11-dimethoxy-
ajmalicine), reserpiline, isoreserpiline), and serpentine.
3- Dihydroindole derivativesThese are chiefly represented by ajmaline, a polycyclic indoline alkaloid
2
Reserpine:
Pale white to slightly yellow or colorless crystals, weak base,
insoluble in H2O, soluble in CHCl3
Salt such as reserpine sulfate are soluble in chloroform.
On treatment with sodium nitrite in the presence of sulfuric
acid, these alkaloids are oxidized to the corresponding 3,4-
dehydro- derivatives: these are colored and can be used for
quantitative estimation.
4
- Rauwolfia alkaloids exert hypotensive effects by depletion of catecholamine
and serotonine stores in many organs, and by reduction of uptake of
catecholamines by adrenergic neurons.
- Their sedative and tranqulizing effect are thought to be related to depletion
of amines in CNS.
Reserpine (used for its neuroleptic properties and antihypertensive activity)
- It is used in combination with diuretics for treating arterial hypertension.
Rescinnamine has the same activity.
Ajmaline (antiarrhythmic agent)
- decrease the rate of depolarization of atrial and ventricular cells.
Ajmalicine (Raubasine) moderates the activity of the vasomotor centers,
the brain and is slightly anxiolytic.
Yohimbine (from the bark of the tree Pausinystalia yohimbe)
- It is hypotensive and a peripheral vasodilator.
- Has reputation as an aphrodisiac, (treated impotence in patients with
vascular or diabetic
5
Catharanthus roseus (Fam. Apocynaceae)
- 0.2-1% alkaloids
- All of them have
(very complex mixture)
an indole or dihydroindole structure (indoline- the
principal constituents) e.g. catharanthine, vindoline and ajmalicine.
The alkaloids with antineoplastic activity belong to a new class of
bisindole derivatives (composed of an indole and a dihydroindole
unit) catharanthine and vindoline respectively.
About 20 binary alkaloids have been isolated from various C. roseus.
Several have cytostatic properties, especially:
-
-
-
1- Vincristine: 0.0003% (i. e 3 g per metric ton of dried drug)
2- Vinblastine: which is a little more abundant.
- These two alkaloids formally comprise a dihydroindole moity
(vindoline) and an indole moiety (velbanamine).
- Vincristine and vinblastine are antimitotics.
6
CH2CH3
COOCH3H
R HO OCCH3
R = CH3 Vinblastine
7
OH
N
N
N
CH2CH3
O
H3CO N OCCH3
O
R = CHO Vincristine
Nux vomica
-
-
ripe seed of Strychnos nux-vomica (Fam. Loganiaceae).
The drug contains from 1-3% total alkaloids chiefly
(strychinine and its dimethoxylated derivative brucine)
Strychinine was formerly used mainly to poison rodents, and
the galenicals obtained from the drug ingredients of tonic
preparation.
Few products based on nux vomica tincture are still used in
homeopathy.
-
-
- Brucine, which is less toxic than strychinie, has been used
commercially as bitters.
8
Strychnine:
Monoacidic base, has no basic
properties, colorless prisms or white,
base and salts are very powerful
poison.
Brucine:
Dimethoxystrychnine, soluble in
alcohol and acetone, insoulble in
NaOH or KOH
Identification:
1-
2-
3-
4-
Strychnine
Strychnine
Strychnine
+
+
+
H2SO4 + K2CrO3 gives reddish-violet color
NH4-Vandate gives violet color (Mandelin’s reagent)
HNO3 gives yellow color
Brucine + HNO3 gives orange-red color
9
R1 N
R2 N
OO
Strychnine = R1 =R2 = H
Brucine = R1 = R2 = OCH3
Separation of a mixture of strychnine
and brucine:1- Acetone dissolves brucine and leave
strychnine.
2- K[Fe3(CN)6]-solution when added to
the mixture, strychnine gives ppt
quickly from its salts than brucine.
10
Quinoline AlkaloidsAlkaloids containing quinoline as their principle nucleus include
those obtained from cinchona (quinine, quinidine,
cinchonidine).
Cinchona
cinchonine and
- bark of C. pubescens (C. succirubra) or
of its varieties (Fam. Rubiaceae).
7-15% alkaloids which occur in
combination with special organic acids
chiefly quinic acid and cinchotannic acid.
Used in the treatment of malaria fever for
many years.
Over doses of cinchona products results in
temporary loss of hearing and in impaired
sight. Ringing in the ears is a symptom of
toxicity (Cinchonism).
-
-
11
Chemistry:
-9-rubanol is the
from the parent
- Ruban nucleus
basic skeleton of these alkaloids, which is derived
compound named ruban.
is composed of quinoline ring system attached
through a methyllene group to a bicyclic ring system named
quinuclidine.
- The principal alkaloids are the stereoisomers, quinine and quinidine,
and their 6'-demethoxylated homologs cinchonine and cinchonidine.
H
HO
R = OCH3 (-_ ) Quinine R = OCH3 ( _ ) Quinidine
12
HHO
N N
R H R H
N N
-
R = H ( _ ) Cinchonidine R = H ( _ ) Cinchonine
Quinine:
- a diastereoisomer of quinidine, occurs as
crystals.
- Quinine is antimalaria agent.
white, odorless, bitter
Quinidine:
- an antiarrththmic class I (sodium channel blockade).
- inhibits the rapid sodium influx,
depolarization, contractility, and
conduction velocity.
- used for treating various cardiac
decreases the rate of
the atrial and intraventricular
arrhythmias e.g. premature atrial,
ventricular contraction, atrial and ventricular tachycardia, and atrial
flutter and atrial fibrillation.
13
The current indications of quinine include the following:
1- treating of pernicious malaria and of cases of malaria resistant
to 4-aminoquinolines.
2- The symptomatic treatment of fevers, aches and flu-like states.
3- Quinine ascorbate, combined with vitamins, used in programs
quit smoking (60-80mg/day in four doses).
to
4- in combination with thiamine, to relieve muscle cramps.
14
Identification:1- With oxygenated acids (e.g. sulphric and acetic acid)
Quinine and quinidine produce a strong blue fluorescence when
dissolved in these acids.
2- Thalleioquin reaction
Quinine and quinidine in solution in dilute H2SO4 can be
treated by Br2 until the fluorescence disappears.
The addition of aqueous NH3 causes the development of an
emerald green color, which can be extracted with chloroform.
3- The addition of K[Fe3(CN)6]-solution in alkaline medium leads
to a purplish red color that can also be extracted with chloroform.
15
Ramzi MM loidsids 22
Camptotheca acuminata (Fam. Nyssaceae)
The bark, and the fruits of this large tree indigenous to southern China
-
-
-
-
contain 0.01-0.03 % camptothecine.
It is characterized by a pyrrol [3,4b]quinoline sequence.
It is a neutral lactam, which does not react with the general reagents for alkaloids
Camptothecine exert cytotoxic and antitumor activity, but because of its
toxicity, its synthetic analogs such as Topotecan and CPT11 have been used.
There was evidence that this compound had some activity on topoisomerase I-
(an enzyme involved in
transcription).
the uncoiling of DNA, a prerequisite for replication and
N
N
16
9 7
10 O
11
12
20 O
OH O
Camptothecine
Histidine- derived Alkaloids
Alkaloids of the Imidazole group
►Alkaloids that possess an imidazole
nucleus are very rare.
► found in some Rutaceae (leaves of
the Pilocarpus of South America)
Jaborandi
► It consists of the leaflets of
Pilocarpus jaborandi, P. microphyllus,
and P. Pinnatifolius (Fam. Rutaceae).
► 0.7 – 1.0 %, the chief constituents is
(3S, 4R)-(+)-pilocarpine and
stereoisomer isopilocarpine.
17
Ramzi MMothanothanaa AlkaloAlkaloidsids 22
► Pilocarpine is a tertiary base containing a lactone group as well
as an imidazole nucleus.
It is an oily syrupy liquid, easily soluble in water, alcohol and
chloroform, but almost insoluble in ether.
The lactone ring is opened by caustic alkali, which forms salts
with the resulting pilocarbic acid (unaffected by ammonia or
alkali carbonates) (destroys the physiological activity)
►
►
► it is demethylated and converted to pilocarpidine, when heated
with acids.
COOH HNN
H
4 34 3 NN
18
4 3
O
N NH2
N O
Histidine Pilocarpidine
H3C H3C
O O
N O N O
(3S, 4R)-Pilocarpine (3R,4R)-Isopilocarpine
Pharmacology:
►
►
Pilocarpine is a parasympathomimetic.
It induces salivary glands, gastric, and sweat hyper-secretion,
it increases intestinal motility, induces broncho-constriction, and
bradycardia.
It directly stimulates the muscarinic receptors in the eye, causing
constriction of the pupil (myosis) and contraction of the ciliary
muscle.
It used in the treatment of narrow-angle glaucoma
Alone or in combination with beta-blocker (timolol) also for
treating intraocular pressure.
Pilocarpine can be used as a sialagogue to relieve dryness of the
mouth (for example, that due to the radiotherapy of mouth and
throat cancers).
►
►
►
►
19
Chemical tests:1- Helch’s test (H2SO4 + H2O2 + KCr2O7)
gives violet color
2- Ekkert’s test (Na-nitroprusside + NaOH)
leave for a period in HCl-solution, it gives
red color
20
Ornithine derived Alkaloids
► 4-aminobutanal and N-methyl-4-aminobutanal which are derived
from ornithine, represent the
alkaloids, namely:
1- Pyrrolizidine alkaloids
2- Tropane alkaloids
precursors of two groups of
Pyrrolizidine alkaloids
pyrrolizidine basic structure.
the Asteraceae and Boraginaceae.►
►
essentially isolated only from
they were found in many genera: Eupatorium, Senecio, Tussligo,
and Echium, Heliotropium Symphtum.
They are hepatotoxic, carcinogenic and mutagenic►
21
► Pyrrolizidine alkaloids have a
Alkaloids of Tropane group
► Tropane alkaloids have in commn a nitrogen-containing bicyclic