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Indole Alkaloids
Alkaloids Derived from Tryptophane
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1) Physostigma alkaloids (Calabar bean alkaloids)
Physostigmine (Eserine)
* Present in the seed of Physostigma venenosum Fam. Leguminosae.
* Eserine is a tertiary base, possessing an ester linkage
Uses
A myotic drug (in the treatment of glaucoma).
, it has a cholinergic effect and stimulates gland secretion.
Being replaced by synthetic anticholinestrase e.g. neostigmine
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• Constituents: Physostigmine (Eserine).
• Properties:
 It is a tertiary base, possessing an ester linkage.
 Contains 3 Nitrogen atoms.
 Eserine on alkaline hydrolysis  Eseroline + Methylamine +
CO2
O
O
Me-HN
HO
Me
Alkaline
Hydrolyses
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1
N 2
N
N
H
Me
Me
Me
Eserine
N-methyl pyrrolidine 1,3-dimethyl
methyl carbamic acid -2,3- dihydroindol
N
H
+ CH3NH2 + CO2
Me
Me
Eseroline
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2- Ergot Alkaloids
•
•
•
Occurrence:
Ergot is the dried sclerotium of a fungus, Claviceps purpurea (Fam. Hypocreacea)
that arise on the ovaries of the rye plant (Secale cereale, Fam. Gramineae).
Consumption of flour contaminated with Ergot led to many serious intoxications
known as (Ergotism- Ignis Fire) in Europe.
Ergot can be detected in flour by using UV light where contaminated flour will
show violet spots.
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•
Classification of Ergot Alkaloids:
A- Clavine Type Alkaloids:
Simple water soluble bases with little medicinal value. All end with “clavine: e.g.
Agroclavine.
B- Lysergic acid Amides:
They are all derivatives of (l)-Lysergic acid and sub classified into:
1- Simple lysergic acid amides:
Composed of Lysergic acid and simple amines.
2- Polypeptide Alkaloids:
Composed of Lysergic acid and at least 3 amino acids.
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•
General Characters:

Ergot alkaloids are N-monosubstituted amide derivatives of both lysergic acid
and its isomer isolysergic acid that differ only in configuration at C-8.
On treatment with ammonia lysergic and isolysergic acids give the
corresponding amides ergine and isoergine respectively.

8
9
11
13
7
17
12
NCH3
NCH3
NCH3
10
CONH2
COOH
COOH
6
5
16
14
15
N
H
1
4
3
2
Lysergic acid


N
N
H
H
Iso lysergic acid
Ergin
Members related to lysergic acid (e.g. ergotamine and ergometrine) are
levorotatory, more active and designated by suffix “ine”.
Members related to isolysergic acid (e.g. ergotaminine and ergometrinine),
are dextrorotatory, less active and designated by suffix “inine”.
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1- SIMPLE LYSERGIC ACID AMIDES
Characters:
1- Composed of Lysergic acid and simple amines.
2- Low molecular weight.
3- Water Soluble.
Ergonovine (Ergometrine)
OH
H 2C
CH3
HC HN
CO
8
Composed of (l)-lysergic acid and 2-aminopropanol.
N
CH3
10
Its (d) isomer is called Ergometrinine.
Uses:
N
H
It causes vigorous contraction of the uterus.
It is mainly used as an oxytocic in order to aid
delivery or to prevent postpartum hemorrhage.
Ergonovine (l) (Ergometrine)
Ergonovinine (d) (Ergometrinine)
=
=
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LYSERGIC ACID DIETHYLAMIDE (LSD)
It is a semisynthetic product.
LSD has potent CNS stimulant effect.
LSD is one of the abused drugs.
C2H5
CON
C2H5
8
N
CH3
10
N
H
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2- POLYPEPTIDE ALKALOIDS
Characters:
They are derivatives of Lysergic acid with a
complex polypeptides of at least 3 amino acids.
They have high molecular weight.
They are insoluble in water.
This class include medicinally important members.
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ERGOTAMINE
Characters:
Its (d) isomer is called Ergotaminine.
The peptide moiety is composed of 3 amino acids:
a-Hydroxyalanine
OH
Phenylalanine
O CH3
N
Proline
O
CO
N
CH2
O
8
N
9
10
N
H
Uses:
Treatment of migraine as it constricts
the peripheral blood vessels.
Has some oxytocic (ecobolic) activity.
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CH3
 STRUCTURE ACTIVITY RELATIONSHIP:
• Lysergic acid must be in the (l) form. The (d)
isomers are inactive.
• Saturation of the 9- 10 double bond of
Ergotamine gives Dihydroergotamine, a
compound with antimigraine effect but no
oxytocic effect.
OH
O CH3
N
O
CO
N
CH2
O
8
N
9
10
N
H
12
CH3

STABILITY:
The active (l) form convert to the (d) isomer by the effect of
Alkalis or prolonged storage in alcohol.
HO
O
C
O
C
R
R
C
H
R
H
8
8
N
CH3
10
10
(l) form
N
8
CH3
N
CH3
10
(d) form
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Chemical Test:
Van-Urk's test
Solution of Ergot alkaloids + Van-Urk's test (pdimethylaminobenzaldehyde in 15% H2SO4) containing
traces of FeCl3
Deep blue color
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3- VINCA (CATHARANTHUS)
ALKALOIDS
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Occurrence:
Catharanthus or Vinca is the dried whole plant of
Catharanthus roseus G. Don (or Vinca rosea L), Fam.
Apocynaceae.
It contains about 150 alkaloids, the most important
are vinblastine and vincristine.
Classification:
1- Monomeric Alkaloids:
These are alkaloids that contain either indole or indoline:

Indole monomers e.g. Catharanthine

Indoline monomers e.g. Vindoline and Vincamine.
2- Dimeric Alkaloids:

Homogenic dimmers: Composed of two indole or indoline
monomers.
Mixed dimmers: One indole and one indoline monomers e.g.
Vincristine
and Vinblastine.
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
1- MONOMERIC ALKALOIDS:
H
N
H3COOC
OH
N
N
H
H3COOC
C2H5
Vincamine
N
N
C2H5
N
CH3
H3COOC
Catharanthine
COOCH3
OH
Vindoline
Vincamine
Enhances the cerebral blood flow, facilitate cerebral
circulation metabolism and increase general activity.
Vincamine is used in cerebral vascular deficiency and
atherosclerosis in elderly patients.
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2- DIMERIC ALKALOIDS:
MIXED DIMMERS
These are dimeric alkaloids having indole and indoline
(dihydro-indole) nuclei e.g. Vinblastine and Vincristine
Vinblastine and Vincristine
They occur in very minute amounts in Vinca (0.003- 0.005); 500 Kg of the
plant yield only 1 gm of vincristine.
They are very important for cancer treatment.
Vincristine is more active but isolated in smaller amounts than
Vinblastine. Vinblastine can be converted to vincristine chemically or by
microbial transformation using Streptomyces albogriseolu .
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 Vincristine and
Vinblastine differ
only in the
substitution on the
N-atom of the
dihydroindole
nucleus.
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Uses:
Vincristine used in treatment of Leukemia in children.
Vinblastine is used for treatment of Hodgkin’s disease
STRUCTURES:
Vinblastine (Vincaleukoblastine) is produced by coupling of
Catharanthine and Vindoline.
Vincristine (leurocristine) has CHO instead of CH3 in the vindoline part of
Vinblastine.
N
N
H
H3COOC
R=CH3 Vinblastine
R=CHO Vincristine
HO
N
N
R
H3COOC
COOCH3
OH
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Uses :
Vinblastine is used for treatment of Hodgkin's disease
(Pseudoleukemia or Lymphatic anaemia) and carcinoma
resistant to other therapy.
Vincristine has a cytotoxic effect .It is useful in the
treatment of leukemia in children, small cell lung cancer,
cervical and vaginal cancers.
Mechanism:
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Both alkaloids are Antimetabolites interfere with the
syntheses of Desoxyribonucleic acids.
 SEMISYNTHETIC DERIVATIVES:
N
Vindesine:
N
H
H3COOC
HO
It is used for treatment of acute
N
lymphoid leukemia in children.
N
COOCH3
CH3
H2NOC
OH
N
Vinorelbine:
N
H
H3COOC
HO
N
N
CH3
H3COOC
COOCH3
OH
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It is an oral anticancer with broader
activity and lower neurotoxicity than
vinblastine.
Tests for identification:
1-Vanillin /HCl reagent gives with:
Vinblastine a pink color.
Vincristine an orange-yellow color.
2-Van-Urk's reagent:
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→ Reddish-brown color.
4- NUX-VOMICA ALKALOIDS
Source:
Seeds of Strychnose nux vomica family Loganiacea and •
Strychnos ignatii (Ignatius beans).
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Constituents: 5% Alkaloids mainly Strychnine and
Brucine.
Properties:
Brucine is the dimethoxy derivative of Strychnine.
Both alkaloids contains 2 Nitrogen atoms.
Hemitoxiferine is a degradation product of strychnine.
Dimerization of hemitoxiferine produces a valuable
skeletal muscle relaxant Toxiferine.
N
R
R
N
O
O
R= H
Strychnine
R= OCH3 Brucine
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Tests for identification:
Nitric acid test:
Drops of concentrated nitric + few crystals of the
alkaloids:
Strychnine gives a faint yellow color that on
evaporation turns to yellow color
Brucine gives an intense red color, that on
evaporation and addition of SnCl2 solution turns to violet.
Tests for strychnine:
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Sulfuric acid-dichromate test:
Few crystals of strychnine + drops concentrated
H2SO4 + few crystals of K2Cr2O7 → deep blue streaks →
violet → purplish red → orange → yellow.
Test with Mandalin's reagent:
Strychnine gives Deep violet blue color, add water →
red → cherry-red.
Uses:
Strychnine is extremely toxic.
It is used in veterinary medicine as CNS stimulant and
tonic.
It is used as antidote in barbiturate poisoning.
It is also used as rodenticide.
Brucine is less toxic than strychnine.
It is sometimes used as CNS stimulant,
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Commercially it is used as alcohol and oil denaturant
4- Rauwolfia Alkaloids (carboline alk.)
• Source: Rauwolfia roots (Rauwolfia
serpentina, Fam. Apocynaceae)
Carboline skeleton
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• Constituents: The most important are Reserpine, Deserpine and
Rescinnamine.
• Properties:
 Reserpine and related alkaloids are weakly basic diester,
tertiary alkaloids and possess a carboxylic group on ring "E".
N
H3CO
N
H
E
H3COOC
R= 3,4,5-trimethoxybenzoic acid
R= 3,4,5-trimethoxycinnamic acid
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OR
Reserpine
Recinnamine
 Alkaline Hydrolysis:
1- Reserpine → reserpic acid + trimethoxybenzoic acid + methanol.
2- Recinnamine → reserpic acid + trimethoxycinnamic acid + methanol.
 Its solution acquires a yellow color and a pronounced fluorescence especially
after the addition of acids or upon exposure to light.
• Tests for reserpine:
 Vanillin /HCl reagent: → violet color.
 Sodium molybdate in H2SO4 → Yellow → Blue in two minutes.
• Uses:
 Reserpine and the related alkaloid rescinnamine are mainly used as
antihypertensives (250-500 mg daily) and as tranquilizers (0.1- 1mg or more
daily).
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Alkaloids of β-carboline type
 The simple β-carboline alkaloids are alkyl derivatives of pyrido (3,4-b) indols
 The most important ones are the 1-methyl- β-carbolin derivatives harmane,
harmine and harmaline.
 Passiflora incanata and Peganum harmala
Passiflora incanata (Fam. Passifloraceae)
It is a climber plant, found in South USA
 It containsabout 0.03 - 0.05% alkaloids in particular,
harmane, besides, harmine, harmol, and harmaline
R
N
H
N
Harmane (R = H)
Harmine (R = OCH 3)
Harmol (R = OH)
Pharmacology:
 These alkaloids are short acting monoamino-oxydase inhibitor , replace
benzodiazepines from their receptors
 High doses are acting psychosmimetic
 Leaves are used as sedative
Peganum harmala (Fam. Zygophylaceae)
 The seeds contain 3-4% alkaloids, harmine, harmol,
and harmaline
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 At first CNS-stimulant, after that sedative
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Passiflora incarnata
Quinoline Alkaloids
Alkaloids Derived from Tryptophane
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Quinoline Alkaloids
- 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).
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Alkaloids containing quinoline as their
principle nucleus include those obtained from
cinchona (quinine, quinidine, cinchonine and
cinchonidine).
Cinchona
Chemical structure of Quinoline Alkaloids
Quinine (Cinchonidine epimer at C-9)
Quinidine (Cinchonine epimer at C-9)
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-9-rubanol is the basic skeleton of these alkaloids, which is derived
from the parent compound named ruban.
- Ruban nucleus 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.
Both
Quinine
and
Quinidine,
Cinchonine
and
Cinchonidine are Diastereoisomers. Each pair differs in
the stereochemistry at C-8 and C-9.
HO
H3CO
HO
9
N
N
H
H
H3CO
N
Quinine
8
H
H
N
Quinidine
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 Quinine:
- a diastereoisomer of quinidine, occurs as white, odorless, bitter
crystals.
- Quinine (l) gives Quinidine (d) among other products when warmed
with KOH in amyl alcohol
- Quinine is antimalaria agent.
 Quinidine:
- an antiarrththmic class I (sodium channel blockade).
- inhibits the rapid sodium influx, decreases the rate of
depolarization, contractility, and the atrial and intraventricular
conduction velocity.
- used for treating various cardiac arrhythmias e.g. premature atrial,
ventricular contraction, atrial and ventricular tachycardia, and atrial
flutter and atrial fibrillation.
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 Cinchonine and cinchonidine are used as anti-inflammatory.
The current indications of quinine include the following:
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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 to
quit smoking (60-80mg/day in four doses).
4- in combination with thiamine, to relieve muscle cramps.
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.
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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.
Structure activity relationship:
For antimalarial activity (Quinine):
Removal of vinyl group
loss of activity
Replacement of CHOH by CH2, Co
decrease of activity
Vinyl group
CH
CH2
CH2
CH2
9
HO H C
N
CH3O
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N
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 the uncoiling of DNA, a prerequisite for replication and
transcription).
9
7
O
10
N
11
12
N
20
OH
O
O
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Camptothecine