Alkaloids of the Indole Group

Indole

N H Indole alkaloids are biosynthetically derived from Tryptophan

amino acid.

This group includes:

Tryptophan

O OH NH2

* Physostigma alkaloids.

* Ergot alkaloids. * Nux vomica alkaloids. * Vinca alkaloids. * Rauwolfia alkaloids.

N H

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
O C H3C HN O H 3C

N N

Eserine

CH3

CH3

Uses
A myotic drug, it has a cholinergic effect and stimulates gland secretion.

2) Nux vomica alkaloids

* Derived from the ripe seed of Strychnos nux

vomica (Fam.Loganiaceae).
* The major alkaloids are Strychnine and Brucine.

* Brucine is Dimethoxy derivative of Strychnine.

N H R1 H H R2 N H O H O

R1 = R2 = H

Strychnine

R1 = R2 = OCH3 Brucine

* Strychnine and Brucine are soluble in alcohol, CHCl3, insoluble in H2O. * Strychnine is insoluble in acetone but Brucine soluble . Strychnine and Brucine are mono-acidic base alkaloids,

because one of the N atoms is incorporated in amide moiety and has no basic character (i.e Neutral).

Uses:
1) Strychnine was formerly used as bitter stomachic, stimulant and improves the appetite.
2) In large doses, it causes violent convulsions, involving the respiratory muscles, death occurs due to asphyxia.

3) Strychnine and Brucine are poisonous alkaloids & are used as poison for rats and other animals.

Chemical Tests
1) Nitric acid test:
Strychnine Brucine HNO3 HNO3 Yellow color Intense orange red color evaporation SnCl2 Violet color

2) Tests for Strychnine:

A) Crystals of Strychnine H2SO4 K2Cr2O7 Violet to purple color

B) Mandalin's reagent (Sulphovanadic acid) Strychnine + Mandalin's reagent Deep violet blue color H2O Cherry-red color

Alkaloids of the Carboline skeleton (Group of Indole Alkaloids)

6 7 8 5 4 3 2

N
1

-Carboline

N9 H

Alkaloids of Rauwolfia or (snake root)

* Rauwolfia is the dried rhizome and roots of Rauwolfia serpentina (Apocynaceae).
* These alkaloids include Reserpine, Deserpine and

Recinnamine.

R
N H H

H3CO N H O

OCH3

OCH3 O H OCH3 O

H3CO

Reserpic acid part

3,4,5-Trimethoxybenzoic acid part

Reserpine R = OCH3 Deserpine R = H

H3CO N H H3CO O H H OCH3 OCH3 OCH3 N H O OCH3 O

Reserpic acid part

Recinnamine

3,4,5-Trimethoxycinnamic acid part

Uses
*Reserpine is an excellent antihypertensive
and tranquillizer.
* Rauwolfia was formerly used as an antidote to snake-
bites ( hence the name Snake root).

Vinca alkaloids (Catharanthus alkaloids)

Catharanthus or Vinca is the dried whole plant of
Catharanthus roseus (Fam. Apocyanaceae).
OH N N H COOCH3 H3CO N OH CH3 COOCH3 OCOCH3 N

R Vincristine (R = CHO) Vinblastine (R = CH3)

* Vinca alkaloids are Dimeric alkaloids having Indole

and Dihydroindole nuclei. * Vincristine and Vinblastine are the major alkaloids in
Vinca, they differs only in the substitution on the N-

atom of the Dihydroindole nucleus.

Uses:
Vincristine used in treatment of Leukemia in children.
Vinblastine is used for treatment of Hodgkins disease.

Ergot Alkaloids
* Medicinal ergot is the dried sclerotium of the fungus Claviceps

purpurea (Clavicipitaceae) developed on the ovary of rye, Secale cereale (Graminae).

* Ergot alkaloids are N-monosubstituted amide derivative of both Lysergic acid and its isomer Isolysergic acid. * These acids forms with ammonia the corresponding amide

Ergine and Isoergine

OH
7

OH
6

CH3 H
4

CH3 H
4

3 2 1

3 2 1

NH

NH

(+)-Lysergic acid

(+)-Isolysergic acid

NH2
7

NH2
6

CH3 H
4

CH3 H
4

3 2 1

3 2 1

NH

NH

Ergine

Isoergine

* Ergot alkaloids include major alkaloids divided into 6 pairs according to their peptide moieties.
* Members related to Lysergic acid e.g. Ergotamine and Ergometrine.These are the pharmacologically active members.

*Members related to Isolysergic acid ending with the suffix inine e.g. Ergotaminine and Ergometrinine & these are pharmacologically inactive.

Classification of Ergot alkaloids:

CH3 Hydrolysis

1) Alkaloids of the Ergometrine group

2-amino propanol

OH H2N

O Hydrolysis

2) Alkaloids of the Ergotamine group

Pyruvic acid

OH + Three amino acids H3 C O O O

Hydrolysis

3) Alkaloids of the Ergotoxine group

Dimethyl Pyruvic acid H3C

O

+ Three amino acids

CH3

The simple Lysergic acid amides

* They are water soluble * They are all amides of Lysergic acid with simple amines (2-

aminopropanol)
*

e.g. Ergometrine (L-lysergic acid with 2-aminopropanol)

and Ergometrinine (D-lysergic acid with 2-aminopropanol)
CH3 OH NH CH3 O N H

NH

Ergometrine

The Polypeptide Alkaloids

* Based on the nature of the three amino acids, these structures can be subdivided into two groups, both contain proline amino acid: 1) Ergotamine group. 2) Ergotoxine group.

* Hydrolysis of ergotamine gives (+)-lysergic acid, proline, and phenylalanine together with pyruvic acid and ammonia.

Proline part

H HO O H3C HN O N

-Phenylalanine part

Pyruvic acid part CH3

N H

Lysergic acid part

NH

Ergotamine

Hydrolysis

Ergometrine
Hydrolysis

Lysergic acid

+ 2-aminophenol

Ergotamine

Lysergic acid + Pyruvic acid + -Phenylalanine + D-Proline

Chemical Test: Van-Urk's test

Solution of Ergot alkaloids + Van-Urk's test (p-dimethylaminobenzaldehyde in 15% H2SO4) containing traces of FeCl3

Deep blue color

Uses
Ergometrine is used as an Oxytocic , and is injected during the
final stages of labour and immediately following childbirth, especially if haemorrhage occurs. Bleeding is reduced because of its vasoconstrictor effects, and it is valuable after Caesarian operations. * Ergometrine is also orally active. It produces faster stimulation of uterine muscle

Ergotamine is used in the treatment of acute attacks of

migraine, Ergotamine is effective orally, or by inhalation in aerosol
form, and may be combined with caffeine.

LSD
Lysergic acid diethyl amide is a semisynthetic Compound prepared from lysergic acid. It is a powerful hallucinogen.

Ergotism
It is a poisonous case resulting from the chronic consumption of rye or wheat flour contaminated with ergot. Alkaloids of ergot cause vasoconstriction especially in the limbs, that may results by time in gangrene of one or more limbs.

Imidazole Alkaloids
ALKALOIDS DERIVED FROM HISTIDINE
H N
H N

OH N NH2

Imidazole

L-Histidine

The imidazole alkaloids found in Jaborandi leaves (Pilocarpus microphyllus and P. jaborandi; Rutaceae)

CH3 N

CH3

CH3 N

CH3

CH3 N

HO H O

O N O N O

O N O

Pilocarpine

Isopilocarpine

Pilosine

* Pilocarpine is oily non-volatile liquid alkaloid.

* Pilocarpine is a mono-acidic tertiary base, having a

lactone ring and an Imidazole nucleus. * The lactone ring in Pilocarpine is opened by caustic alkalis but not affected by ammonia, this leads to loss the activity.
* The imidazole ring in Pilocarpine is destroyed by

oxidation with KMnO4

Uses
* Pilocarpine salts are valuable in ophthalmic practice
and are used in eye drops as miotics and for the treatment of glaucoma. Pilocarpine is a cholinergic agent and stimulates the
muscarinic receptors in the eye, causing constriction of

the pupil . * The effects are similar to those of physostigmine and the two agents are sometimes combined.

* Pilocarpine is antagonistic to Atropine.

* Pilocarpine gives relief for dryness of the mouth that

results in patients undergoing radiotherapy for mouth

and throat cancers.

* As muscarinic agonists, pilocarpine and analogues are

also being investigated for potential treatment of

Alzheimers disease.

Chemical Tests: 1) Helch's test

Aqueous solution of Pilocarpine salt + drops of H2O2 + drops of K2Cr2O7

Violet color

2) Ekkert's test
Aqueous solution of Pilocarpine HCl + Na nitroprusside + dil NaOH
leave few minutes then acidify with HCl

Wine-red color

Na2S2O3

Green color

PURINE ALKALOIDS
* Purines are derivatives of a heterocyclic nucleus consisting of a six-membered Pyrimidine ring fused to a five-membered Imidazole ring.
6 5 7 H N 8 N N 4 9 3 Purine O 6 H N

N N Pyrimidine

HN N Imidazole

1 N 2

1 HN O 2

N N H Xanthine (2,6-dioxy-purine)

Purines are Psudo alkaloids (Are not derived from amino acids
but have nitrogen in a heterocyclic ring)

* The purine alkaloids Caffeine,

Theobromine, and

Theophylline are all methyl derivatives of xanthine.

* The major sources of these compounds are the beverage materials such as tea,
1 H3C O N N 3 CH
3

coffee, cocoa, and cola.

O H N HN O 3 N CH3 7 N CH3 1 H3C N O 3 N CH3 O N 7 CH3

Theophylline (1,3-dimethylxanthine)

Theobromine (3,7-dimethylxanthine)

Caffeine (1,3,7-trimethylxanthine)

* These alkaloids are very week bases, they form salts only with strong acids.

* These alkaloids give No precipitate with Mayers

reagent but give brown precipitate with Wagners reagent. * They give a positive Murexide test.

Occurrence
* Coffee consists of the dried ripe seed of Coffea arabica or other
Coffea species (Rubiaceae).

* Tea is the prepared leaves and leaf buds of Camellia sinensis

(Thea sinensis) (Theaceae).

* Cola, or kola, is the dried cotyledon from seeds of various

species of Cola e.g. C. nitida and C. acuminata (Sterculiaceae).

* Cocoa (or cacao) is derived from the roasted seeds of

Theobroma cacao (Sterculiaceae).

Caffeine
Soluble in H2O, benzene, ethanol and CHCl3

Theophylline
Soluble in H2O, and ethanol

Theobromine
Slightly soluble in H2O, ethanol and CHCl3.
Insoluble in ether and benzene

Sparingly soluble in Insoluble in ether and ether, soluble in benzene. benzene.

Soluble in dil acids

Freely soluble in dil acids, alkali and NH4OH It can form salts with both acids and bases. It is more acidic than Theobromine

Freely soluble in dil acids and alkali but insoluble in NH4OH

Weak base does not form salts). Decomposes by strong caustic alkalis.

ISOLATION OF CAFFEINE, THEOPHYLLINE AND THEOBROMINE FROM TEA

Powdered Tea

Boiled with H2O

Lead acetate

Filtrate
(to ppt. Tannins)

Filter
- Conc
- Add Sod. hydrogen phosphate

Filter

to remove excess lead

Filtrate
Shake with CHCl3

CHCl3 layer

Aq. layer
(Theophylline & Theobromine)

CAFFEINE

Add NH3 Soluble Insoluble

THEOPHYLLINE

THEOBROMINE

Uses
Caffeine
Is the best CNS stimulant of the purine bases and has weak diuretic action.

Theobromine
Has little CNS stimulant action, but has more diuretic activity, and has smooth muscle relaxant effect.

Theophylline
Has low CNS stimulant action and is an effective diuretic, but it is an important smooth muscle relaxant &

used for relief of bronchospasm.

Diterpene Alkaloids

Taxol
* Present in the barks of Yew tree Taxus brevifolia (Fam. Taxaceae).

* Taxol is being used clinically in the treatment of

ovarian and breast cancers, lung cancer, and cancers

of the head and neck.

O H3C H3C

O O O OH CH3 CH3 O OH HO CH3 H O O O O CH3

HN

Taxol