Lecture 2

Lecture (2)
Protoalkaloids
1
Proto alkaloids
(nitrogen atom is NOT involved in a heterocyclic ring)
A. Alkaloids of the phenylalkylamine group
Precursor amino acid: phenyl alanine
1- Ephedra alkaloids
❖Various species of Ephedra are used as a source of the
alkaloids ephedrine and pseudoephedrine.
Ephedrine and its isomers represent 30-90% of the total alkaloidal
content.
D-(-)-ephedrine L- (+)-pseudoephedrine
3
Ephedrine
Ephedrine is closely related to the animal hormone adrenaline
(epinephrine) in chemical structure and pharmacological action
(adrenergic), but ephedrine has the advantages of:
✓ being effective if taken orally.
✓ more prolonged action than that of adrenaline.
HO
OH OH
H3 CH CH CH3 HO CH CH2
H3 NH CH3 NH CH3
(-)-ephedrine Epinephrine (Adrenaline)

4
1- Ephedra alkaloids Stereochemistry
❖Ephedrine has two asymmetric carbon atoms, thus; there are

four possible optically active forms. The erthroracemate (D-) is
called "ephedrine" and the threoracemate (L-) is known as
"pseudoephedrine".
❖ Natural ephedrine D-(-) isomer is the most active of the four
isomers as a pressor amine. Why?
As this isomer has the correct (R) configuration at the carbon atom
bearing the hydroxyl group, and the desired (S) configuration at the
carbon bearing the methyl group for optimal direct action at adrenergic
receptors. OH OH
NHCH 3 NHCH 3
R S S S
CH3 CH3
D-(-) Ephedrine L-(+) Pseudoephedrine

(-ephedrine) 5
Ephedrine properties:
❖The free base is steam volatile, a property that can be utilized for
its separation from non volatile alkaloids.
❖It does not give precipitate with Mayer’s reagent except in
concentrated solutions.
Ephedrine base + chloroform Ephedrine HCl + PHOSGENE

(Toxic fumes)
+ 25% HCl
pseudoephedrine
6
Isolation and extraction
• Ephedra alkaloids from plant material:
Acid- base extraction
• Ephedrine from pseudoephedrine:
1. Steam distillation
2. Fractional crystallization:
a. Pseudoephedrine HCl more soluble in chloroform
and alcohol than ephedrine HCl
b. Pseudoephedrine oxalate more soluble in water
than ephedrine oxalate.
7
Qualitative tests:
1. Chen’s test.
Copper sulphate test (Chen's test):
1.Solution of ephedrine in water + 2 drops of 5%

CuSO4 + 0.5 ml 20% NaOH ➔ violet color.
2.+ 1 ml ether or benzene & shake ➔ violet color in
the organic layer & blue color in the aqueous
layer.
Quantitative tests:
1. Non- aqueous titration
2. Colorimetric estimation
8
9
Note:
It appeared that pseudoephedrine has much less effect on
β-adrenoceptors than ephedrine but has similar activity as far
as the α-adrenoceptors in the nasal blood vessels.
Therefore, is involved in many flu preparations
10
Precautions:
❖May cause hypertension and induce

anginal pain in patients with coronary
insufficiency or ischemic heart disease.
❖NOT to be used with MAOIs,

antidepressants, cardiotonic and
antiarrythmic drugs ex: quinidine and digoxin
as they potentiate their effects.
❖NOT to be combined with caffeine as it may

exacerbate nervousness and irritability. 11
2- Cathe alkaloids
❖ From Catha edulis (local vernacular name "Kat")

and Ephedra vulgaris
❖The fresh plant especially the leaves
and twigs are chewed.
Uses
Cathine has CNS stimulating effect; so, the
alkaloids, as well as the plant are being used
(or even abused) for the same effect.
Prolonged usage can lead to hypertension,
insomnia or even mania
12
2- Cathe alkaloids
Cathine (+)-Nor--ephedrine L- (+) -ephedrine

L-(+) Pseudoephedrine
➢ Cathine is dextrorotatory & gives +ve Chen's

test.
➢ Cathinone is levorotatory & gives in addition
+ve tests for ketones.
Cathinone
13
3- Peyote alkaloids
❖Mescaline is one of the hallucinogenic
alkaloids present in the dried tops of
Cactus lophophora family Cactaceae
❖It is known as peyote or mescal

buttons as stems are cut into slices
resembling buttons in shape.
14
3- Peyote alkaloids
H3CO
❖Properties NH 2
H3CO
▪ Mescaline is a strongly
alkaline primary amine, soluble OCH3
in water, alcohol, chloroform. Mescaline
(3, 4, 5)-trimethoxy-β-phenyl
ethylamine
❖Tests for identity
❖Action and uses
▪ With Marqui’s reagent, it gives ▪ Produces hallucinations &
an orange color. euphoria accompanied with
mydriasis & unusual color
perception.
15
4- Capsicum alkaloids
❖ Capsaicine is a pungent phenolic
compound that occurs in the fruits of
Capsicum species family Solanaceae.
Capsaicine imparts a pungent taste to

water; the pungency is destroyed by
oxidation (KMnO4). .
❖ Capsaicine DOES NOT possess basic

characters owing to the amide group and
thus can be extracted with ether from acid
or alkaline medium. CH3
HO CH2 NH CO (CH2)4 CH =CH CH
CH3
H3CO
Capsaicine
(Vanillyl amide of isodecanoic acid) 16
4- Capsicum alkaloids
Tests for identity
Isolation (read only)
Capsicum powder 1- With FeCl3 solution
------- a green color (due to its
petroleum ether phenolic characters).
Petroleum ether extract
2- When dissolved in conc. H2SO4
- Alkali and a small piece of sucrose
- CO2 ------- a violet color is developed
Capsaicin crystals after few minutes.
uses
▪ Capsicum is used externally as a counter-irritant in the form of ointment and plaster
for the relief of rheumatoid arthritis & osteoarthritis, neuralgia & diabetic
neuropathy
17
B. Tropolone alkaloids
Colchicum alkaloids
Colchicum autumnale (Liliaceae) contain

the alkaloids colchicine and colchiceine
Characterized by the presence of a 7
membered pseudoaromatic ring =
Tropolone nucleus
18
Colchicine
Colchiceine Allocolchicine 19
Tests for identification

1. Colchicine + mineral acids ➔ yellow color.
2. Ferric chloride test:
– Colchicine ➔ red color &
– Colchiceine ➔ olive green color.
This test is used to differentiate

colchicine from colchiceine.
20
Pharmacology and uses:

❖treatment of GOUT
How???
1. Pain-relieving and anti-inflammatory
effects.
2. Decrease production of uric acid
crystals.
21

❖prevention of attacks of
Mediterranean fever
How???
by decreasing production of a
certain protein (amyloid A) that
builds up due to Mediterranean
fever.
22
❖Anti-leukemic
How?? ?
by binding to tubulin that is responsible for
DNA segregation hence, decrease cell
proliferation.
Although, colchicine effectively reduced

tumors in animals it has two problems;
➢ The inhibition of cell division is not
specific for malignant cells,
➢The required dose is borderline toxic.
23
Demecolcine:
A colchicine derivative (where
the CH3-C=O group attached to
Colchicine
the secondary amino group is
replaced by a methyl group) is
used as an anticancer agent.
BUT less toxic than colchicine.
Demecolcine
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SUMMARY
OR
Capsaicin
Phenyl alkyl amine
Colchicine
H3CO
NH 2
H3CO
OCH3
Mescaline Cathine (d-Nor--ephedrine)
Cathinone
L-(+) Pseudoepherine D-(-) Ephedrine

SUMMARY
Colchicine
Colchiceine Allocolchicine Demecolcine

1. Mention the chemical class of this
alkaloid.
2. Mention its uses.
3. How to differentiate between this alkaloid
and its D-isomer ?
27

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Lecture (2)

(-)-ephedrine Epinephrine (Adrenaline)

❖Ephedrine has two asymmetric carbon atoms, thus; there are

D-(-) Ephedrine L-(+) Pseudoephedrine

Ephedrine base + chloroform Ephedrine HCl + PHOSGENE

1.Solution of ephedrine in water + 2 drops of 5%

❖May cause hypertension and induce

❖NOT to be used with MAOIs,

❖NOT to be combined with caffeine as it may

❖ From Catha edulis (local vernacular name "Kat")

Cathine (+)-Nor--ephedrine L- (+) -ephedrine

➢ Cathine is dextrorotatory & gives +ve Chen's

❖It is known as peyote or mescal

Capsaicine imparts a pungent taste to

❖ Capsaicine DOES NOT possess basic

Colchicum autumnale (Liliaceae) contain

Tests for identification

This test is used to differentiate

Pharmacology and uses:

Pharmacology and uses:

Although, colchicine effectively reduced

L-(+) Pseudoepherine D-(-) Ephedrine

Colchiceine Allocolchicine Demecolcine

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