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Alkaloids
Alkaloids
Piperine
indole
Isolasi and Identifikasi
Indole Alkaloids
1- 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).
2- Polypeptide Alkaloids:
Composed of Lysergic acid and at least 3 amino acids.
• 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.
COOH COOH CONH2
8
N CH3 N CH3 N CH3
10
N N N
H H H
Lysergic acid Isolysergic acid Ergine
Ergonovine (Ergometrine)
OH CH3
H 2C HC HN CO
• Uses:
It causes vigorous contraction of the uterus.
It is mainly used as an oxytocic in order to aid N
H
delivery or to prevent postpartum hemorrhage.
= Ergonovine (l) (Ergometrine)
= Ergonovinine (d) (Ergometrinine)
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
2- Polypeptide Alkaloids
• Characters:
OH
N O CH3
CO
O N
• Uses: O 8
CH2 9 N CH3
Treatment of migraine as it constricts 10
the peripheral blood vessels.
Has some oxytocic (ecobolic) activity.
N
H
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
N O CH3
CO
O N
O 8
CH2 9 N CH3
10
N
H
Stability:
• The active (l) form convert to the (d) isomer by the effect of
Alkalis or prolonged storage in alcohol.
O HO O
C R C R C R
H H
8 8 8
N CH3 N CH3 N CH3
10 10 10
Keller’s test: Solution of the alkaloids in acetic acid with traces of FeCl3
+ concentrated H2SO4 on the wall of the test tube → blue layer is formed
between the two phases.
2- Vinca (Catharanthus) Alkaloids
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.
1- Monomeric Alkaloids:
N
N
H
N C2H5
N N
H
H3COOC N COOCH3
H3COOC
OH C2H5 OH
CH3
H3COOC
• 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.
2- Dimeric Alkaloids:
Mixed dimmers
N R=CH3 Vinblastine
H R=CHO Vincristine
H3COOC HO
N COOCH3
OH
R
H3COOC
• Tests for identification:
• Mechanism:
Both alkaloids are Antimetabolites interfere with the syntheses
of Desoxyribonucleic acids.
Semisynthetic derivatives:
N
• Vindesine:
N
H
H3COOC HO
leukemia in children.
N COOCH3
OH
CH3
H2NOC
• Vinorelbine: N
H
HO
H3COOC
N COOCH3
OH
CH3
H3COOC
3- Physostigma (Calabar beans) Alkaloids
• Source: Physostigma venenosum.
• 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 HO
Me-HN Me Me
Alkaline
Hydrolyses
+ CH3NH2 + CO2
N N
N N
H Me H Me
Me Me
Eserine Eseroline
Eserine upon oxidation, in presence of trace of alkali e.g. NaOH, or
traces of metals is transformed to rubreserine (red compound).
Therefore, it could be affected by the alkalinity of glass containers
during storage.
HO O
Me Me
oxidation
O
N N
N N
H Me H Me
Me Me
Eseroline Rubreserine
N
R
R N
O O
R= H Strychnine
R= OCH3 Brucine
• 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:
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.
H2CrO4
Ethyl Acetate
2 hours, -83- -25°C
80-90% yield5
Discovered in 2004
First route to make synthetic
vincristine6
Spectroscopy
• Mass Spectrum4: M+1=825
• UV Spectrum1: 220, 255, 296 nm
• IR Spectrum6: 3445, 2924, 2852, 1740,
1681, 1597, 1498, 1458, 1369, 1230,
1033, 747 cm-1
History and Uses
• Discovered in 1953 by Robert L. Noble,
and cleared by the FDA in 1963 as
Oncovin, marketed by Eli Lilly and Co.
• Used to treat acute leukemias and all
lymphomas
• Side effects include nervous system
damage and constipation
• Work is being done to develop more
effective derivatives with fewer side
effects8
How it works
• Stops division of cells
• Enters cell during mitosis and blocks
formation of microtubules of the mitotic
spindle during metaphase3,7
Bibliography
• (1) Anonymous Vincristine. In The Merck index: an encyclopedia of chemicals, drugs,
and biologicals; O'Neil, M. J., Ed.; Merck: Whitehouse Station, NJ, 2006; pp 1717-
1718.
• (2) Anonymous Chemfinder.com Database and Internet Searching.
http://chemfinder.cambridgesoft.com (accessed Jan. 22, 2007).
• (3) Anonymous Overview: The Mitotic Spindle. http://www.sinauer.com/pdf/nsp-
cellcycle-6-0.pdf (accessed Apr. 15, 2007).
• (4) Choi, Y. H.; Kim, J.; Yoo, K. Supercritical Fluid Extraction and Liquid
Chromatography-Electrospray Mass Analysis of Vinblastine from Catharanthus
roseus. Chem. Pharm. Bull. 2002, 50, 1294--1296.
• (5) Huhtikangas, A.; Laakso, I.; Seppaenen-Laakso, T.; Verma, A. Patent Application
Country: Application: FI; Patent Country: FI Patent 107924, 2001.
• (6) Kuboyama, T.; Yokoshima, S.; Tokuyama, H.; Fukuyama, T. Stereocontrolled total
synthesis of (+)-vincristine. Proc. Natl. Acad. Sci. U. S. A. 2004, 101, 11966-11970.
• (7) Lurie, P. M.; Manaster, J.; Stryckmans, P. A.; Vamecq, G. Mode of Action of
Chemotherapy in vivo on Human Acute Leukemia--II. Vincristine. Europ. J. Cancer
1973, 9, 613--620.
• (8) Szabo, L.; Bolcskei, H.; Eszter, B.; Mak, M.; Szantay, C. Synthesis of vinca
alkaloids and related compounds, Part XCV: Nitration study of vinblastine-type
bisindole alkaloids. Arch. Pharm. Pharm. Med. Chem. 2001, 334, 339--405.
Quinoline
Quinoline Alkaloids
Cinchona Alkaloids
• Cinchona bark contain many alkaloids the majors are:
1- Quinine and Quinidine.
HO COOH
2- Cinchonine and Cinchonidine.
• Cinchona alkaloids are present
as salts with Quinic and
HO OH
Cinchotannic acids.
OH
Quinic acid
HO HO 8
9
N N
H H H
H3CO H
H3CO
N N
Quinine Quinidine
Properties:
• Quinine is very slightly soluble in H2O, soluble in
ethanol, chloroform, ether, benzene and other organic
solvents.
• Quinine is a diacidic base. It forms 2 types of sulfates:
– Quinine monosulfate (neutral and H2O insoluble).
– Quinine bisulfate (acidic and H2O soluble).
• Quinine (l-isomer) gives quinidine (d-isomer) among
other products when warmed with KOH in amyl
alcohol.
• Quinine is levorotatory, while quinidine is dextrorotatory.
Separation of the 4 Alkaloids
Powdered Bark
- Alk. CaO + NaOH + H2O
- Reflux with benzene &
- Filtration while hot
Benzene filtrate (Alkaloidal bases)
dilute H2SO4
Precipitate Filtrate
Cinchonidine tartrate Quinidine tartrate
• Tests for identification
1- Fluorescence test:
Solution of the alkaloid in oxygenated acids (e.g H2SO4, HNO3 or
phosphoric acid) blue fluorescence (+ ve with quinine and quinidine).
2- Thalleoquine test:
Aqueous solution of the alkaloidal salt + Br2 /H2O (few drops till the
appearance of yellow color) + NH4OH emerald green color
(+ ve with quinine and quinidine).
3- Rosequin test (Erythroquinine test):
Aqueous solution of the alkaloidal salt + dil HCl + Br2 /H2O (few drops till the
appearance of yellow color) + CHCl3 + pot. Ferrocyanide + NH4OH
red color in the CHCl3 layer (+ ve with quinine and quinidine).
Uses:
• Quinine is used mainly as anti-malarial in a dose
of 2g of quinine sulfate or other salt for 14 days.
• Quinidine is used as a cardiac depressant
(anti-arrhythmic), particularly to inhibit auricular
fibrillation in a dose of 0.6-1.6 g of quinidine
sulfate daily.
• Cinchonine and cinchonidine are used as anti-
inflammatory.
Isoquinoline Alkaloids
1- Ipecacuanha Alkaloids
• Occurrence:
Ipecac is the dried roots and rhizomes of Cephalis ipecacuanha (Brazilian
ipecacuanha) or Cephalis acuminata (Cartagena or Panama ipecacuanha)
Fam. Rubiaceae.
It contains several alkaloids (2 –2.5 %), mainly emetine (50- 70 % of total
alkaloids), with cephaline and psychotrine.
MeO MeO
OMe OMe
N OMe OMe
RO H N
H HO
H
N N
R = Me Emetine
Psychotrine
R=H Cephaline
• Emetine:
It is non phenolic and levorotatory.
It contains 2 basic nitrogens.
• Cephaline:
It is phenolic and levorotatory.
It gives emetine on methylation with (CH3)2 SO4.
• Psychotrine:
Occurs as yellow prisms.
It is phenolic and gives cephaline on reduction.
It gives emetine on reduction followed by methylation.
Isolation of Ipeca alkaloids:
Powdered root and rhizome
- Ext. alcohol,Conc., lead acetate.
- Filtration
Filtrate Residue
Alkaloidal bases and salts
Non-alkaloidal sub.
- Evap., dil. HCl & Filtration
Ether layer
Aq.alk. solution(Phenolic alkaloids)
Emetine
- HCl (Alkaloidal salts)
- Alk. NH4OH Ext. ether
MeO
N
Me
O OH H
O
H
Me OH
N+
Me
OMe
• Properties:
d-tubocurarine (4ary alkaloid) is freely soluble in H2O. It is a phenolic
dextrorotatory alkaloid. It is a bis-benzyltetrahydroisoquinoline
alkaloid.
• Tests:
Saturated aqueous solution + FeCl3 faint green color green color.
Solution of the alkaloidal HC1 + Na2CO 3 yellow brown precipitate.
• Uses:
Tubocurarine chloride is mainly used by i.m. or i.v. routes as
skeletal muscle relaxant.
It is used to control and reduce convulsions of strychnine
poisoning and of tetanus.
It is used as a diagnostic aid in myasthenia gravis.