Biosynthesis some alkaloids - Organic Chemistry

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Biosynthesis some alkaloids
Piperine
indole
Isolasi and Identifikasi
Indole Alkaloids
• Occurrence:
1- Ergot Alkaloids
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.
• 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 subclassified
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.
•
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
8
N
CONH 2
N
CH3
CH3
N
CH3
10


N
H
N
H
Lysergic acid
Isolysergic acid
N
H
Ergine
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”.
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


Composed of (l)-lysergic acid and 2-aminopropanol.
Its (d) isomer is called Ergometrinine.
CH3
HC HN
CO
8
N
CH3
10
• Uses:
It causes vigorous contraction of the uterus.
It is mainly used as an oxytocic in order to aid
delivery or to prevent postpartum hemorrhage.
N
H
=
=
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
10
N
H
CH3
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.
Ergotamine
• Characters:
 Its (d) isomer is called Ergotaminine.
 The peptide moiety is composed of 3 amino acids:
a-Hydroxyalanine
Proline
Phenylalanine
OH
O CH3
N
• Uses:
Treatment of migraine as it constricts
the peripheral blood vessels.
Has some oxytocic (ecobolic) activity.
O
CO
N
CH2
O
8
N
9
10
N
H
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
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
N
CH 3
10
10
8
CH 3
N
CH 3
10
(l) form
(d) form
• Addition of water to the 9- 10 double bond takes place in
aqueous acidic solutions, upon exposure to day or UV light.
The resulted Lumi alkaloids are inactive.
O
C
R
H
8
HO
10
N
CH3
• Tests for identification:
 Van-Urk's Reagent (p-dimethyl aminobenzaldehyde (PDAB) in 15%
H2SO4, containing traces of FeCl3) + Alkaloid → Deep blue color.
 Erlich Reagent (p-dimethyl aminobenzaldehyde (PDAB) in H2SO4) +
Alkaloid → Deep blue colour.
 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:
H
N
H3COOC
OH
N
N
N
N
H
H3COOC
C2H5
Vincamine
C2H5
N
CH 3
H3COOC
Catharanthine
COOCH 3
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.
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 .
Structures:
• Vinblastine (Vincaleukoblastine) is produced by coupling of Catharanthine
and Vindoline.
• Vincristine (leurocristine) has CHO istead of CH3 in the vindoline part of
Vinblastine.
N
N
H
H3COOC
R=CH3 Vinblastine
R=CHO Vincristine
HO
N
N
R
H3COOC
COOCH 3
OH
• Tests for identification:
 1-Vanillin /HCl reagent gives with:
Vinblastine a pink color.
Vincristine an orange-yellow color.
 2-Van-Urk's reagent:
→ Reddish-brown color.
• 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:
 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 lymphoid
N
leukemia in children.
N
COOCH 3
CH 3
H2NOC
OH
N
• Vinorelbine:
N
H
H3COOC
HO
It is an oral anticancer with broader activity
and lower neurotoxicity than vinblastine.
N
N
CH 3
H3COOC
COOCH 3
OH
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
M e -HN
HO
Me
Alkaline
Hydrolyses
N
N
N
H
Me
Eserine
Me
Me
N
H
Me
Eseroline
+ CH3NH2 + CO2
Me

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
oxidation
Me
O
N
N
H
N
Me
Me
Eseroline
N
H
Me
Me
Rubreserine
•
Tests for identification:

Eserine blue test: Eserine + strong ammonia solution → Yellowish red
color , evaporation → Bluish residue soluble in alcohol (eserine blue).

Eserine + alkali hydroxides → Red color.
•
Uses:

It has a cholinergic effect and stimulates glands’ secretion
(c.f. atropine) act by inhibition of choline-esterase. So used
in poisoning by Solanaceous Alkaloids.

Treatment of Alzheimer’s disease due to cholinergic effect .

Eserine is mainly used as a myotic drug in the treatment of
glaucoma.

Diaphoretic in cases of kidney dysfunction.
4- Nux-Vomica Alkaloids
• Source:
– Seeds of Strychnose nux vomica and Ignatus beans.
• 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
• 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.
Brucine is less toxic than strychnine.
 It is sometimes used as CNS stimulant,
 Commercially it is used as alcohol and oil denaturant
Vincristine
Overview
• I. Physical Properties
• II. Synthesis
• III. Characterization
• IV. History and Uses
• V. How it works
General Information2
•
•
•
•
•
CAS Number: 57-22-7
Molecular Formula: C46H56N4O10
Molecular Weight: 824.97
Melting Point: 218-220°C
Clear liquid
(taken by injection)
Synthesis from a Natural
Source
• Vincristine has two natural sources:
Catharanthus roseus (Vinca rosea), the
Madagascar periwinkle, and
Tabernaemontana pachysiphon
• This yield from the Madagascar periwinkle
is less than 1μg/g (.0003%)6
Synthesis from vinblastine
H2CrO4
Ethyl Acetate
2 hours, -83- -25°C
80-90% yield5
• This is the easiest and most common method of
synthesis, as well as one can give high yields
Synthetic Production
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 17171718.
(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/nspcellcycle-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
• They are diacidic bases form two types of salts:
1- Neutral salts (Monoacidic) (less water soluble.
2- Acidic salts (Diacidic) water soluble.
• Both Quinine and Quinidine, Cinchonine and Cinchonidine
are Diastereoisomers. Each
stereochemistry at C-8 and C-9.
HO
H3CO
N
H3CO
Quinine
in
8
N
H
N
differs
HO
9
H
pair
H
H
N
Quinidine
the
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
Acidic aqueous layer (Alkaloidal bisulphates)
pH to 6.5 with Na2CO3
Precipitate (monosulphate)
Quinine
Hot water, Na2CO3
Aqueous solution (Monosulphates)
quinidine,
cinchonine & cinchonidine
NaOH, ether
Quinine
Ether layer
Quinidine & Cinchonidine
Aqueous layer
-HCl PH=7, Na, K Tart. salt
- filter
Precipitate
Filtrate
Cinchonidine tartrate
Quinidine tartrate
Cinchonine
• 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 antiinflammatory.
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
RO
MeO
OMe
N
H
OMe
H
N
R = Me Emetine
R=H
Cephaline
HO
OMe
OMe
N
H
N
Psychotrine
• 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
Alkaloidal bases and salts
Residue
Non-alkaloidal sub.
- Evap., dil. HCl & Filtration
Filtrate (Alkaloidal HCl salts)
- Alk. with NaOH & Ext. with ether
Ether layer
Emetine
Aq.alk. solution(Phenolic alkaloids)
Aqueous layer
(Psychotrine)
- HCl (Alkaloidal salts)
- Alk. NH4OH Ext. ether
Ether layer
(Cephaline)
 Tests for identification of Ipeca alkaloids:
•
Alkaloidal solution in HCl + Ca hypochlorite  orange color.
•
Emetine and cephaline + Froehd's reagent: dirty green color (the
color with emetine fades by addition of HCl).
•
Psychotrine + Froehd's reagent: pale green color.
•
Cephaline and psychotrine + p-nitrodiazobenzene  dye soluble in
NaOH  purple color.
•
Psychotrine + conc. H2SO4 + HNO3  cherry red color.
•
Emetine + Liebermann's reagent  black color.
 Uses:
• Emetine and cephaeline have antitumour and antiviral
activity, but are too toxic for therapeutic use.
• Emetine and psychotrine are mainly used as emetic
drugs.
• The crude drug is used as expectorant (due to its saponin
content) .
• Emetine HCl and Dehydroemetine (DHE) have
an
antiamoebic effect, and are used for the treatment of
amoebic dysentry and Fasciola.
• Ipeca alkaloids are diaphoretic, alone or in combination with
opium (e.g. Dover's powder).
2- Curare Alkaloids
• Occurrence:
• Curare or South American arrow poison is the dried crude extract, obtained
mainly from Chondrodendron tomentosum (Menispermaceae) and certain
Strychnos species, (Loganiaceae).
•
Curare contains several alkaloids (4-7%), the most important is d-tubocurarine.
MeO
N
Me
OH H
O
O
Me
Me
H
N+
OH
OM e
•
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.



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