Course description - Psau...Course description: The aim of the course is to complete the study of...
Transcript of Course description - Psau...Course description: The aim of the course is to complete the study of...
Course description:
The aim of the course is to complete the study of thechemical constituents of drugs containing: Glycosides andAlkaloids. The course will study some narcotic plants andtoxic plants, especially those present in the Kingdom,aiming to provide students with information about theiridentification and treatment of their poisoning. Examplesfrom marine natural products derived drugs will bediscussed. The course will also cover the herb-druginteractions.
Alkaloids1 1Ramzi Moth
Alkaloids
They are nitrogenous heterocyclic compounds occurring in
Plants, formed biosynthetically from amino acids
1- True Alkaloids
are basic compound nitrogen atom is a part of
heterocyclic system derived from amino acids
3- Protoalkaloids
nitrogen atom is not a2- Pseudoalkaloids
are not derived from
amino acids, such as
terpenoid alkaloids
partof a heterocyclic ring, e.g.colchicine, ephedrine and
cathinone
Ramzi Mothana Alkaloids1 2
Distributionrarely in bacteria, fungi and pteridophytes,
essentially found in Angiosperms e.g. Liliaceae,
Amaryllidaceae, Ranuncolaceae, Papaveraceae,
Solanaceae, Berberidaceae, Rubiaceae,
Apocynaceae and Buxaceae
LocalizationAs soluble salts (citrates, malates, tartrates,
benzoate, meconates) or in combination with
tannins, and localized in peripheral tissues e.g.
external layers of the bark of the stems and roots
Function in PlantsPoisonous agent for protecting the plants
against insects and predator.
Detoxification products.
Reserve materials capable of supplying nitrogen
especially for protein synthesis.
Regulatory growth factors
1-
2-
3-
4-
Detection and Characterization
• A detection technique ought to be, to the extent possible, rapid, simple, reproducible, and sensitive; it must be applicable to small sample.
• The detection methods currently in use are preceded by an extraction and consist, most generally, in precipitating the alkaloids by using fairly specific reagents: the " general reagents of alkaloids".
• The preliminary extraction can be a "classic" alkaloid extraction or an alcoholic maceration, which takes less time: the alcoholic solution is evaporated and the residue redissolved in acidic water; after filtering, the alkaloids are characterized in the filtrate.
• The general reactions of precipitation are based on the fact that alkaloids form combination with metals and metalloids: bismuth, mercury, tungsten, and iodine.
• In practice, what is used is a solution containing iodine and iodide, or a solution containing potassium iodide and mercuric chloride- known as Mayer's reagent-
• or a reagent containing bismuth nitrate and potassium iodide, better known as Dragendorff's reagent. I
• t is also possible to use silicotugestic acid (a mixture of tungsten and silicon oxide), or alkaline solution of iodoplatinates.
• The specificity of these reagents is not absolute: proteins, α-pyrones, some coumarins, hydroxyflavones, lignans, and other compounds can give false positive reactions with Dragendorff's reagent.
Ramzi Mothana Alkaloids1 4
Detection and characterization:
A- Precipitation by certain reagents
Mayer’s reagent (potassium-mercuric iodide)
Yellowish-white precipitate
Dragendorff’s reagent(potassium-bismuth
iodide) give orange color
Wagner’s reagent (potassium triiodide)
red color
1-
2-
3-
B- Color reactions with certain reagents
1- Froehd’s reagent (sulphomolybdic acid)
2- Marqui’s reagent (formaldehyde + H2SO4)
3- Mandalin’s reagent (sulphovanadic acid)
4- Mecke’s reagent (selenic acid + H2SO4)
5- Erdmann’s reagent (HNO3 + H2SO4)
Extraction of Alkaloids
• The extraction of alkaloids is based, as a
general rule, on the fact they normally
occur in the plant as salts and on their
basicity, in other words on the differential
solubility of the bases and salts in water
and organic solvents.
A. Extraction per se
• Solvents Extraction in Alkaline Medium
* First step. The powdered defatted drug is
mixed with an alkaline aqueous solution
which displaces the alkaloids from their
combinations as salts; the free bases are
then extracted with an organic solvent.
• Second step.
• The organic solvent containing alkaloids as bases is separated from the residue and if necessary, partially concentrated by distillation under reduced pressure.
• The solvent is then stirred with an acidic aqueous solution: the alkaloids go into solution in the aqueous phase as salts, whereas the neutral impurities remain in the organic phase.
• The operation is repeated as many times as necessary until the organic phase no longer contains any alkaloids.
* Third step.
• The aqueous solution of the alkaloid salts, combined, and if necessary, "washed" with an apolar solvent (hexane, diethyl ether) are alkalinized with a base in the presence of an organic solvent not miscible with water.
• The alkaloids as bases precipitate and dissolve in the organic phase.
• The extraction of the aqueous phase continues until the totality of the alkaloids has gone into the organic phase (which is easy verified as Mayer's reaction on the aqueous phase becomes negative).
• The purification step may be carried out, like the previous one and depending on the quantity, in an separation funnel, or in more or less complex apparatuses: centrifugal extractors and other types of on-line set ups.
* Finally,
• the organic solvent containing the alkaloid
as bases is decanted, freed from possible
traces of water by drying over an
anhydrous salt (for example, sodium
sulfate),
• and evaporated under reduced pressure.
• A dry residue is left: the total basic
alkaloids.
Extraction of alkaloids
A- Solvent extraction on alkaline medium
Powdered defatted drug
+ NH3 or Na2CO3
+ organic solvent (CHCl3)
Residue CHCl3-Phase
(Alkaloid-Bases)evaporation
d (HCl)
Organic phase
(CHCl3-Phase containing
impurities)
Aqueous phase
(Alkaloid- salts)
+ NH3 or Na2CO3
+ organic solvent
Organic phase
(Purified alkaloid-bases)Aqueous phase
B- Solvent extraction on acidic medium
+ dilt. Aci
+ NH3 or
+ organic
Extraction in Acid Medium
• Two approaches are possible: in the first one, the pulverized drug is extracted directly with acidified water; in the second case, it is extracted with an acidified alcoholic or hydroalcoholic solution.
• In the latter case, the extraction is followed by a distillation under vacuum which eliminates the alcohol and leaves behind an acidic aqueous solution of the alkaloid salts.
• In both cases, the result is an aqueous solution of alkaloid salts requiring purification. This can be accomplished by:
1. Alkalinizing the solution and extracting the bases
with an immiscible organic solvent, this leads
back to the above step;
2. Selectively adsorbing the alkaloids contained in
the solution on an ion-exchange resin, then
eluting them with a strong acid;
3. Precipitating the alkaloids as iodomercurates.
The resulting complex is recovered by filtration,
dissolved in a mixture of water, alcohol, and
acetone, and decomposed by passing it through
an ion-exchange resin. This technique can be
used to extract quaternary ammonium salts.
Powdered Drug
Extracted marcorganic extract
(alkaloids, lipids, pigments)
base(NH4OH, Na2CO3, etc.)
organic solvent
not miscible with water
(CHCl3, CH2Cl2, Et2O, etc.)
extracted solvent(neutral alkaloids)
concentrationextraction by
a dilute acid
(HCl, H2SO4, etc)
acidic aqueous solution(alkaloid salts)
Priciples of alkaloid
extraction in
alkaline medium
extraction by an organic solvent
not miscible with water
(CHCl3, CH2Cl2, Et2O, etc.)
extractedaqueous solution
(quaternary alkaloids)
organic alkaloidsolution
TOTAL (basic)ALKALOIDS
Ramzi Mothana Alkaloids1
Alkaloids Derived from Phenylalanine and Tyrosine
The following groups of alkaloids belong to this class:
1- Phenylalkylamine group
2- Isoquinoline group
3- Tropolon group
4- Amarylidaceae group
7
1- Phenylalkylamine group
1.1. Benzylamine type 1.2. Phenylethylamine type
1.3. 2-Aminophenylpropan type
8
2
N
R R
N
R R
N
R R
Ramzi Motha
Papaver somniferum
Llkalaoitdse1x (Opium) 16
Morphine:
First isolation in 1805 by Surtner
Crystallize from dilute ethanol as colorless prisms, stable in air
Morphine base is springly soluble inCHCl3, insoluble in ehter
It dissolves in caustic alkali
It is a pentacyclic molecule with five asymmetric centers
Methylation of morphine
Acetylation of morphine
Chemical tests:
codeine
heroin
1- Iodic acid test: morphine + H2SO4 + IO3, the color disappears
2- aqueous solution of morphin + K3[Fe(CN)6] + FeCl3
deep blue color
then shake with CHCl3 violet color is produced
3- Morphine solution + conc. HNO3
then yellow color, then destroy after a period.
Pharmacology:
orange red color
1- Morphine exerts a depressant action on the CNS
(hypnotic, narcotic)
2- Morphine depresses the cough center.
3- It causes myosis.
4- It acts on the pituitary to decrease the secretion of FSH, LH
and ACTH.
5- Morphine can be used as starting material for the synthesis of
apomorhine (as emetic drug used),
17
Ramzi Mothana Alkaloids1 18
Codeine
Codeine is methyl morphine
It may be obtained from opium or by methylation of
morphine or from thebaine by reduction and demethylation.
Codeine and its salt occur as fine needles or as white
crystalline powders.
Pharmacology: Codeine has an antitussive activity
Codeine is also a potent analgesic, acting like morphine on
enkephalinergic receptors, but with a much less intense action.
Papaverine:
Insoluble in H2O, soluble in CHCl3, in the form of prisms
It is smooth muscle relaxant (antispasmodic)
its ability to inhibit the phosphodiestrase, which hydrolyzes
cAMP, and to decrease the intracellular Ca-concentration.
Tests:1- in H2SO4, give colorless solution, which becomes red at
2- Warren’s test
with KMnO4 mixed and by adding Marqui’s reagent, green
color appears, which rapidly changes to blue
110 C
Bisbenzyltetrahydroisoquinolines
Curare alkaloidsdried extract from the bark and stems of Strychnos species
e.g. S. castelnaei, S. toxifera, S. crevauxii (Fam. Loganiaceae)
and from Chondodendron species (Fam. Menispermaceae)
used as arrow poison by certain native tribes of the Amazon
regions of South America.
According to the containers in which the drug was packaged
there are 3 preparations:
1- Calabash (gourd) curare
-
-
-
poured into the fruits of various Bignoniaceae
originally from Colombia, Venezuela
from the genus Strychnos (Loganiaceae) including S. toxifera
and S. letails etc.
2- Tube (bamboo) curare
-
-
-
poured into bamboo tubes
from Brazil and Peru, used as arrow poison.
composed chiefly of extracts of stems of Menispermaceae
of the genus C. tomentosum
3- Pot (clay pot) curare
-
-
-
poured into clay pots of various shapes,
specific to the upper Orinoco and upper Amazon basin
contains a mixture of extracts of Menispermaceae and
Loganiaceae.
The active constituent of curares are very different
according to the plant extract used.
1- Menispermaceous curares
- 2 to 10% bisbenzyltetrahydroisoquinoline alkaloids,
(+)-tubocurarine (quaternary ammonium structure
with two ether bridges), the other alkaloids are
tertiary bases : (-) curine, (+) - isochondrodendrine
and (+) chondrocurine.
- (+)-tubocurarine
- a white or yellowish white to grayish white, odorless,
derived from tube curare and isolated in 1898,
soluble in water and in alcohol, insoluble in acetone,
chloroform and ether.,
- it is a non-depolarizing neuromuscularblocking
agent , employed i. m or i. v. as a skeletal muscle
relaxant to secure muscle relaxation in surgical
procedures.
- Its use was discontinued about ten years ago. A
semisynthetic derivative of C-toxiferine is used
N, N-diallylnortoxiferinium dichloride
(=alcuronium), which is used i. v. as adjunct in
anesthesia.
2- Loganiaceous Curares:
- are symmetrical bis quaternary ammonium
alkaloids, C-toxiferine (calabash), C-curarine,
C-alkaloid G and E, C- calebassine and other
(indole alkaloids)
- The crude extract exhibits a paralyzing effect on
voluntary muscle (curari-form effect) by
blocking nerve impulses to skeletal muscles
at the myoneural junction.
- It also produces a toxic action on blood vessels
as well as histamine-like effect.
Identification:
1- Aq. Solution + FeCl3 faint green c.
Yellow-brown ppt2- Aq. Solution + Na2CO3
Ramzi M na Alkaloids1 32
Alkaloids Derived from Tryptophane
This group of alkaloids is classified into two main subclasses:
1- Indol alkaloids 2- Quinoline alkaloids
A- Simple Indol alkaloids B- Monoterpenoid Indol alkaloids
1- Indolalkylamine type
e.g. bufotenine,
psilocybine
2- Physostigmine-type
e.g. physostigmine
N
otha
N
H R R
Indolealkylamine-type
N N
H H
Physostigmine-type
Ramzi Mothana Alkaloids1 33
3- β- Carboline-type 4- Ergoline-type
e.g.e.g. harmaine, harman
and harmaline ergometrine, ergotamine
N
B- Monoterpenoid Indol alkaloids
In Apocynaceae, Rubiaceae and
Loganiaceae
1-
2-
3-
4-
5-
6-
7-
Ajmallicine type (e.g. Raubasine)
Eburnamine type (e.g. vincamine)
Yohimbine type (e.g. yohimbine, reserpine)
Ajmaline-type (e.g. ajmaline)
Aspidsperma type (e.g. vindoline)
Iboga type (seco form as monomer I of vincaleukocristin)
Strychnine type (e.g. strychinin, C-toxiferine)
N
H
Carboline-type
NH
NH
Ergoline-type
Ramzi Mothana Alkaloids1 37
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
Harmine (R = OCH3)N
Harmol (R = OH)R N
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
At first CNS-stimulant, after that sedative
Harmane (R = H)
N Harmine (R = OCH3
H
Claviceps purpurea
Ergometrine:
- a potent oxytocic,
- it increases the frequency and strength of uterine
contractions.
- methylergonovine (methylergometrine) is the
preferred medication, this is the amide of lysergic
acid and of 2-aminobutanol, a semisynthetic
derivative that is more active on the uterus and
practically devoid of alpha-adrenergic antagonist
activity;
- It is indicated for treating afterbirth delivery and
post-partum hemorrhages, after cesarean sections.
Ergotamine:
- at low doses potent vasoconstrictor acting by
stimulation of the alpha-adrenergic receptors.
- at higher doses, an adrenergic antagonist activity
appears, which is weak. , in addition ,
- Ergotamine tartrate is used for treating the acute attack
of migraine headache and related vascular headaches.
Isomerisation of ergot alkaloids:
1- Ergot alkaloids (l)-form can be converted to ergot
alkaloids (d)-form under reflux with methanolic alkali.
2- Ergot alkaloids (d)-form can be converted to ergot
alkaloids (l)-form under reflux with alcoholic acetic
acid and phosphoric acid.
3- Ergot alkaloids (l)-form produce in aqueous solution
under the influence of light, especially UV-light
Lumi-alkaloids. N-RN-R
CH3CH3 O = C
HO = C
H
NN UV H
H
HO
Lumi-alkaloid
Identification:1- Van-urk reaction
(with dimethylaminobenzaldehyde in
gives blue color)2- Keller’s reaction
acidic conditions
(with glacial acetic acid, traced of FeCl3 and H2SO4, intense
3- Aqueous solution of the alkaloids gives blue
fluorescence under UV-light (365 nm)
blue color is formed)