Transcript PHG322_2 )2016(.pptx

Alkaloids Derived from Tryptophan
1- Indole Alkaloids
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Drugs containing indole Alkaloids
1- Physostigma alkaloids (Calabar bean alkaloids)
The drug is the seed of Physostigma venenosum (Leguminosae)..
It contains alkaloids (0.2-0.3%), chiefly represented by
physostigmine (eserine) and eseramine.
Physostigmine is a tertiary base, possessing an ester linkage.
Uses
It is a reversible cholinestrase inhibitor,
it behaves as parasympatomimetic causing myosis,
bradycardia, hypotension
used as a myotic drug (in the treatment of glaucoma).
Being replaced by synthetic anticholinestrase e.g.
neostigmine
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Properties of Physostigmine (Eserine)
It is a tertiary base, possessing an ester linkage.
colorless crystals , soluble in H2O, CHCl3, unstable and rapidly
oxidized if exposed to air and light.
Contains 3 Nitrogen atoms.
Eserine on alkaline hydrolysis  Eseroline + Methylamine +
CO2.
O
O
Me-HN
HO
Me
Alkaline
Hydrolyses
3
1
N 2
N
N
H
Me
N
Me
H
+ CH3NH2 + CO2
Me
Me
Me
Eseroline
Eserine
N-methyl pyrrolidine 1,3-dimethyl
methyl carbamic acid -2,3- dihydroindol
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2- 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).
• Ergot can be detected in flour by using UV light where
contaminated flour will show violet spots.
• Consumption of flour contaminated with Ergot led to many serious
intoxications known as (Ergotism- Ignis Fire or Holy fire) in Europe.
• Symptoms: (burning and convulsions, hallucinatins with imaginary
sounds, gangrene and loss of limbs).
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Classification of Ergot Alkaloids
• A- Clavine Type Alkaloids: (possess at C-8 methyl- or hydroxymethyl- group)
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.
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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.
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”.
HOOC
CH3
8
H
9
N
5
H
CH3
8
HOOC
H
9
5
H
NH
NH
Lysergic acid
N
Isolysergic acid
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ergine
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1- Simple Lysergic acid amides
• Characters:
They Composed of Lysergic acid and simple amines.
They are of Low molecular weight and Water Soluble.
e.g. Ergonovine (Ergometrine)
Ergometrine Composed of (l)-lysergic acid and 2-aminopropanol.
Its (d) isomer is called Ergometrinine.
• Uses:
OH
It causes vigorous contraction of the uterus.
It is mainly used as an oxytocic in order to aid
delivery or to prevent postpartum hemorrhage.
H2C
CH3
HC HN
CO
8
N
CH3
10
N
H
=
=
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Ergonovine (l) (Ergometrine)
Ergonovinine (d) (Ergometrinine)
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Lysergic acid diethylamide (LSD)
It is a semisynthetic product.
LSD has potent CNS stimulant effect.
LSD is one of the abused drugs.
C 2H 5
CON
C 2H 5
8
N
CH3
10
N
H
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‫المهلوسات نصف مشيدة‬
‫ثنائي اثيل امايد حمض الليزرجيك (‪)LSD‬‬
‫يحضر هذا العقار من حمض الليزرجيك الذي يوجد في‬
‫فطر االرجوت الذي ينمو على سنابل الشعير و الشوفان‪.‬‬
‫لهذا العقار تاثيرات هلوسة كبيرة جدا و يعتبر اقوى‬
‫المهلوسات حيث تقدر قوته بحوالي ‪ 4000‬مرة مقارنة‬
‫بقوة عقار المسكالين‪.‬‬
‫في عام ‪1960‬م عمم عقار ال اس دي لالستعمال الطبي‪ ,‬بيد انه‬
‫في عام ‪1970‬م اسي استعماله في غير االغراض الطبية‪.‬‬
‫يباع في االسواق غير المشروعة على هيئة اقراص او كبسوالت‬
‫او على هيئة ورق نشاف‪.‬‬
‫يستمر تاثير الجرعات العالية (‪ )< 100 µg‬لمدة ‪ 12‬ساعة‪.‬‬
‫‪9‬‬
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‫تاثير عقار ال سي دي‬
‫االعراض النفسية‪:‬‬
‫تشمل تقلبات في المزاج فقد ينتقل الشخص من نشوة الى حالة اكتئاب و من‬
‫ابتهاج الى توتر وقلق وذعر وقد تسيطر عليه موجة من الضحك دون اي‬
‫سبب او ينتابه الحزن و البكاء التفه االسباب‪.‬‬
‫تغير ادراك الفرد بالزمن‪ ,‬هلوسة بصرية و سمعية‪.‬‬
‫االعراض الوظيفية‪:‬‬
‫زيادة معدل ضربات القلب‪ ,‬ارتفاع ضغط الدم‪ ,‬اتساع حدقة العين‪ ,‬وهن‬
‫العضالت والتنميل و الرعشات وجفاف الفم و الغثيان و التقيؤ‪ ,‬ارتفاع درجة‬
‫الحرارة و زيادة معدل التنفس‪ ,‬العرق و زيادة الفترة الزمنية لالحالم مع‬
‫حدوث رعشات‪.‬‬
‫‪10‬‬
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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 is an important example.
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Ergotamine
• Characters:
 Its (d) isomer is called Ergotaminine.
 The peptide moiety is composed of 3 amino acids:
a-Hydroxyalanine
Proline
N
Phenylalanine
O
• Uses:
OH
O CH3
CO
N
CH2
O
8
N
9
CH3
10
Treatment of migraine as it constricts
the peripheral blood vessels.
Has some oxytocic (ecobolic) activity.
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N
H
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Ergotamine
(Contin..)
• 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
CH3
10
N
H
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Ergotamine
(Contin..)
• 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
CH3
10
10
(l) form
N
8
CH3
N
CH3
10
(d) form
Chemical Test:
Van-Urk's test
Ergot alkaloids + Van-Urk's test (p-dimethylaminobenzaldehyde in 15%
H2SO4) containing traces of FeCl3
Deep blue color.
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3- Vinca (Catharanthus) Alkaloids
Occurrence:
Catharanthus or Vinca is the dried whole plant of Catharanthus
roseus (or Vinca rosea ), Fam. Apocynaceae.
It contains about 150 alkaloids, the most important are vinblastine
and vincristine.
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Vinca Alkaloids
•
(contin..)
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.
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1- Monomeric Alkaloids:
H
N
H3COOC
OH
N
N
H
H3COOC
C2H5
Vincamine
N
N
C2H5
N
CH3
H3COOC
Catharanthine
COOCH3
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.
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2- Dimeric Alkaloids: (Mixed dimmers)
• These are dimeric alkaloids having indole and indoline (dihydroindole) 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 .
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Structure
Vincristine and Vinblastine differ only in the
substitution on the N-atom of the dihydroindole
nucleus.
Vinblastine (Vincaleukoblastine) is produced by
coupling of Catharanthine and Vindoline.
Vincristine (leurocristine) has CHO instead of CH3
in the vindoline part of Vinblastine.
Uses:
Vincristine used in treatment of Leukemia in children,
small cell lung cancer, cervical and vaginal cancers.
Vinblastine is used for treatment of Hodgkin’s disease.
Mechanism of action:
They are antimitotics.
They bind to tubuline and prevent the formation of
the microtubules and so block the mitosis in meta
phase.
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Semisynthetic derivatives of Vinca alkaloids
• Vindesine:
N
It is used for treatment of acute lymphoid
leukemia in children.
N
H
H3COOC
HO
• Vinorelbine:
N
It is an oral anticancer with broader activity
and lower neurotoxicity than vinblastine.
N
CH3
H2NOC
Tests for identification of Vinca alkaloids:
 1- Vanillin /HCl reagent gives with:
Vinblastine a pink color.
Vincristine an orange-yellow color.
 2- Van-Urk's reagent: → Reddish-brown color.
N
N
H
H3COOC
HO
N
N
CH3
H3COOC
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COOCH3
OH
COOCH3
OH
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4- Nux-Vomica Alkaloids
Ripe Seeds of Strychnose nux vomica and S. ignatii (family
Loganiacea ).
The drug contains up to 5% Alkaloids mainly Strychnine and Brucine.
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
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4- Nux-Vomica Alkaloids
(contin..)
Identification:
1- Strychnine + H2SO4 + K2CrO3 gives reddish-violet color which
changed after while to orange and after that to yellow.
2- Strychnine + NH4-Vandate gives violet color (Mandelin’s reagent)
3- Strychnine + HNO3 gives yellow color
4- Brucine + HNO3 gives orange-red color
Uses:
Strychnine is extremely toxic and used in veterinary medicine as
CNS stimulant and tonic.
It is also used as antidote in barbiturate poisoning.
It is also used as rodenticide.
Brucine is less toxic than strychnine and is sometimes used as CNS
stimulant.
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5- Rauwolfia Alkaloids (carboline alk.)
• RAUWOLFIA (SNAKEWOOD)
roots and rhizomes of Rauwolfia serpentina
( Fam. Apocynaceae).
total alkaloids (0.5-2.5%) form a complex mixture of nearly 30
different compounds, mostly indoles.
It is used by the traditional healers of India to treat a variety of
ailments, ranging from snake-bite to insanity.
Carboline skeleton
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Rauwolfia Alkaloids
(contin…)
• The most important alkaloids are Reserpine, Deserpine, Rescinnamine,
ajmaline and ajmalicine.
 Reserpine and related alkaloids are weakly basic diester, tertiary
alkaloids and possess a carboxylic group on ring "E".
• Reserpine is pale white to slightly yellow or colorless crystals, weak
base, insoluble in H2O, soluble in CHCl3.
Reserpine
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Rauwolfia Alkaloids
(contin…)
 Alkaline Hydrolysis:
1- Reserpine → reserpic acid + trimethoxybenzoic acid + methanol.
2- Recinnamine → reserpic acid + trimethoxycinnamic acid + methanol.
• Tests for reserpine:
 Vanillin /HCl reagent: → violet color.
 Sodium molybdate in H2SO4 → Yellow → Blue in two minutes.
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Rauwolfia Alkaloids
(contin…)
Effects of Rauwolfia alkaloids
exert hypotensive effects by depletion of catecholamine and serotonine stores
in many organs, and by reduction of uptake of catecholamines by adrenergic
neurons.
Their sedative and tranquilizing effect are thought to be related to depletion
of amines in CNS.
Reserpine
It is used for its neuroleptic properties and antihypertensive activity.
It is used in combination with diuretics for treating arterial hypertension.
Rescinnamine (It has the same activity).
Ajmaline (antiarrhythmic agent)
decrease the rate of depolarization of atrial and ventricular cells.
Ajmalicine (Raubasine)
moderates the activity of the vasomotor centers, especially in the brain stem.
It causes a transient increase of the blood flow to the brain and is slightly
anxiolytic.
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Simple β-carboline alkaloids
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.
Pharmacology:
These alkaloids are short acting monoamino-oxydase inhibitor , replace
benzodiazepines from their receptors .
High doses are acting psychosmimetic .
Leaves are used as sedative.
R
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N
H
N
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Harmane (R = H)
Harmine (R = OCH 3)
Harmol (R = OH)
Drugs containing simple β-carboline alkaloids
Passiflora incanata (Fam. Passifloraceae)
It is a climber plant, found in South USA.
It contains about 0.05% alkaloids in particular, harmane, harmine and harmol.
High doses are acting psychosmimetic .
Leaves are used as sedative agent.
Peganum harmala (Fam. Zygophylaceae)
 The seeds contain 3-4% alkaloids harmine, harmoland harmaline.
 At first CNS-stimulant, after that sedative.
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PHG322, Alkaloids2incarnata
Passiflora
Alkaloids Derived from Tryptophan
2- Quinoline Alkaloids
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1- Cinchona Alkaloids
Cinchona
bark of C. pubescens (C. succirubra) or of its
varieties (Fam. Rubiaceae).
7-15% alkaloids which occur in combination with
special organic acids chiefly quinic acid and
cinchotannic acid.
Major alkaloids are quinine, quinidine, cinchonine
and cinchonidine).
The drug is used in the treatment of malaria fever
for many years.
Over doses of cinchona products results in
temporary loss of hearing and in impaired
sight. Ringing in the ears is a symptom of
toxicity (Cinchonism).
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Chemical structure of cinchona alkaloids
9-rubanol is the basic skeleton of these alkaloids, which is derived
from the parent compound named ruban..
Ruban nucleus is composed of quinoline ring system attached
through a methyllene group to a bicyclic ring system named
quinuclidine.
The principal alkaloids are the stereoisomers, quinine and quinidine,
and their 6'-demethoxylated homologs cinchonine and cinchonidine.
Quinine (Cinchonidine epimer at C-9)
Quinidine (Cinchonine epimer at C-9)
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• Both Quinine and Quinidine, Cinchonine and Cinchonidine
are Diastereoisomers. Each
stereochemistry at C-8 and C-9.
HO
H3CO
differs
HO
9
in
the
8
N
N
H
H
pair
H3CO
N
H
H
N
Quinine
Quinidine
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Quinine:
a diastereoisomer of quinidine, occurs as white, odorless, bitter
crystals.
Quinine (l) gives Quinidine (d) among other products when warmed
with KOH in amyl alcohol.
Quinine is antimalaria agent.
Quinidine:
an antiarrththmic class I (sodium channel blockade).
It inhibits the rapid sodium influx, decreases the rate of depolarization,
contractility, and the atrial and intraventricular conduction velocity.
It is used for treating various cardiac arrhythmias e.g. premature atrial,
ventricular contraction, atrial and ventricular tachycardia, and atrial
flutter and atrial fibrillation.
Cinchonine and cinchonidine are used as anti-inflammatory.
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The current indications of quinine include the following:
1- treating of pernicious malaria and of cases of malaria resistant
to 4-aminoquinolines.
2- The symptomatic treatment of fevers, aches and flu-like states.
3- Quinine ascorbate, combined with vitamins, used in programs to
quit smoking (60-80mg/day in four doses).
4- in combination with thiamine, to relieve muscle cramps.
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Identification:
1- With oxygenated acids (e.g. sulphric and acetic acid)
Quinine and quinidine produce a strong blue fluorescence when
dissolved in these acids.
2- Thalleioquin reaction
Quinine and quinidine in solution in dilute H2SO4 can be
treated by Br2 until the fluorescence disappears.
The addition of aqueous NH3 causes the development of an
emerald green color, which can be extracted with chloroform.
3- The addition of K[Fe3(CN)6]-solution in alkaline medium leads
to a purplish red color that can also be extracted with chloroform.
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Structure activity relationship:
For antimalarial activity (Quinine):
Removal of vinyl group
loss of activity
Replacement of CHOH by CH2, CO
decrease of activity
Vinyl group
CH
CH2
CH2
CH2
9
HO H C
N
CH3O
N
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2- Camptotheca Alkaloids
Camptotheca acuminata (Fam. Nyssaceae)
The bark, and the fruits of this large tree indigenous to southern China.
It contain 0.01-0.03 % camptothecine.
It is characterized by a pyrrol [3,4b]quinoline sequence.
It is a neutral lactam, which does not react with the general reagents for
alkaloids.
Camptothecine exert cytotoxic and antitumor activity, but because of its
toxicity, its synthetic analogs such as Topotecan and CPT11 have been used.
There was evidence that this compound had some activity on topoisomerase I
(an enzyme involved in the uncoiling of DNA, a prerequisite for replication and
transcription).
9
7
O
10
N
11
12
N
20
OH
O
O
Camptothecine
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