aloidsids 22 11

Monoterpenoid Indole alkaloids

RAUWOLFIA (SNAKEWOOD)

roots and rhizomes of

Rauwolfia serpentina

( Apocynaceae).

total alkaloids (0.5-2.5%) form a

complex mixture of nearly 30

different compounds, mostly indoles.

used by

India to

ranging

the traditional healers of

treat a variety of ailments,

from snake-bite to insanity.

Three main groups of alkaloids are distinguished:

1- Yohimbane-type Derivatives.The most interesting ones are substituted at the 16- 17, and 18 positions):

reserpine (trimethoxybenzoate of methyl reserpate) and

recinnamine (trimethoxycinnamate of methylreserpate).

2- Heteroyohimbane Derivatives.very closely related to the previous ones, with heterocyclic E ring:

Ajmalicine (also known as raubasine), reserpiline, 10, 11-dimethoxy-

ajmalicine), reserpiline, isoreserpiline), and serpentine.

3- Dihydroindole derivativesThese are chiefly represented by ajmaline, a polycyclic indoline alkaloid

2

Reserpine:

Pale white to slightly yellow or colorless crystals, weak base,

insoluble in H2O, soluble in CHCl3

Salt such as reserpine sulfate are soluble in chloroform.

On treatment with sodium nitrite in the presence of sulfuric

acid, these alkaloids are oxidized to the corresponding 3,4-

dehydro- derivatives: these are colored and can be used for

quantitative estimation.

4

- 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 tranqulizing effect are thought to be related to depletion

of amines in CNS.

Reserpine (used for its neuroleptic properties and antihypertensive activity)

- It is used in combination with diuretics for treating arterial hypertension.

Rescinnamine 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,

the brain and is slightly anxiolytic.

Yohimbine (from the bark of the tree Pausinystalia yohimbe)

- It is hypotensive and a peripheral vasodilator.

- Has reputation as an aphrodisiac, (treated impotence in patients with

vascular or diabetic

5

Catharanthus roseus (Fam. Apocynaceae)

- 0.2-1% alkaloids

- All of them have

(very complex mixture)

an indole or dihydroindole structure (indoline- the

principal constituents) e.g. catharanthine, vindoline and ajmalicine.

The alkaloids with antineoplastic activity belong to a new class of

bisindole derivatives (composed of an indole and a dihydroindole

unit) catharanthine and vindoline respectively.

About 20 binary alkaloids have been isolated from various C. roseus.

Several have cytostatic properties, especially:

-

-

-

1- Vincristine: 0.0003% (i. e 3 g per metric ton of dried drug)

2- Vinblastine: which is a little more abundant.

- These two alkaloids formally comprise a dihydroindole moity

(vindoline) and an indole moiety (velbanamine).

- Vincristine and vinblastine are antimitotics.

6

CH2CH3

COOCH3H

R HO OCCH3

R = CH3 Vinblastine

7

OH

N

N

N

CH2CH3

O

H3CO N OCCH3

O

R = CHO Vincristine

Nux vomica

-

-

ripe seed of Strychnos nux-vomica (Fam. Loganiaceae).

The drug contains from 1-3% total alkaloids chiefly

(strychinine and its dimethoxylated derivative brucine)

Strychinine was formerly used mainly to poison rodents, and

the galenicals obtained from the drug ingredients of tonic

preparation.

Few products based on nux vomica tincture are still used in

homeopathy.

-

-

- Brucine, which is less toxic than strychinie, has been used

commercially as bitters.

8

Strychnine:

Monoacidic base, has no basic

properties, colorless prisms or white,

base and salts are very powerful

poison.

Brucine:

Dimethoxystrychnine, soluble in

alcohol and acetone, insoulble in

NaOH or KOH

Identification:

1-

2-

3-

4-

Strychnine

Strychnine

Strychnine

+

+

+

H2SO4 + K2CrO3 gives reddish-violet color

NH4-Vandate gives violet color (Mandelin’s reagent)

HNO3 gives yellow color

Brucine + HNO3 gives orange-red color

9

R1 N

R2 N

OO

Strychnine = R1 =R2 = H

Brucine = R1 = R2 = OCH3

Separation of a mixture of strychnine

and brucine:1- Acetone dissolves brucine and leave

strychnine.

2- K[Fe3(CN)6]-solution when added to

the mixture, strychnine gives ppt

quickly from its salts than brucine.

10

Quinoline AlkaloidsAlkaloids containing quinoline as their principle nucleus include

those obtained from cinchona (quinine, quinidine,

cinchonidine).

Cinchona

cinchonine and

- 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.

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).

-

-

11

Chemistry:

-9-rubanol is the

from the parent

- Ruban nucleus

basic skeleton of these alkaloids, which is derived

compound named ruban.

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.

H

HO

R = OCH3 (-_ ) Quinine R = OCH3 ( _ ) Quinidine

12

HHO

N N

R H R H

N N

-

R = H ( _ ) Cinchonidine R = H ( _ ) Cinchonine

Quinine:

- a diastereoisomer of quinidine, occurs as

crystals.

- Quinine is antimalaria agent.

white, odorless, bitter

Quinidine:

- an antiarrththmic class I (sodium channel blockade).

- inhibits the rapid sodium influx,

depolarization, contractility, and

conduction velocity.

- used for treating various cardiac

decreases the rate of

the atrial and intraventricular

arrhythmias e.g. premature atrial,

ventricular contraction, atrial and ventricular tachycardia, and atrial

flutter and atrial fibrillation.

13

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

quit smoking (60-80mg/day in four doses).

to

4- in combination with thiamine, to relieve muscle cramps.

14

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.

15

Ramzi MM loidsids 22

Camptotheca acuminata (Fam. Nyssaceae)

The bark, and the fruits of this large tree indigenous to southern China

-

-

-

-

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

transcription).

the uncoiling of DNA, a prerequisite for replication and

N

N

16

9 7

10 O

11

12

20 O

OH O

Camptothecine

Histidine- derived Alkaloids

Alkaloids of the Imidazole group

►Alkaloids that possess an imidazole

nucleus are very rare.

► found in some Rutaceae (leaves of

the Pilocarpus of South America)

Jaborandi

► It consists of the leaflets of

Pilocarpus jaborandi, P. microphyllus,

and P. Pinnatifolius (Fam. Rutaceae).

► 0.7 – 1.0 %, the chief constituents is

(3S, 4R)-(+)-pilocarpine and

stereoisomer isopilocarpine.

17

Ramzi MMothanothanaa AlkaloAlkaloidsids 22

► Pilocarpine is a tertiary base containing a lactone group as well

as an imidazole nucleus.

It is an oily syrupy liquid, easily soluble in water, alcohol and

chloroform, but almost insoluble in ether.

The lactone ring is opened by caustic alkali, which forms salts

with the resulting pilocarbic acid (unaffected by ammonia or

alkali carbonates) (destroys the physiological activity)

►

►

► it is demethylated and converted to pilocarpidine, when heated

with acids.

COOH HNN

H

4 34 3 NN

18

4 3

O

N NH2

N O

Histidine Pilocarpidine

H3C H3C

O O

N O N O

(3S, 4R)-Pilocarpine (3R,4R)-Isopilocarpine

Pharmacology:

►

►

Pilocarpine is a parasympathomimetic.

It induces salivary glands, gastric, and sweat hyper-secretion,

it increases intestinal motility, induces broncho-constriction, and

bradycardia.

It directly stimulates the muscarinic receptors in the eye, causing

constriction of the pupil (myosis) and contraction of the ciliary

muscle.

It used in the treatment of narrow-angle glaucoma

Alone or in combination with beta-blocker (timolol) also for

treating intraocular pressure.

Pilocarpine can be used as a sialagogue to relieve dryness of the

mouth (for example, that due to the radiotherapy of mouth and

throat cancers).

►

►

►

►

19

Chemical tests:1- Helch’s test (H2SO4 + H2O2 + KCr2O7)

gives violet color

2- Ekkert’s test (Na-nitroprusside + NaOH)

leave for a period in HCl-solution, it gives

red color

20

Ornithine derived Alkaloids

► 4-aminobutanal and N-methyl-4-aminobutanal which are derived

from ornithine, represent the

alkaloids, namely:

1- Pyrrolizidine alkaloids

2- Tropane alkaloids

precursors of two groups of

Pyrrolizidine alkaloids

pyrrolizidine basic structure.

the Asteraceae and Boraginaceae.►

►

essentially isolated only from

they were found in many genera: Eupatorium, Senecio, Tussligo,

and Echium, Heliotropium Symphtum.

They are hepatotoxic, carcinogenic and mutagenic►

21

► Pyrrolizidine alkaloids have a

Alkaloids of Tropane group

► Tropane alkaloids have in commn a nitrogen-containing bicyclic

structural element, namely azabicyclo-[3,2,1]octane (Tropane).

► They are 8-methyl-8-azabicyclo(3,2,1)octanes.

7

35

7 3

6

Distribution:

►Approximately 200 alkaloids are

in Solanaceae, Erythroxylaceae

convulvulaceae, Euphorbiaceae,

known in

and more

this group, distributed

sporadically in

Brasicaceae and Olacaceae.

22

8

H3C N 1 2 1 2

4

= 8 N CH 3

6 5 4

Tropane

Structure:

► Tropane alkaloids are esters of tropane alcohols and of acids of

different structures, either aliphatic or aromatic.

►These tropane alcohols are divided into two series based on the

orientation of hydroxyl group at the 3- position:

1- derivatives

2- derivatives

of

of

tropan-3α-ol

tropan-3β-ol

(the most common)

(specific to the Erythroxylaceae)

1

3 CH8 N= 33

► The tropanols (Tropins) are often hydroxylated at the 6- or

7-position or both, and sometimes 6,7-epoxidized.

23

H3C N

OH OH

5

Pseudotropine

H3C N 1

= 8 N CH3 OH

5

HO

Tropanol or Tropine (3-Hydroxytropane)

33

o

The acids may be aliphatic (acetic, butyric, isovaleric, tiglic and

angelic acids) or aromatic (tropic, truxillic, cinnamic, benzoic acids).

HO

(Atropic acid)

COOH

24

HO O H

COOH COOH

OH

Tropic acid Apotropic acid O

alpha-truxillic acid

COOH

COOH

Angelic acid Tiglic acid Isovaleric acid

H3C N 1 H3C N COOH

= O 8 N CH OH OH

OH 5 Ecgonine

Scopine

The principal alkaloids of medicinal interest in this group are

1- (-) Hyoscyamine. This fragile ester is rapidly converted, in acidic

as well as basic conditions, to tropanol and tropic acid, and the

latter is transformed by intramolecular dehydration, into apotropic

(atropic acid), which is optically inactive.

2- Racemate of hyoscyamine: a simple reflux in chloroform is

enough to transform hyoscyamine into (±) atropine.

3- Hyoscine (scopolamine), which is converted by acidic or basic

hydrolysis to osine (scopine) and tropic acid.

OCH3N OO CHN

25

CH2OH CH2OH

3

O O

Hyoscyamine, Atropine Scopolamine (Hyoscine)

Characterization of tropane alkaloids.

1- Vitali-Morin reaction

After treating with fuming nitric acid and redissolving the residue

with acetone, by adding solution of potassium hydroxide in

methanol, purple color is developed, which is changed to red.

2- Gerrard reaction

Atropine and hyoscyamine react with 2% solution of mercuric

chloride in 50% alcohol to produce a red color. Scopolamine

gives white precipitate.

3- Schaer’s reaction

Tropane alkaloids gives with a prepared solution of 1 volume of

30%H2O2 mixed with 10 volumes of conc. H2SO4 a green color.

26

Drugs containing tropane alkaloids:

Datura stramonium

Atropa belladonna Hyocymus niger

27

Pharmacological activity of the alkaloids:

Atropine and Hyoscyamine

►Atropine and hyoscyamine have the same activity.

► They are parasympatholytics (block the muscarinergic and

cholenergic receptors by forming cationic, anionic and polar

bonds with the receptors).

► It increases the heart rate, induces relaxation and motor

inhibition, decreases intestinal tone and peristalsis, paralyzes the

ureters, increases bladder pressure,

and blocks the bronchoconstricting

Secretions of saliva, sweat, gastric,

decreases biliary duct tone,

effect of acetylcholine.

pancreatic, bronchial, and

lachhrymal secretions

mydriasis.

are all decreased. Atropine induces

Scopolamine

► parasympatholytic activity,

possesses sedative, depressant,

especially of the myocardium. It

and hypnotic with amnesia.28

29

Coca alkaloids

Coca or coca leaves are the dried

leaves of Erythroxylum coca and E.

novogranatense var. truxillense

(Fam. Erythroxylaceae).

► 0.5-1.5% alkaloids

► The leaves contain three basic types

of alkaloids according to the

principal nucleus in the molecule:

1- Deivatives of ecgonine:

e.g. cocaine, cinnamylcocaine

Derivatives of pseudotropine:

e.g. Tropacocain

Deivatives of pyrrolidine:

e.g. hygrine

2-

3-

30

H3C N COOCH3

► The chief alkaloid (30-50%) is the cocaine, which is an ester,

volatile as a free base, colorless crystals, cause numbness to the

lips and tongue, soluble in alcohol and CHCl3.Pharmacology

► Cocaine is a local anesthetic. (It blocks ion channels in neuron

membranes, and interrupts the propagation of action potentials

corresponding to the sensory message).

sympathomimetic. It acts as an adrenergic

reuptake blockade (hyperthermia,

► Cocaine is also

stimulant by noradrenaline

mydriasis and vasoconstriction)

a

31

O

Cocaine: R =

O R O

Cinnamoycocaine: R =

Identification of Cocaine:

1- solution of cocaine + gold-chloride (AuCl4) gives stellate rods

2- solution of cocaine + PtCl6 gives yellow needles

3- Solution of cocaine + KMnO4 + alum (50%-solution) gives

violet crystals of cocaine-pemenganate.

32

Alkaloids derived from aspartic acid

Alkaloids of the Pyridine group

This group of alkaloids could be divided into 4 subgroups

nucleus of the molecule is one of the following nuclei:

1- Pyridine alone:

e.g. trigonelline

and the

2- Pyridine with other nitrogenous rings (e.g. pyrrol-ring)

3- Tetrahydropyridine

e.g. areca alkaloids

Pyridone

e.g. ricinine

4-

33

Biogenesis of pyridine alkaloids:

COOH

N COOHH

COORL- lysine COOR

Guvacoline(R = CH3)N

Guvacine(R = H)N

Anabasine N

N

34

O P COOH

HO CH2 H

CHO NH2 COOH quinolinic acid

glyceraldehyde aspartic acid

OCH3 COOH

CN

NN O nicotinic acid

CH3

Ricinine

L-Ornithine N N

CH3 H

N

H Arecoline (R = CH3)

H Arecaidine (R = H)

CH3 N

Nicotine N

Nicotelline

Drugs containing pyridine alkaloids:

Tobaccos

► The leaves of the tobacco plant

Nicotiana tabacum (Fam: Solanaceae)

are used for production of Cigarettes.

► They are toxic plants which contain

alkaloids, chiefly represented by

nicotine.

►Other close structurally alkaloids have

been found such as nornicotine,

the N-oxidized derivatives of nicotine,

e.g. nicotyrine, anabasine and anatabine.

35

Tobacco-alkaloids:

► 4-6% several volatile, non-volatile and crystalline alkaloids:

1- Volatile liquid alkaloids

e.g. nicotine, nor-nicotine, anabasine

2- Non-volatile liquid alkaloids

e.g. nicoteine and nicotyrine

3- Solid-alkaloids

e.g. nicotelline

and anatabine.

Identification1- Nicotine + p-dimethylaminobenzaldehyd

rose-red color

+ HCl gives

2-

3-

aq. Solution of nicotine + acidic vanillin gives red color

aq. Solution of nicotine + formaldehyde + HNO3 gives red color

36

Pharmacology►Nicotine possesses a high affinity to the gangionic-cholinergic

(nicotinic) receptors.

► So, it stimulates all autonomic ganglia,

► it

► it

► It

acts on the CNS causing tremors and convulsions,

also stimulates the respiratory and vomiting centers.

acts on the smooth muscle of the intestine, by increasing

tone and motor activity.

► It acts on the cardiovascular system, by inducing vasoconstriction

and an increase in arterial blood pressure.

cardiovascular, pulmonary diseases.

► It is used in the form of chewing gum or transdermal

relieving the symptoms of withdrawal of cigarettes.

► It is also used as insecticide.

system for

37

Alkaloids derived from Lysines

1- Alkaloids of the Piperidine group

Black Pepper

► dried fruits of Piper nigrum (Fam.

Piperaceae), a perennial plant in

(India and cultivated also in Indonesia,

Sri Lanka and South America).

► the pungent taste to piperidine amides

(5-10 %).

► The chief constituent is piperine

(insecticide), an amide of piperidine

and of piperic acid.

► The other amides are piperidines

(piperanine, piperettine) piperolein A and

Piperolein B, pyrrolidines (piperyline).

38

O

ON

O

Piperoleine B (n = 5)

H

39

O OH O

NO N

CH3 O

Lobeline Piperine

O

O (CH2)n N

O

Piperyline Piperoleine A (n = 3)

O

N

Pelletriene

Piperine:► Colorless, odorless, needles or prisms with burning taste,

insoluble in H2O, soluble in alcohol, chloroform and ether.

exhibits only weak basicity

On hydrolysis, gives piperidine and piperic acid

Used as stomachic and insecticide

Has CNS depressant and anticonvulsant effects in rats

►

►

►

►

Identification of Piperine:

1- On the addition of Wagner’s reagent, steel blue needle crystals

of piperine periodide are formed.

Piperine on treating with platiniumchloride solution gives

orange red needles.

Piperine on treating with H2SO4 gives a red color.

2-

3-

40

PomegranateThe plant is a shrub widespread Punica

granatum (Fam. Punicaceae).

► The bark contains 0.5- 0.7% total

alkaloids: (-) pelletierine,

isopelletierene, and N-methylated

analogs.

► The plant was used as anthelmintic.

H

41

O

N

Pelletriene

Alkaloids derived from Glycine

Purine Alkaloids

► Purines are derivatives of a heterocyclic nucleus consisting

of the six-membered pyrimidine ring fused to the five

membered imidazol ring.

► Purine itself does not occur in the nature but numerous

derivatives are biologically well-known such as Adenin and

guanin.

► The purine nucleus is not very common in higher plants.

► Purine alkaloids are secondary metabolites of methylated

xanthines (2,6-dioxopurine).

42

R1 R3N N Caffeine: CH CH CH

► Caffeine

isolated

is 1,3,7-trimethylxanthine,

in 1820,

the first purine base to be

► occurs in the seeds of coffee plant, of Cola plant and in Tealeaves.

► Theophyline is 1,3-methylxanthine, which occurs in small

quantities in Tea leaves and in Cola nuts.

► Theobromine is 3,7-dimethylxanthine, which accumulates

(0.9-3%) in cacao beans other purine base are (E)-zeatin,

cytokinin, and its derivatives.

► caffeine and theophylline are used in therapeutics.

43

O

R1 R2 R3

3 3 3

Theophylline: CH3 CH3 H

O N N Theobromine: H CH3 CH3

R2

Caffeine

1,3,7-trimethylxanthine

White powder, bitter taste, very weak base, soluble in hot

water, in alcohol and CHCl3, sparingly in

Doesn’t precipitate with Mayer’s reagent

ether.

Theophyline

1,3-dimethylxanthine

White, odorless, bitter crystalline, soluble in H2O, alcohol

Sparingly soluble in ether and CHCl3

Theobromine

3,7-dimethylxanthine (mainly in seeds of Theobroma cacao

White, odorless, bitter crystalline, sparingly soluble H2O

)

Insoluble in ether 44

PharmacologyCaffeine

► stimulation of CNS, effect on the psychic centers

► Causes flow of thought, lessen drowsiness,

gives a sense of comfort and well-being

relieve headaches and

Theobromine

►Diuretic effect and used in the treatment of various types of edema

Theophylline

► smooth muscle relaxant, myocardial stimulant and diuretic

Identification:Murexide reaction

Alkaloids + H2O2 + HCl

which turns to red-violet

gives after evaporation yellow-red color

upon addition of NH3.

45

46