Alkaloids

autumn crocus
source of colchicine

Introduction I
Definition of alkaloids
Structure:
mostly
nitrogen
containing
compounds
(heterocyclic ones) with basic nitrogen atoms occurring in the
nature as salts of organic acids. (Lactic, tartaric, citric, acetic,
succinic, maleic and oxalic acid.)
Source: produced by plants or animals (secondary metabolites).
y strong
gp
physiological
y
g
activity.
y
Bioactivity:
Application: used as precursors by the pharmaceutical industry.
g
amount),
), secondaryy alkaloids
Primaryy alkaloids ((found in higher
(found in slight amounts)

Introduction IIII

Classification of alkaloids
A
According
di
to
t their
th i source
According
g to their chemical structure
According to the bioactivity

Classes of alkaloids I

Classes of alkaloids IIII

Classes of alkaloids IIII

II (according
(according to
structure))
structure
Heterocyclic compounds
Indole alkaloids (strychnine, lysergic acid, ergotamine)
Isoquinoline alkaloids (papaverine*)
Morphinan alkaloids (isoquinoline gr.) (morphine*, codeine,
thebaine))
Tropane alkaloids (atropine*, hyoscyamine, cocaine*,
scopolamine)
p
)
Pyridine alkaloids (nicotine*)
Piperidine alkaloids (piperine
(piperine, coniine
coniine*))
Quinoline alkaloids (quinine*)
Purine alkaloids (caffeine*,
(caffeine* theobromine*,
theobromine* theophylline*)

Classes of alkaloids IV
IV (according
(according to
structure
structure)
t
t
)
Heterocycles without nitrogen
Tetrahydrocannabinol*
y
Taxol*
N
Non-heterocyclic
h t
li alkaloids
lk l id
phenylalkylamine derivatives
ephedrine
Mescaline
Mescaline*
Capsaicin*

Alkaloids of p
phenylalkyl
y
y amine skeleton I
Ephedrine isolated from various plants in the genus Ephedra
(Ephedra sinica)
Structure: 2-(methylamino)-1-phenylpropan-1-ol
2 (methylamino) 1 phenylpropan 1 ol (it contains two
chiral centers), applied as hydrochloride.
3

CH3
*
H C 2 NHCH3
H C* OH

CH3
*
H C NHCH3
HO C* H

NHCH3
CH2
HO C* H

OH
(-)-ephedrine

(+)-pseudoephedrine

OH
adrenalin

Ephedra chinensis

Alkaloids of p
phenylalkyl
y
y amine skeleton II
Ph i l i l activity
Physiological
i i off ephedrine
h d i
It is a sympathomimeticum, it increases the blood pressure, it acts
as a bronchodilator,
bronchodilator used as a decongestant.
decongestant
Medical use: therapy of rhinitis and asthma, also used in
incontinence.
incontinence
Pseudoephedrine is less active (used as decongestant).
Abuse of ephedrine
supplements).

by

athletes
athletes,

ephedrine

(in

Amphetamines (see this family in the lecture Amines)

dietary

Capsaicines
Isolation: from genus Capsicum
O
H3CO

N
H

capsaicin*

HO

O
H3CO

HO

N
H

Capsicum annuum

dihydrocapsaicin

Chemistry: they are amides of benzylamine (nonanic- or

nonenic acid moiety)
Medical use: capsaicin is used topically to relieve pain (analgesic)

Pyridine, piperidine and pyrrolidine alcaloids

Nicotine and anabasine I
I l ti
Isolation:
f
from
S l
Solanaceae
( i ht h d family),
(nightshade
f il ) Nicotiana
Ni ti
t b
tabacum
.
In small amount it is present in eggplant and in tomato.
Ch
Chemistry:
i t
chiral
hi l compounds
d (pyridine
( idi ring
i and
d pyrrolidine
lidi or piperidine
i idi
skeleton).
*
3

N
CH3

nicotine*
i ti *

N
anabasine
b i

N
H
Ni ti
Nicotiana
tabacum
t b

It works as a antiherbivore compound with specific acitivity to insects.

They are applied in the agriculture as insecticide.
insecticide

Nicotine and anabasine II

Physiological activity: it binds to the nicotinic acetyl choline

receptors, (agonist of cholinerg system), thus causes
tachycardia, nausea, hypo- or hypertony, migraine, etc.
It acts as a stimulant in mammals, nicotine addiction.
It is toxic (It absorbs through the skin.)
The nicotine content of a cigarette:
g
up
p to 10-20 mg.
g In the smoke:
0.4-1.2 mg.
The components of smoke: 3000
3000-4000
4000 compounds, 40
carcinogenic (benzpyrene, benzanthracene, 2-naphthylamine,
nitrosamines,
t osa
es, etc
etc.))

Nicotine and anabasine III

Damages caused by smoking: higher incidence of cardiac

infarct, chronic bronchitis, lung carcinoma and other
tumors, etc.
Medical usage: pharmacological research

Coniine

Isolation: from poison hemlock (Conium maculatum)

Structure: 2-propylpiperidine (one chiral center)
It is toxic causing respiratory paralysis. (Its effect is a nicotine like
effect and a curare like one.))
Socrates was sentenced to death by coniine.

coniine*

poison
i
hemlock
h l k

Epibatidine I
Isolation: from an animal (Epipedobates tricolor,
tricolor called as
phantasmal poison frog) a poison dart frog living in Eucuador. Its
toxin is one of the strongest toxins of frogs.
frogs
Chemical structure: pyridine derivative with a pyrrolidine side
chain.
H
N
HN

Cl

epibatidin

Cl

Epipedobates tricolor

Epibatidine
p
II
Ph i l i l activity:
Physiological
ti it
it is
i painkiller
i kill
200 times
ti
as potent
t t as
morphine.
No addiction.
addiction Because of its toxicity it is not used in human medicine.
medicine
Analogues of epibatidine
Tebanicline ABT-594
effective analgesic activity

H
N
O

with less toxicity

toxicity.
N

Cl

Piperine
Isolation from
Isolation:
f om black pepper
peppe (Piper
Pipe nigrum).
nig m)
Structure: it is a piperidine derivative (amide linkage of
unsaturated aromatic carboxylic acid),
acid) it is an amide of piperoic
acid.
O

O
C

Piperin is responsible for the pungency of pepper.

Piper nigrum

Tropane skeleton
8

H2C
H2C
6

H
C1
HN 8
C
H
5

N
H

H2
C

C
H2

3 CH2

7
6

2
4

N-Methyl-8-azabicyclo[3.2.1]octane= piperidine + pyrrolidine

rings, symmetrical

Conformation: piperidine: chair, pyrrolidine: envelope

The tropane alkaloids: esters of tropin, or pseudotropinisomeric alcohols.
alcohols

Atropine I
Isolation: from
Isolation
f om deadly
deadl nightshade (Atropa
At opa belladonna),
) also in
other plants of Solanaceae.
H3C

N
H

HOOC
HOH
O 2C

atropine
at
ropine*
*

C*

CH2OH

Atropa belladonna

Tropic acid

Structure:: ester of tropin with (+/-) i.e. (racemic) tropic acid.

Structure

The main alkaloid is hyosciamine isomerized to atropine during

i l ti
isolation.
B i compound,
Basic
d used
d as a salt,
lt sulphate.
l h t

Atropine IIII
Physiological
Ph
i l i l effects:
ff t parasympatholyticum,
th l ti
it inhibits
i hibit the
th
effect of acetylcholine on muscarin receptors.
Atropine derivatives in medicine: dilate pupils
(ophthalmology), acts as a spasmolytic of bronchial
spasms. Treatment for poisoning by organophosphate
insecticides and nerve gases.
Overdose: tachycardia, nausea, hallucination, etc.
Hyoscyamine
It is the levorotatory isomer of atropine

Scopolamine
p
or hyoscine
y
Isolation: Japanese
p
belladonna (Scopolia
p
jjaponica)
p
)
H3C

O
H
O
C

CH
HO

Scopolia japonica

C
H2

Structure: veryy similar to that of atropine

p
containing
g an extra epoxy
p yg
group.
p
Physiological

effect:

parasympatholyticum,

it

inhibits

the

acetylcholine on muscarin receptors.

Usage in medicine: against sea sickness and intestinal cramping

effect

of

Cocaine I
Isolation: Erythroxylon coca (1860)

Erythroxylon
y
y
coca
cocaine*
ocaine*

Structure: ester of pseudotropine (stereoisomer of tropine)

having two ester groups (four chiral centers).

Cocaine II

Physiological effects: topical anaesthetic, stimulant of the CNS

and
d the
th autonomic
t
i nervous system,
t
etc.
t
Overdose: blocks breathing, cardiac infarction, ischemia, stroke,
hyperthermia
Medical usage: topical anaesthetic for nasal and lacrimal duct
surgery (rarely used)
Dependency: very strong psychological dependency.

Quinoline and isoquinoline alkaloids

Quinine I
*
H2C*
HO

*
CH

CH

CH2

H2C
N

H3CO

Cinchona pubescens

quinine
uinine*
*

Isolation from Cinchona pubescens

(isolation from the bark of the tree).

Mosquito, vector
of malaria

Structure: isoquinoline skeleton, quinuclidine ring (alifatic tertiary

amine) with four chiral centers and two basic groups, it is applied as a
sulphate
l h t or chloride.
hl id

Quinine IIII
Q

Bioactivity: It was the first effective medicine for malaria

caused
d by
b Plasmodium
Pl
di
f l i
falciparum
a protozoan
t
parasite.
it
Antipyretic activity and effect on the CNS.
Other use of quinine: it is a flavour component of tonic
water
t and
d bitter
bitt lemon.
l
Importance
p
of synthetic
y
derivatives of quinine.

Papaverine
Isolation: from poppy (Papaver somniferum)
somniferum), it is an opium alkaloid.
alkaloid
H3CO
N
H3CO
H2C

OCH3

OCH3

Structure:

isoquinoline

skeleton

with

papaverine
apaverine*
*

benzyl

group

(methoxy

substituents), weak base

Synthetic
y
derivative: drotaverine with ethoxyy g
groups
p
Physiological activity: it is a smooth muscle relaxant
Medical usage: spasmolytic agent (the gastrointestinal tract, bile ducts
and ureter)

Opium
p
alkaloids I
Isolation: from poppy (Papaver somniferum) = opium alkaloid.
alkaloid
Morphine is the most abundant alkaloid (10%) in opium (50 other).

Jnos Kabay (1896-1936),

(1896-1936)
pharmacist

inventor (new

procedure
p
o du for
o the extraction
a o
of

morphine

from

dry

trashed poppy straw).

Papaver somniferum
Opium alkaloids: morphine, codeine, thebaine, papaverine, narcotin,

narcein

Opium alkaloids II
Structure

Morphine*:
R1O

morphinan

skeleton

with

piperidine ring,
ring
O

*
*

R4
*
N

monomethoxy

derivative;

Medical use:

cough medicine

R3

Codeine:

R2O

naloxone: N-alllyl
y derivative

R1

R2

R3

R4

name

with oxo group; Medical

OH

OH

CH3

morphine

use: used as an antidote in

OCH3

OH

CH3

codeine

opiate overdose, (heroin or

OH

=O

CH2CH=CH2

OH

naloxone*

morphine overdose), narcotic

* = no double bond

antagonist.
t
i t

Opium alkaloids III

III

Physiological effect: morphine binds to opioid receptor as the

endorphines
Medical use: narcotic analgesic
Side effects: constipation, myosis, euphoria
Overdose: respiratory depression,
depression coma,
coma pinpoint pupils
Morphine addiction: tolerance, psychological and physiological
dependence are extremely high.

Opium alkaloids IV
IV
Thebaine

H3CO

O
N
CH3
H3CO

Structure: it differs from morphine (two methyl groups and an

extra double bond)
Physiological effect: convulsant, toxic.
U
Usage:
used
d as a precursor in
i the
th pharmaceutical
h
ti l industry
i d t

Opium alkaloids V
Heroine
H3CCOO

H
N
CH3

H3CCOO

Structure: diacetyl derivative of morphine

Physiological effect: as that of morphine, but its bioavailability is
much better (more hydrophobic), myosis, cold, wet skin, weak
breathing, narcosis.
Medical use: no

Opium alkaloids VI
Morphine analogues (opioid analgesics)
HO

N CH3

O
O

pethidine

C6H5

CH3
CH3

N
CH3

methadone

H
N
CH3

HO

morphine

Structure
pethidine: a piperidine derivative
methadone: a tertiary amine derivative
Physiological effect: similar to morphine
Medical use: opioid analgesics, treatment of opioid dependence

Indole alkaloids

Ergot alkaloids
Strichnine
Yohimbine
Strichnine, brucine: very toxic alkaloids (no medical
use); brucine is used for resolution of racemic mixtures
mixtures.
Vinca alkaloids

Ergot alkaloids I
Lysergic
yse g c acid
ac d
Isolation: Claviceps purpurea (ergot fungus)

Claviceps purpurea

There are about 12 ergot

g alkaloids.
It is a precursor for a wide range of ergoline alkaloids.
Structure: it a fused ring system composed of an indole and a
quinoline skeleton.

Ergot alkaloids IIII

Ergotamine

L-Pro

Lysergic acid

OH
N

O
H
N

O
H

CH2

O
CH3
N
H

H
N

CH3
H

L-Phe
NH

Structure: an amide derivative of lysergic

y g acid.
Physiological effect: it has a complex mechanism of action (similarity to
neurotransmitters as serotonin, dopamine, and epinephrine) binding to their
receptors.
Medical use: treatment of acute migraine; gynaecology: immediately postpartum to decrease uterine bleeding.

Ergot alkaloids IIII

II
LSD* (Lysergic
(L se gic acid diethylamide)
dieth lamide)

O
H
H3C

N
CH3

N
*

CH3
H

NH

Structure: diethylamide of lysergic acid, it is a semisynthetic drug.

Physiological effect: hallucinogenic, psychological effects as closed and
open eye visuals, an altered sense of time.
Side effects: flash back
Medical use: no
Addiction: non-addictive

Norharmane alkaloids
Vinca alkaloids I
Isolation: Vinca minor
H
HO N
H3CO
O

vincamine

CH3

ethyl apovincaminate

Vinca minor

Structure: vincamine belongs to a special class of indole alkaloids

(norharmane skeleton=indole+pyridine)

Vinca alkaloids II
II

Physiological
effect:
vincamine
proved
to
be
antihypertensive in 1954, but because of low activity was
not marketed.
The
semisynthetic
derivative,
vinpocetine
(ethyl
apovincaminate) was prepared as a more effective cerebral
dilator.
dilator
Medical use: applied as nootropic for the improvement of
memory (it helps to maintain the memory and
concentration)

Tetrahydrocannabinol
y
((THC)) I
It is the major alkaloid of the hashish or marihuana, grass
Isolation: Cannabis indica
CH3

H
H3 C
H3 C

OH

CH3

tetrahydrocannabinol*
y

Cannabis sativa

Structure: it is not a basic compound; it is an aromatic

terpenoid with low water solubility

Tetrahydrocannabin
Tetrahydrocannab
y
inol
ol ((THC)) II
II
Physiological activity: it binds to the cannabinoid receptors, it
acts on the CNS, causing euphoria, hallucinogenic, disturbance
of the perception, increases the appetite, antiemetic, etc.
Medical use: therapy of cancer or radiation therapy as analgesic
and antiemetic agent, therapy of glaucoma.
No physical or psychological dependence.
Synthetic derivative: nabilon without hallucinogenic effect used
for the same therapy.

Taxol or paclitaxel I
Isolation from Pacific yew tree (Taxus brevifolia)
O
O
O

NH

O OH

O
O

OH

taxol
axol*
*

OH O
O

O
O
O

Taxus brevifolia

Structure: oligoester derivatives of tetracyclic diterpene alkaloids

(special oxetane ring)
Special building unit: phenylisoserine attached to taxane skeleton.
P d
Production:
i
f
from
the
h bark
b k off Taxus
T
b if li
brevifolia.

Taxol II

Physiological activity-mechanism of action: it acts on the Nterminal end of -tubuline stabilizing the microtubule polymer
and protecting it from disassembly; it inhibits the mitosis,
(inhibits the spindle function).
Medical
M
di l use: lung,
l
ovarian,
i
prostate,
t t bladder,
bl dd breast
b
t cancer, head
h d
and neck cancer, Kaposis sarcoma
Side effects:
Sid
ff t
h
hyperallergic
ll i reactions,
ti
nausea and
d vomiting,
iti
diarrhoea, alopecia, water retention, etc.
Some other vinca alkaloids as vincrystin and vinblastine act on
the microtubules in opposite way inhibiting the
polymerization of microtubules.
microtubules