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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5467_Библиотеки_им_академика_М_И_Перельмана.pdf
172
Pharmaceutical Chemistry of Natural Products
S. no. Alkaloids Source (Family) Pharmacological properties/uses
30. Caffeine Coffea arabica (Rubiaceae)
CNS stimulant and weak diuretic.
31. Theophylline Thea sinensis
(Theaceae)
CNS stimulant and weak diuretic.
32. Theobromine Thea sinensis
(Theaceae)
CNS stimulant and weak diuretic.
33. Aconitine Aconitum napellus and other Aconitum
spp (Ranunculaceae)
In the treatment of neuralgia, sciatica,
rheumatism, infl ammation, analgesic and
cardiac depression.
34. Conessine Holarrhena antidysenterica
(Apocynaceae)
Antiprotozoal, used in the treatment of
dysentery.
35. Ephedrine Ephedra gerardiana
and other Aconitum spp
(Ephedraceae)
Sympathomimetic and used in the treatment
of asthma.
Used in the treatment of allergic condition
such as hay fever.
36. Adrenaline Adrenal glands Sympathomimetic
37. Taxol
(paclitaxel)
Taxus brevifolia
(Taxaceae)
Anticancer
38. Colchicine Colchicum autumnale
and other Aconitum spp
(Liliaceae)
In the treatment of gout and rheumatism.
Antitumour activity.
Abbreviations: CNS, central nervous system; CVS, cardiovascular system.
Some of the pharmaceutically important alkaloids are described with their structural elucidation
herein.
Tropane Alkaloids
Atropine
1
2
3
4
5
6
7
8
N(CH )
3
OCC
CH OH
2
H
2
1
O
8-Methyl-8-aza-bicyclo[3.2.1]octan-3-yl-3-hydroxy-2-phenylpropanoate
3
Atropine is a naturally occurring belladonna alkaloid that is extracted from the belladonna plant.
It is the racemic mixture of L-hyoscyamine, and hence it can also be called (±) hyoscyamine. It is the
tropine ester of racemic tropic acid and occurs mainly in the roots of deadly nightshade (Atropa
belladonna), thorn apple ( Datura stramonium) of the Solanaceae family along with L-hyoscyamine
(an optically active form).
Mode of action: It is a competitive antagonist for the muscarinic acetylcholine receptor. Atropine
reduces the parasympathetic activity of all muscles and glands regulated by the parasympathetic
nervous system through muscarinic (M) receptors. M
1
and M
3
receptors function through Gq
Alkaloids
173
protein and activate membrane-bound phospholipase C, generating inositol triphosphate and
diacylglycerol which releases calcium ions to produce depolarization in glands and smooth muscles.
M
2
receptors open through Gi proteins to activate potassium channels resulting in hyperpolarization
(decreases the cardiac function). Atropine equally blocks the M
1
, M
2
and M
3
subtypes of receptors
and antagonizes the actions.
Properties and uses: It is a white, crystalline powder or colourless crystals. Freely soluble in alcohol
and well soluble in water. The greater molar potency of atropine helps it to block several moles of
acetylcholine. The umbrella-like atropine molecule may mechanically or electrostatically inactivate
adjacent receptors on the cell surface so that these receptors are also unavailable for acetylcholine
or other parasympathomimetic stimulants. It is well absorbed from the gastrointestinal (GI) tract
and distributed throughout the body. It crosses the blood–brain barrier to enter the central nervous
system (CNS), where large doses produce stimulant effects and toxic doses produce depressant
effects. Atropine is also absorbed systemically when applied locally to mucous membranes. The
drug is rapidly excreted in the urine. Atropine is used in ophthalmology for its mydriatic action on
eye, and it is also used to relieve night sweats as it diminishes salivary and gastric secretions.
Structural elucidation
The structure of atropine is established as follows:
1. Molecular formula: The molecular formula of atropine is found to be C
17
H
23
NO
3
.
2. Atropine is an ester: Atropine on hydrolysis yields tropine and (±) tropic acid. Therefore,
atropine is a tropine ester of tropic acid (tropine tropate).
CHNO
17 23 3
⫹
HO
2
Ba(OH)
2
CH NO
815
⫹
CH O
9103
Atropine Tropine Tropic acid
Structure of tropic acid (C
9
H
10
O
3
)
Results of the usual standard tests reveal that tropic acid is found to possess one 1° alcohol
(–OH) and –COOH group.
Upon strong heating tropic acid is converted to atropic acid, which on further oxidation yields
benzoic acid. This indicates atropic acid and tropic acid have benzene ring with a side chain.
CH O
9103
⫺HO
2
⌬
CHO
982
(O)
COOH
Therefore, atropic acid is having one –COOH, one double bond and one benzene nucleus.
CHC
65
H CH.COOH⫽C H C COOH
65
⭈
CH
2
III
Structure II is known to be cinnamic acid, hence I is atropic acid.
As atropic acid is obtained by dehydration of tropic acid, addition of water molecule to atropic
acid yields tropic acid—compound III or IV.
174
Pharmaceutical Chemistry of Natural Products
CH
3
C H C COOH
65
⭈⭈
OH
III
CH OH
2
C H C COOH
65
⭈⭈
H
IV
The structure (IV) is found to be correct, as it has one 1° alcohol [fi rst point under the section
‘Structure of Tropic Acid (C
9
H
10
O
3
)’] and it is confi rmed by synthesis.
Synthesis of tropic acid from acetophenone
CH C O
65
⭈⫽
CH
3
HCN
CH C
65
⭈
CH
3
OH
CN
HCl
CH C
65
⭈
CH
3
OH
COOH
Atrolactic acid
Acetophenone
Heat
⫺HO
2
C H C COOH
65
⭈⭈
CH
2
ether
HCl
C H CH COOH
65
⭈⭈
CH Cl
2
Na CO
HO
23
2
C H CH COOH
65
⭈⭈
CH OH
2
( )-Tropic acid⫹
Structure of tropine (C
8
H
15
NO)
Results of the usual standard tests reveal that the ‘N’ atom is found to be present as 3° N.
By Herzig–Meyer method, it is found to possess one
N—CH
3
group.
Results of the usual standard tests reveal that it is found to possess one 2° alcohol (–OH) group
(benzoylation and oxidation reaction).
Ladenburg performed the following reactions on tropine.
C H NO
815
Tropine
HI
Tropine iodide
CH NI
814
(H)
Tropane
Distil
hydrochloride
CH Cl
3
⫹
nor-Tropane
CH N
713
Zn dust
CH
25
2-Ethylpyridine
N
CH N
814
On this basis, Ladenburg proposed that tropine is a reduced pyridine derivative.
CH CH OH
22
N
CH
3
CHOH CH⭈
3
N
or
CH
3
Alkaloids
175
Oxidation of tropine: Tropinic acid is a dicarboxylic acid obtained upon oxidation (possessing same
number of carbon atom as in alcohol) and hence the alcoholic group in tropine must be present
in ring structure and hence, Ladenburg structure is discarded.
Tropine
CrO
3
Tropinone
CrO
3
( -Tropinic acid⫾)
CH NO
815
CH NO
813
CH NO
813 4
Furthermore, it found that tropinone yields dibenzylidene derivative which is a characteristic
of –CH
2
–CO–CH
2
. This confi rms that the ketone and alcohol in tropine is linked to a ring
structure.
In HEM, tropinic acid yields pimelic acid. Formation of pimelic acid confi rms the presence of
seven-membered carbon chain in tropinic acid and tropine.
CH NO
813 4
Tropinic acid
HEM
CHNO
78 4
4H
HOOC (CH ) COOH⭈
25
⭈
Piperylene
carboxylic acid
Pimelic acid
Presence of fi ve-membered ring is confi rmed on the basis of the formation of N-methylsuc-
cinimide from tropinic acid on oxidation.
HC
2
HC
2
CH
NCH⭈
3
CH
CH COOH
2
COOH
Tropinic acid
CrO
3
HSO
24
HC
2
HC
2
CO
CO
N-Methylsuccinimide
NCH⭈
3
Thus, the structure of tropinone and tropine can be proposed as follows:
HC
2
HC
2
CH
CH
NCH⭈
3
CH
2
CH
2
CO
HC
2
HC
2
CH
CH
NCH⭈
3
CH
2
CH
2
CHOH
2
3
4
5
6
7
1
2
3
4
5
6
7
NCH⭈
3
OH
Tropinone Tropine
1
All the foregoing reactions of tropine are explained with the above structure as mentioned
below:
Formation of 2-ethyl pyridine from tropine
Tropine
NMe⭈
OH
HI
NMe⭈
NMe⭈
I
[HI]
Dihydrotropidine
(tropane)
HCl
Distil
MeCl
⫹
NH
Nordihydrotropidine 2-Ethylpyridine
Zn
CH CH
23
N
176
Pharmaceutical Chemistry of Natural Products
Formation of tropinone and tropinic acid from tropine
Tropine Tropinone
Tropinic acid Dibenzylidenetropionone
PhCHO
NMe⭈
NMe⭈
NMe⭈
NMe⭈
OH
O
CO H
2
CH CO H
22
CHPh
O
CHPh
Formation of tropilidene (cycloheptatriene) from tropine
NMe⭈
NMe⭈
⫹
NMe⭈
2
Tropine
OH
HSO
24
⫺HO
2
(i) MeI
(ii) AgOH
OH
–
Vacuum
distil
(i) MeI
(ii) AgOH
(iii)Vacuum
distil
Tropilidene
NMe
2
Formation of pimelic acid from tropinic acid
NMe⭈
CH CO H
22
CO H
2
(i) MeI
(ii) AgOH
Tropinic acid
⫹⫺
NMeOH⭈
2
CH CO H
22
CO H
2
Heat
NMe
2
CHCO H
2
CO H
2
(i) MeI
(ii) AgOH
(iii)Heat
CHCO H
2
CO H
2
Na–Hg
Pimelic acid
CO H
2
CO H
2
The proposed structure of tropine is confi rmed by the synthesis.
Willstatter’s synthesis:
Suberone
Cycloheptene
(i) HI
(ii) [HI]
KOH
CHOH
25
Br
2
Br
Br
Me NH
2
NMe
2
Exhaustive
methylation
Cycloheptadiene
Br
Br
Br
2
Cycloheptatriene
Quinoline
150°C
HBr
Me NH
2
NMe
2
(i) Na/EtOH
(ii) Br /HBr
2
O
I
Br
Alkaloids
177
NMe
2
Br
Br
Warm
in Et O
2
⫹
NMe⭈
2
Br
⫺
(i) KBr (Br
(ii)AgCl (I
I)
CI)
Br
Cl
⫺
Heat
N.Me
HBr
AcOH
N.Me
Br
NMe⭈
⌿-Tropine
OH
H
CrO
3
O
200°C H SO
24
NMe⭈
TropinoneTropine
NMe⭈
H
OH
Zn
HI
⫹
NMe⭈
2
Robinson synthesis:
CHO
CHO
⫹ CH NH
32
⫹
COO
⫺
COO
⫺
O
NCH
3
COO
⫺
COO
⫺
O
HCl
NCH
3
O
Succindialdehyde Acetone dicarboxylate
Tropinone
Structure of atropine
By knowing the structure of tropine and tropic acid, atropine can be drawn as follows, which is
confi rmed by the synthesis.
NCH
3
OH
Tropine
HOOC
CH
CH
65
CH OH
2
HCl
NCH
3
OOCCH
CH
65
CH OH
2
⫹
Tropic acid
Atropine
Phenanthrene Alkaloids
Morphine
HO
O
HO
H
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
NCH⭈
3
178
Pharmaceutical Chemistry of Natural Products
Morphine is an alkaloid obtained from opium, a dark brown resinous material obtained from the
poppy (P. somniferum) capsule. It has two types of alkaloids, namely (i) phenanthrene derivatives
and (ii) benzylisoquinoline derivatives.
Opium has been known from 1500 BC. Serturner, a pharmacist, isolated the active principle of
opium in 1806 and named it morphine.
Pharmacologically, morphine is classifi ed under opioid analgesics. The main pharmacological
action of analgesics is on the cerebrum and medulla of the CNS which causes relief from pain and
depression of CNS associated with the drug dependence. Another effect is on the smooth muscle
and glandular secretions of the respiratory and GI tract.
Morphine also depresses the cough centre and vasomotor centre to inhibit cough and to
decrease the BP, respectively. Miotic action is produced because of the action of morphine on
third cranial nerve. It also reduces hypothalamic pituitary secretions, but can increase the ADH to
decrease the urine volume.
Morphine is conjugated by hepatic enzyme at phenolic (3-OH) position to form 3-glucuronide
metabolite. Glucuronidation of morphine also leads to N-demethylation to normorphine which
has decreased opioid activity and undergoes N- and O-conjugation and is excreted.
Mode of action: Morphine bind to µ and κ receptors (G protein coupled type) associated with
inhibitory channels. This fi rstly enhances the opening of K
+
channels and secondly inhibits
the opening of Ca
2+
channels. This hyperpolarizes the membrane and inhibits the release of
neurotransmitters, respectively. Both of these events inhibit the transmission of nociceptive signals
to ascending pathways to the brain to exert the analgesic action. It acts in the substantia gelatinosa
of dorsal horn to inhibit release of excitatory transmitters from primary afferents carrying pain
impulse.
Properties and uses: It is a white or almost white, crystalline powder or colourless, silky needles
or cubical masses, effl orescent in a dry atmosphere. It is soluble in water, slightly soluble in ethanol,
insoluble in toluene. Used as an opioid receptor agonist and analgesic.
Structural elucidation
The structure of morphine is established as follows:
1. Molecular formula: The molecular formula of morphine is found to be C
17
H
19
NO
3
.
2. Nature of the nitrogen atom: Results of the usual standard tests reveal that the nitrogen
atom of morphine is tertiary. By Hofmann degradation, ‘N’ atom is found to be present in
the ring.
3. Nature of the oxygen group:
(a) Results of the usual standard tests reveal that it possesses two –OH groups (diacetyl
or dibenzoyl derivative obtained when morphine is treated with acetic anhydride or
benzoyl chloride).
(b) One of the –OH groups is found to be phenolic (formation of violet colour with neutral
ferric chloride).
(c) The other –OH group is alcoholic in nature (when halogen acids reacted with morphine
it gives monohalogenated derivative).
Alkaloids
179
(d) Points (b) and (c) are confi rmed by the following reaction:
(i) When morphine reacts with methyl iodide monomethylated derivative is obtained,
which does not give violet colour with neutral ferric chloride, indicating that the
phenolic –OH group is methylated. The methyl morphine upon oxidation with
chromic acid gives a ketone (codeinone) indicating that the methyl morphine
(codeine) has one secondary alcohol (–OH) group.
(e) From the unreactivity of third ‘O’ atom and products obtained on degradation, it is
assumed that it is present as an ether linkage.
4. Presence of unsaturation: Results of the usual standard tests (e.g. catalytic reduction)
reveal that it possesses one olefi nic double bond.
5. Presence of benzene nucleus: Bromination of morphine yields bromo derivative with
the liberation of hydrogen bromide indicating the presence of benzene nucleus.
6. Presence of a cyclic 3° N: Codeine on reaction with methyl iodide gives codeine
methiodide, which upon heating with alkali yields α-codeimethine. These changes are
related to Hoffmann degradation which indicates the presence of ‘N’ atom in the ring.
7. Presence of phenanthrene:
(a) On distillation with zinc dust, morphine yields phenanthrene, indicating the presence
of phenanthrene nucleus.
(b) When α-codeimethine is heated with alkali, double bond shifting takes place with the
formation of isomeric β-codeimethine. Both these products yield methyl morphenol,
trimethylamine and ethylene when reacted with methyl iodide followed by alkali.
Methyl morphenol when heated with HBr yields morphenol which on reduction with
Na–alcohol gives morphol.
␣-Codeimethine
with alkali
Heat
-Codeimethine
Methyl morphenol
HBr
Morphenol
Na/C H OH
25
Morphol
(–OCH , ether)
3
Na–C H OH
25
(Phenolic group
and ether)
(Two phenolic group)
Methylmorphol
(–OCH and phenolic group)
3
HBr
(i)
CH I
3
(ii)
OH
⫺
(i)
CH I
3
(ii)
OH
⫺
Morphol is chemically 3,4-dihydroxyphenanthrene and this is confi rmed by the
synthesis of its dimethyl derivative.
180
Pharmaceutical Chemistry of Natural Products
HO C
2
Ac O
2
HCO
3
HCO
3
NO
2
CHO
⫹
3,4-Dimethoxy-2-nitrobenzaldehyde
Phenylacetic acid
(sodium salt)
3,4-Dimethoxy-2-nitro-
−phenylcinnamic acid␣
HCO
3
HCO
3
NO
2
CH
CCOOH
(i) [H]
(ii) NaNO –H SO
(iii) Cu powder
224
HCO
3
HCO
3
HCO
3
HCO
3
COOH
Heat
Dimethylmorphol
(morphol when CH H)
3
⫽
(c) Morphenol on fusion with KOH gives 3,4,5-trihydroxyphenanthrene, whereas on
reduction (using Na–ethanol) it yields morphol. Hence, the structure of morphenol is
confi rmed as follows:
HO
HO
HO
KOH
O
HO
3,4,5-Trihydroxy phenanthrene Morphenol Morphol
Na–alcohol
HO
HO
Alkaloids
181
8. Position of three oxygen atoms:
(a) The structure of morphenol and its formation from codeine confi rms the position of
two of the three oxygen atoms of morphine.
(b) Codeine on reaction with methyl iodide gives codeine methiodide and on reaction with
methyl iodide it gives codeinone methiodide. Both the products on heating individually
with acetic anhydride–sodium acetate yield 3-methoxy-4-acetoxyphenanthrene and
3-methoxy-4,6-diacetoxy phenanthrene, respectively.
Dimethyl aminoethanol
⫹ (CH ) NCH CH OH
32 2 2
AcO
HCO
3
Ac O
2
AcONa
Codeine methiodide
Codeinone methiodide
HCO
3
AcO
AcO
3-Methoxy-4-acetoxyphenanthrene
⫹ (CH ) NCH CH OH
32 2 2
3-Methoxy-4,6-diacetoxyphenanthrene
Dimethyl aminoethanol
Ac O
2
AcONa
Thus, the position of all oxygen atoms of morphine is established as follows:
Phenolic –OH group at C
3
Ether linkage between C
4
and C
5
2° Alcohol at C
6
9. Structure of morphine:
(a) The fact that morphine forms monobromo derivative and monosodium salt indicates
the presence of only one benzenoid nucleus.
As stated earlier, ethylene is obtained as one of the products during the exhaustive
methylation of codeimethines and dimethyl amino ethanol is formed from methyl
morphine (codeine). Formation of these products indicates that a –CH
2
–CH
2
–N–CH
3
chain must be present in morphine. Also a double bond and 3° N atom is present.