By : Vishal Sachan B.pharma (4th Yr)
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By : Vishal Sachan B.Pharma (4th yr)
1
Definition: the term “alkaloid” (alkali-like) is commonly used to designate basic heterocyclic, nitrogenous compounds of plant origin that are physiologically active.
2
Basicity: Some alkaloids are not basic e.g. Colchicine, Piperine, Quaternary alkaloids. Nitrogen: The nitrogen in some alkaloids is not in a heterocyclic ring e.g. Ephedrine, Colchicine, Mescaline. Plant Origine: Some alkaloids are derived from Bacteria, Fungi, Insects, Frogs, Animals. 3
True (Typical) alkaloids that are derived from amino acids and have nitrogen in a heterocyclic ring. e.g Atropine Protoalkaloids that are derived from amino acids and do not have nitrogen in a heterocyclic ring. e.g Ephedrine Pseudo alkaloids that are not derived from amino acids but have nitrogen in a heterocyclic ring. e.g Caffeine False alkaloids are non alkaloids give false positive reaction with alkaloidal reagents.
4
Biogenetic. Based on the biogenetic pathway that form the alkaloids.
Botanical Source. According to the plant source of alkaloids.
Type of Amines. Primary, Secondary, Tertiary alkaloids.
Basic Chemical Skeleton
5
Phenylalkylamines: e.g. Ephedrine
CH2 CH
CH3
NH2
Pyridine and piperidine e.g. lobeline, nicotine
N
N H
Tropane e.g. Atropine. NCH3
OH
Indole e.g.ergometrine N H
Imidazole
N
e.g. pilocarpine
N
Purine e.g. caffeine
6 1 N
5
7 N
H
8 2 N 4 3 Purine
N
9
Quinoline e.g.quinine quinidine
and
N
Isoquinoline e.g. papaverine
Phenantheren e.g. Morphine
N
Quinoline e.g.quinine quinidine
and
N
Isoquinoline e.g. papaverine
Phenantheren e.g. Morphine
N
Steroidal e.g.
Solanum Veratrum alkaloids
Terpenoid e.g. Taxol
and
Extraction and purification
Method I: The powder is treated with alkalis to liberates the free bases that can then be extracted with water immiscible organic solvents.
Method II: The powdered material is extracted with water or aqueous alcohol containing dilute acid. Alkaloids are extracted as their salts together with accompanying soluble impurities. Method III: The powder is extracted with water soluble organic solvents such as MeOH or EtOH which are good solvents for both salts and free bases. 11
Plant material and solvent
Organic solvent dissove Alkaloids Extract
Organic solvent dissove Impurities
Concentration
Acidification Alkalinization
Acidified Extract (Alk. as salts) Alkaline aqueous layer
Repeated Acid-Base procedures: Render extract Acidic, extract with organic solvent (dissolve non alkaloidal impurities), Alkalinize and extract again with organic solvents (Dissolve Alkaloids). Precipitation with alkaloidal precipitating agent. Convert to crystalline salts.
13
Role of SHIKIMIC ACID PATHWAY in Alkaloid synthesis
14
Shikimic acid pathway is the part of Phytochemistry i.e study ofchemicals derived In plant( secnd. Metabolites).
Q – 1 Diff. b/w Phytochemistry & Biochemistry ? Q- 2 What are primary and secondory metabolites?
Starting material for Shikimic acid pathway are1-Phosphoenolpyruate , 2- Erythrose-4-phosphate. Both are ultimately the product of glucose.
15
Shikimic acid is a precursor fora)Aromatic amino acidsPhenylalanine, Tyrosine, b)Indole ,Indole derivative, aromatic amino acid tryptophan, c)Many alkaloid & other aromatic metabolites, d)Tannins, flavonoids & lignin. 16
THE SHIKIMIC ACID PATHWAY This pathway (unique to plants) leads to the formation of the aromatic amino acids phenylalanine and tyrosine and to the formation of many other phenyl-C3 compounds.
C C C
Phenylpropanoids Phenyl-C3
Cleavage of the C3 side chain leads to many phenyl-C1 compounds.
C C C
C
Phenyl-C1 17
GLUCOSE pentose phosphate pathway
Erythrose-4-phosphate
glycolysis
ORIGINS OF THE SHIKIMIC ACID PATHWAY
PEP Phosphoenol pyruvate
Acetyl-CoA Shikimic Acid
The pentose phosphate pathway is one that converts glucose into sugars of different sizes (different numbers of C) by acyl interchanges. Erythrose is a 4-carbon sugar. 18
FORMATION OF SHIKIMIC ACID phosphoenol pyruvate
H H
COOH
O
O HO P
O C
H PO CH2
HO P
O
HO
H
O
H+
H
CH2
B:
CH2
O
HO
O C
COOH
H
CH2 HO
O
OH H
O
HO
H
erythrose-4-phosphate H+ COOH
HO
COOH
H+ O C
COOH
CH2
H
NADPH
H2C
HO
OH OH
COOH
O
OH OH
O
H
OH
OH OH
H
O
HO
H
shikimic acid 19
FORMATION OF CHORISMIC ACID hydrolysis of PEP
COOH
COOH
ATP HO
P O
OH
CH3
OH
C O
OH
OH
COOH
shikimic acid
H+
pyruvic acid nucleophilic addition to C=O
COOH
COOH
- H3PO4
H
CH2 O C OH
COOH
:B
COOH
- H2O
CH2 P O
O C OH
COOH
CH3 P O
O C OH OH
COOH
chorismic acid 20
COOH
O CH2
OH
O C OH
NH2
COOH
chorismic acid
O
NH2 Anthranillic Acid
Tryptophan
N H
Alkaloids containing Indole Ring ex- Vincristine , vinblastin, Resrepine
21
PREPHENIC ACID chorismic acid
HOOC
COOH O C CH 2 H
Claisen Type Rearrangement
C OH
HO
C O
CH2 C O H O
H
O
OH
prephenic acid
pseudoaxial conformation
Prephenic acid can be converted to phenylpyruvic acid or to 4-hydroxyphenylpyruvic acid: O
NADPH
NADP+
HOOC
CH2 C
p-hydroxyphenylpyruvic acid
tyrosine
-H+ - CO2 -H-
H
OH
COOH
phenypyruvic -H+ - CO2 -OH acid
phenylalanine 22
CLAISEN REARRANGEMENT A THERMAL REARRANGEMENT
CHR O
H heat
CHR
CHR O
H+
OH
enolization
an allyl ether
an allyl phenol
23
PREPHENIC ACID TO PHENYLALANINE HOOC C O
CH2
:B-Enz
CH2 C COOH
C O H O
H OH
O
- CO2 - H2O
phenylpyruvic acid
prephenic acid
H+
transamination
Ephedrine, Mescaline
CH2 CH COOH NH2 phenylalanine
24
PREPHENIC ACID TO TYROSINE HOOC C O
CH2
:B-Enz
CH2 C COOH
C O H O
H NAD+
OH
O
- CO2
HO
prephenic acid
4-hydroxyphenylpyruvic acid
transamination
hydride transfer to NAD+
CH2 CH COOH Codeine
Thebaine
NH2 HO tyrosine
Morphine 25
Papaverine (against spasms)
O N
O
O O
NH2 CO2H
NH
HO
Tyr
HO OH
O NH
HO
OH HO
OH
N
O O
O
O
OH
O OH
Norlaudanosoline
O
N
H3C O
O
CH3
O CH3
Thebaine
N
H3C O
O
CH3
OH
codeine
N
HO
CH3
O
OH
Morfin
26
PHENYLALANINE AND TYROSINE COME FROM A COMMON SOURCE AND ARE NOT CONVERTED PREPHENIC ACID
phenylpyruvic acid
CH2 CH COOH NH2
4-hydroxyphenylpyruvic acid
CH2 CH COOH
X
NH2 HO
phenylalanine
tyrosine
Although most plants could convert phenylalanine to tyrosine using hydroxylases, this conversion is a minor pathway. Most plants make enough tyrosine without converting phenylalanine. 27
A PRELIMINARY OVERVIEW
28
Shikimate Pathways
SHIKIMIC ACID CHORISMIC ACID
PREPHENIC ACID TYROSINE PHENYLALANINE
Thebaine , Codeine, Morphine
Anthranillic acid
Tryptophan Alkaloid having Indole ring like Vincristine, Vinblastine, Reserpine etc
Ephedrine, Mescaline 29
30
31
1
Definition: the term “alkaloid” (alkali-like) is commonly used to designate basic heterocyclic, nitrogenous compounds of plant origin that are physiologically active.
2
Basicity: Some alkaloids are not basic e.g. Colchicine, Piperine, Quaternary alkaloids. Nitrogen: The nitrogen in some alkaloids is not in a heterocyclic ring e.g. Ephedrine, Colchicine, Mescaline. Plant Origine: Some alkaloids are derived from Bacteria, Fungi, Insects, Frogs, Animals. 3
True (Typical) alkaloids that are derived from amino acids and have nitrogen in a heterocyclic ring. e.g Atropine Protoalkaloids that are derived from amino acids and do not have nitrogen in a heterocyclic ring. e.g Ephedrine Pseudo alkaloids that are not derived from amino acids but have nitrogen in a heterocyclic ring. e.g Caffeine False alkaloids are non alkaloids give false positive reaction with alkaloidal reagents.
4
Biogenetic. Based on the biogenetic pathway that form the alkaloids.
Botanical Source. According to the plant source of alkaloids.
Type of Amines. Primary, Secondary, Tertiary alkaloids.
Basic Chemical Skeleton
5
Phenylalkylamines: e.g. Ephedrine
CH2 CH
CH3
NH2
Pyridine and piperidine e.g. lobeline, nicotine
N
N H
Tropane e.g. Atropine. NCH3
OH
Indole e.g.ergometrine N H
Imidazole
N
e.g. pilocarpine
N
Purine e.g. caffeine
6 1 N
5
7 N
H
8 2 N 4 3 Purine
N
9
Quinoline e.g.quinine quinidine
and
N
Isoquinoline e.g. papaverine
Phenantheren e.g. Morphine
N
Quinoline e.g.quinine quinidine
and
N
Isoquinoline e.g. papaverine
Phenantheren e.g. Morphine
N
Steroidal e.g.
Solanum Veratrum alkaloids
Terpenoid e.g. Taxol
and
Extraction and purification
Method I: The powder is treated with alkalis to liberates the free bases that can then be extracted with water immiscible organic solvents.
Method II: The powdered material is extracted with water or aqueous alcohol containing dilute acid. Alkaloids are extracted as their salts together with accompanying soluble impurities. Method III: The powder is extracted with water soluble organic solvents such as MeOH or EtOH which are good solvents for both salts and free bases. 11
Plant material and solvent
Organic solvent dissove Alkaloids Extract
Organic solvent dissove Impurities
Concentration
Acidification Alkalinization
Acidified Extract (Alk. as salts) Alkaline aqueous layer
Repeated Acid-Base procedures: Render extract Acidic, extract with organic solvent (dissolve non alkaloidal impurities), Alkalinize and extract again with organic solvents (Dissolve Alkaloids). Precipitation with alkaloidal precipitating agent. Convert to crystalline salts.
13
Role of SHIKIMIC ACID PATHWAY in Alkaloid synthesis
14
Shikimic acid pathway is the part of Phytochemistry i.e study ofchemicals derived In plant( secnd. Metabolites).
Q – 1 Diff. b/w Phytochemistry & Biochemistry ? Q- 2 What are primary and secondory metabolites?
Starting material for Shikimic acid pathway are1-Phosphoenolpyruate , 2- Erythrose-4-phosphate. Both are ultimately the product of glucose.
15
Shikimic acid is a precursor fora)Aromatic amino acidsPhenylalanine, Tyrosine, b)Indole ,Indole derivative, aromatic amino acid tryptophan, c)Many alkaloid & other aromatic metabolites, d)Tannins, flavonoids & lignin. 16
THE SHIKIMIC ACID PATHWAY This pathway (unique to plants) leads to the formation of the aromatic amino acids phenylalanine and tyrosine and to the formation of many other phenyl-C3 compounds.
C C C
Phenylpropanoids Phenyl-C3
Cleavage of the C3 side chain leads to many phenyl-C1 compounds.
C C C
C
Phenyl-C1 17
GLUCOSE pentose phosphate pathway
Erythrose-4-phosphate
glycolysis
ORIGINS OF THE SHIKIMIC ACID PATHWAY
PEP Phosphoenol pyruvate
Acetyl-CoA Shikimic Acid
The pentose phosphate pathway is one that converts glucose into sugars of different sizes (different numbers of C) by acyl interchanges. Erythrose is a 4-carbon sugar. 18
FORMATION OF SHIKIMIC ACID phosphoenol pyruvate
H H
COOH
O
O HO P
O C
H PO CH2
HO P
O
HO
H
O
H+
H
CH2
B:
CH2
O
HO
O C
COOH
H
CH2 HO
O
OH H
O
HO
H
erythrose-4-phosphate H+ COOH
HO
COOH
H+ O C
COOH
CH2
H
NADPH
H2C
HO
OH OH
COOH
O
OH OH
O
H
OH
OH OH
H
O
HO
H
shikimic acid 19
FORMATION OF CHORISMIC ACID hydrolysis of PEP
COOH
COOH
ATP HO
P O
OH
CH3
OH
C O
OH
OH
COOH
shikimic acid
H+
pyruvic acid nucleophilic addition to C=O
COOH
COOH
- H3PO4
H
CH2 O C OH
COOH
:B
COOH
- H2O
CH2 P O
O C OH
COOH
CH3 P O
O C OH OH
COOH
chorismic acid 20
COOH
O CH2
OH
O C OH
NH2
COOH
chorismic acid
O
NH2 Anthranillic Acid
Tryptophan
N H
Alkaloids containing Indole Ring ex- Vincristine , vinblastin, Resrepine
21
PREPHENIC ACID chorismic acid
HOOC
COOH O C CH 2 H
Claisen Type Rearrangement
C OH
HO
C O
CH2 C O H O
H
O
OH
prephenic acid
pseudoaxial conformation
Prephenic acid can be converted to phenylpyruvic acid or to 4-hydroxyphenylpyruvic acid: O
NADPH
NADP+
HOOC
CH2 C
p-hydroxyphenylpyruvic acid
tyrosine
-H+ - CO2 -H-
H
OH
COOH
phenypyruvic -H+ - CO2 -OH acid
phenylalanine 22
CLAISEN REARRANGEMENT A THERMAL REARRANGEMENT
CHR O
H heat
CHR
CHR O
H+
OH
enolization
an allyl ether
an allyl phenol
23
PREPHENIC ACID TO PHENYLALANINE HOOC C O
CH2
:B-Enz
CH2 C COOH
C O H O
H OH
O
- CO2 - H2O
phenylpyruvic acid
prephenic acid
H+
transamination
Ephedrine, Mescaline
CH2 CH COOH NH2 phenylalanine
24
PREPHENIC ACID TO TYROSINE HOOC C O
CH2
:B-Enz
CH2 C COOH
C O H O
H NAD+
OH
O
- CO2
HO
prephenic acid
4-hydroxyphenylpyruvic acid
transamination
hydride transfer to NAD+
CH2 CH COOH Codeine
Thebaine
NH2 HO tyrosine
Morphine 25
Papaverine (against spasms)
O N
O
O O
NH2 CO2H
NH
HO
Tyr
HO OH
O NH
HO
OH HO
OH
N
O O
O
O
OH
O OH
Norlaudanosoline
O
N
H3C O
O
CH3
O CH3
Thebaine
N
H3C O
O
CH3
OH
codeine
N
HO
CH3
O
OH
Morfin
26
PHENYLALANINE AND TYROSINE COME FROM A COMMON SOURCE AND ARE NOT CONVERTED PREPHENIC ACID
phenylpyruvic acid
CH2 CH COOH NH2
4-hydroxyphenylpyruvic acid
CH2 CH COOH
X
NH2 HO
phenylalanine
tyrosine
Although most plants could convert phenylalanine to tyrosine using hydroxylases, this conversion is a minor pathway. Most plants make enough tyrosine without converting phenylalanine. 27
A PRELIMINARY OVERVIEW
28
Shikimate Pathways
SHIKIMIC ACID CHORISMIC ACID
PREPHENIC ACID TYROSINE PHENYLALANINE
Thebaine , Codeine, Morphine
Anthranillic acid
Tryptophan Alkaloid having Indole ring like Vincristine, Vinblastine, Reserpine etc
Ephedrine, Mescaline 29
30
31
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