Transcript - ISpatula

Shikimic Acid Pathway
H
O
O
OH
OH
OH
Shikimic Acid
Illicium anisatum L. Illicinaceae {Shikimino-ki in Japanese} (1885)
E. coli mutant strains pathway intermediate
Shikimic Acid Pathway
• Important for aromatic compounds
• Precursor of aromatic amino acids (Phe, Tyr, Try)
biosynthesis in bacteria, fungi & higher plants.
ANIMALS! HUMAN!
• Building block for other compounds: certain
alkaloids, coumarins, phenyl propanes, vol. oils,..
• Starting point for tannins in all plants
• Provide protection of plants against microorganisms
Biosynthesis of shikimic acid
Scheme of the conversion of shikimic acid to cinnamic acid
Shikimic acid → Chorismic acid → Prephenic acid → p-OH-phenylpyruvate
↓
↓
Anthranilic acid
↓
Tryptophan
↙
↓
↙
p hytohormones (indol-3-
↓
Phenylpyruvate
↓
Phenylalanine
Tyrosine→alkaloids
↓
p-coumaric acid
↓
↘
Cinnamic acid ↘
ace tic acid
Alkaloids
alkaloids
Possibilities of derivatives of cinnamic acid
• 1-Substitution in aromatic ring
• 2-State of the oxidation of the side chain
• -CH=CH-COOH →Propenic acid, cinnamic acids
•
•
•
•
•
-CH=CH-CH2OH → Propenol, coniferylalcohols
CH2-CH=CH2 →Allyl, Eugenol (volatile oil)
-CH=CH-CH3 → Propenyl, Anethol (volatile oil)
-CH2-CH2-CH3 →n-propyl
3- Shortening of the side chain
Formation of phenol carboxylic acids and simple phenols
Cinnamic acids
Cinnamic acid
p-coumaric acid
Caffeic acid
Ferulic acid
Sinapic acid
5-OH-ferulic acid
Tri-OH-cinnamic acid
Formation of Phenylpropane
Derivatives with Shorter Side Chain:
Shortening of side chain by β-oxidation and subsequent
decarboxylation (simple phenols) which might be linked
to oxidation→hydroquinone → quinone
COOH
O
O
H
OH
O
OH
p-Coumaric acid
OH
p-Hydroxybenzoic acid
OH
Hydroquinone
O
Quinone
Benzoic acids related to cinnamic
acids
Cinnamic acid ………………...Benzoic acid
p-coumaric acid……………….p-OH-benzoic acid
Caffeic acid………………........Protocatechuic acid
Ferulic acid………………………Vanillic acid
Sinapic acid……………………..Syringic acid
Tri-OH-cinnamic acid……….Gallic acid
Derivatives of dehydroshikimic acid
Vanilla planifolia (Orchidaceae)
•
•
Vanillin produced from eugenol (in plants) or lignin is a degradation by-product of
paper from wood (large scale preparation of vanillin)
H
O
H
O
Fermentation under blankets in the sun
fermentation
OCH3
OCH3
O-Glucose
Eugenol
Coniferylalcohol (lignin)
Vanilloside
Vanilloside (odourless ) is liberated during fermentation & oxidized to vanillin
CH2OH
fermentation
OCH3
O-Glucose
Vanilloloside
•
CH2OH
H
O
fermentation
OCH3
OH
Vanillyl alchohol
OCH3
OH
Vanillin
Fine aroma and taste is due to other compounds better than pure vanillin
OH
Vanillin
5
6
4
3
2
1 O
O
5,6-Benzopyran-1-one
isocoumarin
5
Coumarins
4
1
6 O
3
2
O
5,6-Benzopyran-2-one
coumarin
Name derived from Coumarouna (local Guyana
name) for the seeds of Dipteryx odorata (Fabaceae)
common name for Tonka bean
Seeds as spirits spice (not used now, hepatotoxic &
carcinogenic)
Characteristic new mown hay smell
Commonly used as sun UV protector
Absorb short wave UV 230-315 nm & transmit longwave UV 315 - 400 nm resulting in brown sun tan
Characters of Coumarins
• Free coumarins are organic solvents-soluble
• Derivatives of α-chromone, differ in benzene ring substitutions
(OH, OCH3, CH3)
• Common in Apiaceae, Asteraceae, Fabaceae, Lamiaceae, Poaceae,
Moraceae, Rutaceaea & Solanaceae
•
•
•
•
•
Characteristic UV (blue, yellow & purple) enhanced by ammonia
Umbelliferone R1=OH, R2=H
R1 6
Aseculetin R1=R2= OH
R2 7
O
O
Scopoletin R1=OCH2, R2= OH
Aseculus hippocastanum (horse-chestnut) (Hippocastanaceae)
rich in aesculin (6β-D-glucosyloxyl-7-OH-coumarin ); used in sun
tan preparations (both glycoside & aglycone)
• Symptomatic Rx of cutaneous capillary fragility
Biosynthesis of the coumarins
OH
OH
Dicoumarol
O
O O
O
• Melilotus officinalis (Fabaceae) mould-infected sweet clover
• Discovered by studying grazing cattle coagulation pattern
(sweet clover disease)
• Dicoumarol replaces vitamin K in prothrombin result in anticoagulant effect
• Prevention of thrombosis
• Pharmaceutical industry: synthetic derivatives for p.o
preparations
• Extract: p.o & topically to Rx minor vascular disorders & acute
attacks of piles
Furanocoumarins (Photosensitizers)
6
O
7
O
O
Furnaocoumarin
Furan ring is derived from isopentyl pyrophosphate
(mevalonic acid pathway)
6,7 or 7,8 furanocoumarins
Furanocoumarins-rich plant families:
Apiaceae, Fabaceae, Moraceae & Rutaceae
 Roots, fruits or seeds
Furanocoumarin Natural Derivatives
R1
•
Psoralea corylifolia (Fabaceae) fruits
4'
5'
6
5
7
O
4
1
8
O
3
2
O
R2
Ammi majus (Apiaceae) fruits ‫الخلّة الشيطاني‬
Ammi visnaga !!!
Cause dermatitis after consumption or direct contact of skin
with such plants followed by exposure to sun (only 6,7furanocoumarins; 7,8-furanocoumarin derivatives are
inactive)
Medicinal value:
1) Photo chemotherapy: Rx of vitiligo as part of PUVA for
repigmentation of skin
2) UVA= 320nm + p.o+ topical psoralen or derivatives
Psoriasis: abnormal epidermal production of scaly skin
•
•
•
Example of Medicinally-valuable
Furanocoumarins
R1
4
• Commonly known as Psoralens
5
4'
6
3
• Psoralen
R1=R2= H
5'
7
2
1
O
O
O
• Bergapten R1= OCH3, R2=H [5-MOP]
8
R2
• *Xanthotoxin R1= H , R2= OCH3
* Xanthotoxin= Methoxsalen = 8-MOP nat. or semisynthetic
derivative of psoralen p.o medication
• Imperatorin R1=H , R2 = CH2-CH=C(CH3)2
• Trioxalon = TMP 4,5,8-trimethylpsoralen (synthetic) topical or
bath sol. Then exposure to UVA @ 320-380 nm
MOP of PUVA & Toxicity
1. Interfere with DNA by forming bridges
between its base pairs (pyrimidine part)
2. Double bonds of furanocoumarin are
activated by UV radiation
3. Inhibits replication & transcription of DNA &
synthesis of RNA & cell division
4. Rx of psoriasis is based on the basis of DNA
synthesis, inhibitory effect by
furanocoumarins
Photosensitization Mechanism: Binding of activated 3,4double bond in furanocoumarin with 5,6-double bond of
pyrimidine base pair in DNA
Binding of 4’,5’-double bond of psoralen molc. with a second
molecule of pyrimidine base of another base pair
Sug
ar
Adenine
N
N
N
N
Sugar
P
H
N
Cytosine
P
O
N
H
O
N
O
N
Sugar
Thymine P
CH3
N
4`
5`
O
4
6
7
O
OCH3
Xanthotoxin
3
O
Lignin & Lignans
• Lignin is plant polymer acting as strengthening
material for plant cell wall & matrix for cellulose
micro-fibrils
• Represent a large no. of aromatic material based on
C6C3 building unit
• Lignins formed by oxidative coupling of
hyroxycinnamyl alcohol monomers by peroxidase
enzymes [p-coumaryl-, coniferyl- and sinapyl-alcohol]
• Lignans are dimeric phenylpropanes (C-18) coupled
at the central carbon of the side chain [via their ßcarbon of the side chain]
20
Formation of the lignans
•
Dimers of cinnamic acid linked via their ß-carbons and further
modifications; i.e. Podophyllotoxin
↓
↓
Podophyllotoxin: 2 C6C3 [Coniferylalcohol]
via several intermediates
• Dried root & rhizhome of Podophyllum peltatum [May apple,
mandrake] (Berberidaceae) USA & Canada
• Structure elucidated in 1930’s; planar structure with 4 chiral
centers
• C2H5OH extract = Podophyllin (20% podophyllotoxin, 10% βpeltatin, 5% α-peltatin)
• Traditionally as cathartic, purgative, antiviral, warts remedy
• Trans lactone ring is essential for anti-tumor action; aromatization
of ring C↓activity. Too toxic to be used clinically!
• [OH-] converts into inactive isomer (e.g.epi-podophyllatoxin)
• Classified as microtubule inhibitor [inhibits polymerization of
tubulin and stop cell division at the beginning of metaphase] 22
Etoposide and teniposide
• As semisynthetic anticancer agents developed from 4’demethylepipodophyllotoxin
• They act as Topo II inhibitors (prevention of DNA synthesis
and replication)
• Etoposide : small cell lung cancer, breast cancer, leukemia &
Hodgkin’s disease,… Teniposide : brain and bladder cancer,…
• Glycosides < active than genins < side effects
Podophyllotoxin & Peltatins
• Lignans formed by oxidative coupling of 2 cinnamic
acid residues (dimeric phenylpropane derivatives)
known as LIGNANS
R3
H R2
O
O
O
H
H3CO
O
Podophyllotoxin
Alpha-Pelatin
Beta- Pelatin
R1=CH3 R2= OH
R1= H R2= H
R1= CH3 R2= H
R3= H
R3= OH
R3= OH
OCH3
OR1
24
Tannins & Gallic acid
• Gallic acid is the building block of many tannins
COOH
COOH
COOH
Tannins
HO
OH
OH
Shikimic acid
O
OH
OH
3-Dehydroshikimic Acid
HO
OH
OH
Gallic acid
Properties of Tannins:
• H2O solubility !! (colloidal aq. Solution in A` PH)
• Binds proteins to form indigestible complex (leather tanning)
• Amorphous
• Astringent taste (unripe fruits, in all organs or organ-specific)
• Fe+2 salts binding producing dark blue or greenish black sol. Complexes (ink)
• Ppt with metals e.g. Cu, Pb (acetate salts to separate tannins from extracts);
ppt gelatin and alkaloids;
• Large MW (1000-5000)
• Pseudotannins (MW~500)
Hydrolysable tannins
• Possibilities of condensation of the gallic acid
OH
OH
HO
HO
OH
O
COOH
O
COOH
HO
OH
OH
HO
COOH
HO
HO
COO
HO
OH
O
Hexahydroxydiphenic acid OH
HO
O
3-galloyl-gallic acid
Ellagic Acid
Classification of Tannins
Hydrolysable
Condensed
H+ or enzymes Rx produce • H+ or Enzymes Rx
simple molecules
produce complex
insoluble compounds
A) Ellagitannins
• Complex polymers
OH
O
O
OH
• Biosynthesis from
H
Ellagitanins
acetate or shikimate
+ Sugar
Enzymes
HO
O
O
pathway
B) Gallotannins OH
Ellagic Acid
• Building units are
catechins + flavonoids
estrefied with gallic acid
+
HO
Gallotannins
H+
Enzymes
+ Sugar
HO
OH
OH
Gallic Acid
OH
O
OH
CO2H
OH
OH
Catechin
Medicinal Value of Tannins
Limited Application:
Based on ability to bind proteins to form indigestible
complex
1. Diarrhea
2. Bleeding gums
3. Skin injuries preparations
Plant Material
H2O/Alc
Ether
Tannins (sugar + gallates)
+
Free Gallic A`
Hamamelis
•
Dried leaves of Hamamelis virginiana L.
COOH
(Hamamelidaceae)
• North America & Canada
HO
OH
• Gallotanins
OH
Uses:
Gallic acid
1. Infussions & extracts in haemorrhoids (topical
pharmaceuticals)
R'O
2. Topically skin inflammation H O
R= GALLIC ACID
OR
H
3. Face lotions as astringent
OR
H
OH
R' = TRIGALLIC ACID
H
OH
Galls
•
•
Vegetable growths as a result of insect infections of the
leaves & twigs of Quercus infetoria (Fagaceae)
70-80% tannins from Turkey, Syria, Greece & Iran
COOH
O
O
O
Uses:
O
OH
HO
HO
1. Rx of catarrh & infection
OH
HO
TRIGALLIC ACID
OH
2. Stop bleeding locally
3. Alkaloid poisoning remedy (insoluble comlex)
4. Ink preparation
R'O
O
H
5. Textiles dyeing esp. leather
R= GALLIC ACID
OR
HO
OH
OR
H
H
H
OH
R' = TRIGALLIC ACID