PLANT PHENOLS
Very wide group of compounds, which cannot be defined in simple
way.
Basic structural characteristic is a presence of at least one aromatic
ring substituted at least one hydroxyl group (free or bonded –
representing other functionality (for example ether, ester. Or
glycoside).
Based on this definition, this group of compound can include
substances structurally very different and much more variable
from the biological activity and phytochemical classification point
of view, for example:
• alkaloids: morphine, boldine,
• terpenoids: thymol, gossypol, carnosol,
• tannins
Therefore, it is necessary to know biosynthesis, precursors, and to
well determine borders of unique phytochemical groups.
PLANT PHENOLS
O
N CH3
H
OH
OH
N
CH3
OH
OH
MeO
MeO
OH
OH
OH
OH
OH
CHO OH
OH
OH
CHO
O
O
OH
OH
OH
OH
O
O
1
3
4
5
6
7
8
9
10
11
12
13
14
15
16
A
B
C D
Morphine Boldine
Thymol Carvacrol Gossypol
Ellagic acid
PLANT PHENOLS
Plants and microorganism only* are able to biosynthetise
aromatic core. Animals are almost ever dependent on:
• intake of aromatic compounds via nutrition
• symbiosis, which brings possibility to produce
necessary metabolites containing aromatic structural
features (amino acids, vitamins, pigments, toxins)
* Several exceptions exist, for example biosynthesis of
estrogene
PLANT PHENOLS
Structural difference of plant phenols is based on two different
biosynthetic pathways
• shikimate
• acetate
Structural difference is increased by common combination of shikimic
acid and acetate pathway, for example flavonoids, stilbenes,
pyrones, and xanthones.
Sometimes the third synthone enters biosynthesis – a mevalonate
• shikimate + mevalonate: furanocoumarins, pyranocoumarins,
some quinones
• acetate + mevalonate: cannabinoids, hop bitter acids
Sometimes all three precursors share one biosynthetic product:
prenylflavonoids, rotenoids
PHENOLS FORMATED VIA SHIKIMIC AND ACETATE PATHWAYS
OH
MeO
OMe
CO2H
O
OH
OH O
OH
OH
O
OOH
OHOH
CH3
O
O
OH OHO
OH CH3
O
OH CH3
OHOH
sinapic acid
phenylpropanoic acid
aesculetine
coumarine
magnoliol
neolignane
S
h
i
k
i
m
a
t
e
s
A
c
e
t
a
t
e
sjuglone
naphtoquinone
chrysophanol
anthraquinone
hypericine
naphtodianthrone
PHENOLS FORMED VIA COMBINATION OF METABOLIC PATHWAYS
OH
OH
OH
O
OH
OOH
OH
OH
OH
O
O
OH
OH
OH
OH
Glc
8
7
6
10
9
6
4
3
2
1
OH
C5H11
5
O
S
h
i
k
i
m
a
t
e
s
+
A
c
e
t
a
t
e
s
resveratrol
stilbene
quercetine
flavonol
mangiferine
xanthone
A
c
e
t
a
t
e
+
M
e
v
a
l
o
n
a
t
e
a
THC
NATURAL MEDICINES DERIVED FROM SHIKIMIC ACID
• Shikimic acid is precursor of majority of compounds possessing
aromatic ring
• Substantially lower amount of aromatics is formed via acetate pathways
• Origin of aromate - according to the position of hydroxyl
groups:
• Shikimic acid derived aromatic compounds – OH at position
1,2 (ortho, catechol), or 1,2,3 (pyrogallol). If there is one
phenolic hydroxyl only, it is at para position.
• Acetate derived aromatic compounds – OH directed into
meta- position, for example derivatives of resorcinol and
phloroglucine
LOCALIZATION OF HYDROXYL GROUPS AT PHENOLICS
- SHIKIMIC ACID ORIGIN - ACETATE ORIGIN
OH
OH
OH
OHOH
COH C COOH
catechol pyrogallol
p-coumaric acid
OH
OH
OH
OH OH
resorcinol phloroglucinol
.....CH2COCH2COCH2CO.....
FORMATION OF SHIKIMIC ACID
CH2 O
OH
OH
H
PO
CH2
PO
COOH
OH
OHOH
OPO
COOH
OH
O OH
OH COOH
OH
OH OH
OH COOH
OH
OH
COOH
O
OH
OH
COOH
OH
+
erythrose-4-phosphate 2-phospho-enol
-pyruvate
2-keto-3-deoxy-7-phospho-D-araboheptonic
acid
quinic acid 3-dehydroquinic acid 3-dehydroshikimic acid shikimic acid
SHIKIMATE DERIVATIVES
OH
O OH
COOH
OH
OH OH
COOH
OH
PO OH
COOH
OH
COOH
O
C
CH2
COOH
OH
CH2COCOOHHOOC
C
COOH
CH2
OP
3-dehydroshikimic acid shikimic acid 5-phosphoshikimic acid
gallic acid
protocatechuic acid
p-aminobenzoic acid
anthranilic acid
p-hydroxybenzoic acid
salicylic acid
chorismic acid
prefenic acid
SHIKIMATE DERIVATIVES
NH2
OH
COOH
COOH
O
(HO)
COOH
NH2
(HO)
COOH
NH2
COOH
(HO)
COOH
N
H
NH2
COOH
OH
CH2COCOOHHOOCchorismic acid
prefenic acid
arogenic acid phenylpyruvic acid
anthranilic acid
phenylalanine
(tyrosine)
NADP+ reduction
amination
tryptophan
cinnamic acid
(p-coumaric acid)
-NH3
phosphoribosyl-
diphosfate,
serine
prefenic acid
- CO2
- H2O
transamination
FORMATION OF CINNAMIC ACID FROM
PHENYLALANINE
NH2
COOH
R
COOH
R
L-phenylalanine- or
L-tyrosine-amonialyase
R = H = phenylalanine
R = OH = tyrosine
cinnamic acid
p-coumaric acid
Phenylalanine proteins
alkaloids
cinnamic acid and its derivatives
L-tyrosine-amonia-lyase exclusivelly in grass (Graminae)
L-phenylalanine-amonia-lyase generally widespread stereospecific
deamination of natural L-acids
CINNAMIC ACID AND ITS DERIVATIVES
COOH
OH
COOH OH
OH
COOH
OH
COOHMeO
OH
OH
COOHMeO
OH
COOH
OMe
MeO
COOHMeO
MeO
OMe
cinnamic acid p-coumaric acid caffeic acid
ferulic acid
sinapic acid
(as a ester bound in rescinnamine)
trimethoxycinnamic acid
CAFFEIC ACID ESTERS
OCO C C
OH
OH
OH
OH
OH
CO2
H
H
H
chlorogenic acid
3-O-caffeoylquinic acid
baktericidal effects, cumulation in the place of wound of plant
TRANSFORMATION OF CINNAMIC ACID
COSCoA
ArCOCH2CO SCoA
ArCO SCoA ArCOCH3
ArCH CHCHO
ArCH CHCH2OH
ArCH CHCH3
ArCH2CH CH2
ArCH CH(CH2CO) CH2COOHn
C6-C1 C6-C2
C6-C3 C6-C3(C2)n
cinnamoylcoenzym A
+ malonylcoenzym A
reduction
-oxidation
oxidation
COUMARINS AND FURANOCOUMARINS
Derivatives of 5,6-benzo-2-pyrone (α-chromone)
• different in substituents at benzene ring (OH, OCH3, CH3)
O O1
2
5
6
7
8
5,6-benzo-2-pyrone
COUMARINS AND FURANOCOUMARINS
Biosynthsis
OH
O
OH
O
OH
OH
O
O-Glc
O-Glc
OH
O
O O
trans-cinnamic acid o-coumaric acid o-coumaric acid glucoside
o-coumaric acid glucoside coumarin
COUMARINS
Lactones of o-hydroxycinnamic acid, 2-benzopyrone derivatives (Fabaceae,
Poaceae); characteristic odour)
COOH COOH
OH O
Glc
COOH
OO
COOH
OH
COOH
OHOH O
Glc
COOH
OH OOOH
COOH
OH
OH COOH
OH
OH
OH O
Glc
COOH
OH
OH OO
OH
OH
cinnamic acid
p-kumaric acid
caffeic acid aesculetin
umbelliferon
coumarin
DICOUMAROL
zapaření sena, microorganisms → compound with anticoagulant
effect
Melilotus officinalis
O OO O
OH OHR
R = H = dicoumarol
R = COOC2H5 = pelentan
FURANOCOUMARINS
Furanocoumarins contain additional furane ring, which is derived from metabolism
of 3-methyl-3-butenyldiphosphate.
Furanocoumarins linear – psoralen (furane ring connected at position 6 and 7)
angular – angelicin (furane ring connected at position 7 and 8)
O OO O OO
6
7 8
7
psoralen angelicin
PSORALENES
Occurrence
Rutaceae: Citrus bergamia
Apiaceae: Apium graveolens, Ammi majus
Fabaceae: Psoralea corylifolia
Moraceae: Ficus
Utilization: photochemotherapy of vitiligo (pigmentation disorder), psoriasis
O OO
R1
R2
O O
R2
R1
O6
7 1 2
3
45
8
R1 R2
Psoralene H H
Bergaptene OCH3
H
Xanthotoxin H OCH3
Imperatorin H =CH2-CH=(CH3)2
1
2
3
4
5
6
7
8
PHENYLPROPANOIDS
different degree of oxidation of three carbon side chain
CH2
OH CHO CH2
OH
OH
MeO
MeO
O
MeO
MeO
MeO OMe
OH
MeO
OH
MeO
O
O
O
MeO MeO
O
O
hydroxycinnamoylalcohol cinnamoylaldehyde coniferylalcohol
anethol aniseketone -asarone
eugenol isoeugenol foeniculin
myristicine isomyristicine
LINDLEIYN
OH
OH
OH
O
O
O
OH
OH
O
O
O
O
OH
OH
OH
phenylbutanone
glucose
gallic acid gallic acid
Myristicae semen – content compounds
MeO
OMe
OMe
CH2
CH
CH2
MeO
OMe
OMe
CH2
CH2
NH2
O
O
OMe
CH2
CH
CH2
Elemicine Meskaline, AnhaloniumMyristicine
Zingiberis rhizoma – content compounds
O
Zingiberene Zingiberol
OH
CH3
O
O
OH
(CH2)4
CH3
O
O
CH3
CH3O
CH3O
(CH2
)4
OHO
CH3
zingerone
shogaol
methylgingerol
Cynarae radix, folium – content compounds
OH
OH
CO O
OH OH
O OC
COOH
OH
OH
OH
O OH
OH
COOH
COC
H
C
H
OH
OH
Cynarin
Chlorogenic acid
LIGNINE AND LIGNANS
• Wide spread
phenylpropanopids
• Lignin – the most widespread
polymeric phenolic compound
of plant origin
• Formed by oxidative
dimerisation o polymerisation
of C6-C3 units
• Basic monomers show always
p-hydroxyphenylpropanoid
structure
• p-coumarylalcohol
• Coniferylalcohol
• sinapylalcohol
C
C
C
OH
R1 R2
R1 = R2 -H, -OH, -OCH3
POLYMERISATION OF CONIFERYLALCOHOL
RADICAL MECHANISM – FORMATION OF MESOMERIC RADICALS
CH
O
CH
CH2
OH
OMe
CH
O
CH
CH2
OH
OMe
CH
O
CH
CH2
OH
OMe
C
CH
O
CH
CH2
OH
OMe
C
CH
O
CH
CH2
OH
OMe
Ra Rb Rc Rd
- e
FORMATION OF DILIGNOLS FROM MESOMERIC RADICALS
CH
CH
OH
HOH2C
O
CH
CH
CH2OH
OMe
OMe
CH
CH
OH
CH2
OMe
CH
O
O
CH2
CH
O
MeO
O
CH
CH
CH2OH
OMe
O
CH
CH
CH2OH
OMe
dehydrodiconyferylalcohol
Rb + Rc
DL-pinoresinol
Rb + Rb
quinonmetide
Ra + Rb
CONIFERYLALCOHOL – CONIFERINE
CH2
OH
OH
MeO
CH2OHMeO
OO
CH2OH
(-D-glucopyranosyl)
coniferylalcohol
coniferin
LIGNIN AND ITS TYPES
OH
COOH
OH
CHO
OH
CH2
OH
OH
COOH
OMe
OH
CHO
OMe
OH
CH2
OH
OMe
OH
COOH
OMeMeO
OH
CHO
OMeMeO
OH
CH2
OH
OMeMeO
sinapic acid sinapylaldehyde sinapylalcohol
ferulic acid conifericaldehyd coniferylalcohol
p-coumaric acid p-coumarylaldehyde p-coumarylalcohol
lignine of conifers
lignine of grasses
lignine of broad-leaf trees
UTILIZATION OF LIGNINE
- listed in group of fibers, but is not used as dietary fiber
individually
- material for synthesis of vanillin and syringaldehyde
- filler for phenolic plastics
- stiffening (especially of rubber for outsoles)
- additive for greases
- stabilizer of asphalt emulsions
- for precipitation of proteins
LIGNANS
formed by connection of two C6-C3 compounds (phenylpropanes) via βcarbon
atom
(oxidative dimers of coniferylalcohol)
CH
CH
CH2OH
OH
CH
O
OH
CH
CH2
OH
OMeMeO
CH
OH
CH2
O
CH
CH
CH2
OH
O
CH
MeO
OMeC
OH
C
C
OMe
C
C
C
OH
MeO










olivil
pinoresinol
hydronaphtalene type
(for example podofyllotoxin)
diarylbutane type
(for example kubebin)


cyclooctadiene type
(for example schisandrin)
Structure of Etoposide and Teniposide
O
O
O
O
O
OOH
OH
O
O
H
H
MeO OMe
OH
CH3
S
O
O
O
O
O
OOH
OH
O
O
H
H
MeO OMe
OH
7
8
4'
Etoposide, Vepesid
7
8
4'
Teniposide
Biosynthesis of podophylline lignans
OH
OMe
C - 
C - 
C - 
2


type of hydronaphtalene
BIOSYNTHESIS OF SALICINE
CO SCoA CO SCoA
OH
CO SCoA
OH
OH
CHO
O
CHO
GlcO
CH2OH
Glc
helicinesalicine
cinnamic acid o-coumaric acid
o-hydroxybenzaldehyde
UDP-Glcred.
TEMPORARY FORMATION OF C6-C3-C2 UNIT AT
CURCUMINE
CO
OH
SCoA
OMe
O
CO
OH
SCoA
OMe
CO
CH2
COOH
SCoA
CO
OH
SCoA
OMe
O
OH
OMe
CO
O
O
SCoA
OMe
HSCoA
O
OH
OMe
O
OH
OMe
+
-CO2
+
1) H2O
2) -CO2
curcumine
Curcuma tinctoria (Zingiberaceae)
Curcumae xanthorrhizae rhizoma – content
compounds
OH
MeO
CH CH CO CH2 CO CH CH
OH
OMe
Curcumine
O
Turmerone Curcumene Zingiberene
VANILLAE FRUCTUS
CH2OH
O-Glc
OMe
CH2OH
OH
OMe
OH
OMe
CHO
O-Glc
OMe
CHO
vanilloside
hydrolysis
vanillic alcohol
oxidation
vanilline
hydrolysis
vanilloside
FLAVONOIDS
1st level – formation of chalcone
CO CH2
CO2
SCoA
CO CH2
CO2
SCoA
CO CH2
CO2
SCoA
OO
O O
SCoA
OOH
OH OH
- -
-
3 x malonyl-CoA cinnamoyl-CoA
A
B
2',4',6'-OH-chalcone
FLAVONOIDS
OOH
OH OH
OOH
OH O
OOH
OH O
OOH
OH O
OOH
OH O
OH
OH
OH O
+
OH
OH
OH O
OH
OH O
OH
OH
A
B
A
B
A
B
5,7-OH-isoflavone 2',4',6'-OH-chalcone 5,7-OH-flavanone
5,7-OH-dihydroflavonol
5,7-OH-flavonolanthocyanidine 5,7-OH-flavone
5,7-OH-flavane5,7-OH-flavandiol
catechine
VENOPHARMACS – DRUGS FOR TREATMENT OF
VENOUS DISEASES
RUTOSIDE
SOPHORAE FLOS
Sophora japonica L. – Chinese Scholar Tree or
Japanese Pagoda Tree (Fabaceae).
Producents: China, Japan
Drug – not-untrolled flower buds with content of
up to 20 % rutoside
Semi-synthetic derivate tris-β-hydroxy-ethyl =
troxerutine, CILKANOL
FAGOPYRI HERBA
Fagopyrum – buckwheat (Polygonaceae)
Drug contains 1-2 % of rutoside, isolation
difficult
O
O
OH
OH
OH
O
OOH
OH
OH
OH
CH2
O
O
OH OH
OH
H
CH3
glucose rhamnose
rutinose
rutoside
quercetine
Silybi mariani fructus – content compounds
Silybum marianum – milk thistle
OH
OH
O
O
OH
O
O CH2OH
OH
OMe OH
OH
O
O
OH
OH
OH
OH
OH
O
O
OH
OH
O
CH2OH
OH
OMe
OH
OH
O
O
H
H
O
OH
O
OH
OMe
TaxifolineSilybine (benzodioxane)
Coniferylalcohol
Silychristine
Silydianine
Dihydrobenzofurane
Oxatricyclodecene
TANNINS
Characterization
• Heterogeneous organic polyphenols of high molecular weight
• Amorphous compounds formatting in water colloid acid solutions of
astringent taste
• With protein format insoluble substances → limiting therapeutic usage;
leather manufacturing industry – tan the furs (skin) to leathers
• Almost insoluble substances formatting with heavy metals and alklaoids
(with exception of morphine, atropine, cocaine), with salts of iron
produce inks
• Ability ot agglutinate erythrocytes
• Oxidation, condensation and polymerization to non-effective
phlobaphenes
• On the certain stage of development plant defense against
microorganisms
Occurrence:
Dicotyledonous plant with exception of Papaveraceae and Brassicaceae
Rarely monocotyledonous plants
CLASSIFICATION OF TANNINS
ACCORDING TO THE STRUCTURE
TANNINS
HYDROLYZABLE CONDENSED
(glycosidal)
GALLOTANINS ELLAGITANINS CATECHINS
Gallic acid Ellagic acid hydrogenated
+ sugar + sugar flavonols resp.
catechins
BASIC BUILDING BLOCKS OF TANNINS
C
OH
OHOH
OH O
O
O
OH
OH
OH
OH
O
O
OOH
OH
OH
OH
H
OH
H
Gallic acid Ellagic acid Catechine
EXAMPLE OF DEPSIDIC BOND
ESTER BOND BETWEEN CARBOXYL GROUP OF ONE MOLECULE AND HYDROXYL OF THE
SECOND MOLECULE OF THE SAME SUBSTANCE
OH
OH OH
C
OH
O
OH
OH
O C
O
OH
OHOC
O
O
H
H
OR
H
OR
OH
H
H
OR
CH2 OR
R
R
m-trigallic acid
Tannine
= gallic acid
= m-trigallic acid
CONNECTION OF GALLIC ACID MOLECULES WITH C-C
BOND
OH
OH
OH
COOH
OH
OH
OH
COOH
- H2O
OH
OH
OH
OH
OH
OH
COOH
COOH
Hexahydroxydiphenic acid
(dimer of gallic acid)
FORMATION OF ELLAGIC ACID
OH
OH O
C
H
O OH
OH
OHO
C
H
OOH O
O
OH
OH
OH
OH
O
O
- H2O
Hexahydroxydiphenic acid Ellagic acid
CONDENSED TANNINS (CATECHINS)
Basic building block is catechine and its isomers, further blocks are
hydroxyflavandiols (leucoanthocyanidins), hydroxyderivatives of cinnamic
acid.
Majority of condensed tannins is poduced by „postmortal“ condensation with
influence of enzymes.
Catechins condense in weakly acidic environment of cytosol into true in water
soluble amorphous tannins. This is observed during the postmortal
procedures when wood is stored. Condensation can proceed into dark in
water insoluble phlobaphenes.
Enzymatic transformation of catechins by polyphenoloxidases (for example red
pigmentation of cacao beans).
Some catechine tannins are in form of esters of catechine with gallic acid (for
example epicatechine-3-gallate in Theae folium).
CONDENSED TANNINS (CATECHINS)
OOH
OH
OH
OH
OH
OOH
OH
OH
OH
OH
OH
OOH
OH
OH
OH
OH
OH
OOH
OH
OH
OH
OH
Catechine (3-flavanol) Leucoanthocyanidins (3,4-flavandiol)
Dimeric condensation product
as the first step of tannins formation
from flavandiol and catechine
DRUGS WITH CONTENT OF TANNINS
Tanninum – Tannine ČL 2005 Quercus infectoria, gall oak (Fagaceae)
Hamamelidis folium – Vilínový list ČL 2005 Hamamelis virginiana, witch hazel
(Hamamelidaceae)
Quercus cortex – Dubová kůra ČL 2005 Quercus robur, English oak, Q.
petraea, sessile oak (Fagaceae)
Agrimoniae herba – Řepíková nať ČL 2005 Agrimonia eupatoria, agrimony
(Rosaceae)
Myrtilli fructus recens – fresh blueberry ČL 2005
Myrtilli fructus siccus – dried blueberry ČL 2005 Vaccinium myrtillus,
(Vacciniaceae)
Tormentillae rhizoma – ČL 2005 Potentilla erecta (P. tormentilla), tormentil
(Rosaceae)
FURTHER DRUGS WITH TANNIN CONTENT
Juglandis folium – Juglans regia, hasel nut (Juglandaceae)
Bistortae rhizoma – Polygonum bistorta, bistort (Polygonaceae)
Rubi fruticosi folium – Rubus fruticosus, blackberry (Rosaceae)
Catechu – Katechu (Acacia catechu – mimosa catechu, Mimosaceae)
Solidified extract of wood of Indian/African tree, containing up to
50 % of catechine tannins. Pwerfull astringent.
Kino – Kino (Pterocarpus marsupium – indian kino tree, Fabaceae)
Solidified juice flowing from stem after wounding, tree of eastern
India and Sri Lanka, containing up to 85 % of catechine tannins.